Note: Descriptions are shown in the official language in which they were submitted.
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CELL CYCLE CHECKPOINT PIK-RELATED KINASE
1VIATERIALS AND METHODS
FIELD OF THE INVENTION
The present invention generally relates to genes encoding cell-cycle
checkpoint phosphatidylinositol kinase (PIK)-related genes and proteins
essential to
DNA damage responses in cells. The checkpoint kinases play a role in the
surveillance of DNA damage that occurs as a result of replication errors, DNA
mismatches, radiation treatment, or chemotherapeutic drugs. These kinases are
required in regulatory pathways that lead to cell cycle arrest following DNA
damage,
giving the cell notice and time to correct lesions prior to the initiation of
DNA
replication. More particularly, the invention relates to a novel human PIK-
related
kinase, Mammalian Cell Cycle Surveillance 1(MCCS 1), polynucleotides encoding
the PIK-related kinase, and methods for assaying and modulating the enzymatic
activity of the kinase and related kinases.
BACKGROUND
The process of eukaryotic cell growth and division is the somatic or
mitotic cell cycle which consists of four phases, the G, phase, the S phase,
the G,
phase, and the M phase. The G,, S, and G2 phases are collectively referred to
as
interphase of the cell cycle. The cell cycle is structurally and functionally
conserved
in its basic process and mode of regulation across all eukaryotic species.
During the
G, (gap) phase, biosynthetic activities of the cell progress at a high rate.
The S
(synthesis) phase begins when DNA synthesis starts and ends when the DNA
content
of the nucleus of the cell has been replicated and two identical sets of
chromosomes
are formed. The cell then enters the G2 (gap) phase which continues until
mitosis
starts. In mitosis, the chromosomes pair and separate and two new nuclei fonn,
and
in cytokinesis the cell itself splits into two daughter cells each receiving
one nucleus
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containing one of the two sets of chromosomes. Mitosis and cytokinesis
together
form the M (mitosis) phase of the cell cycle. Cytokinesis terminates the M
phase and
marks the beginning of interphase of the next cell cycle. The sequence in
which the
events in the cell cycle proceed is tightly regulated such that the initiation
of one cell
cycle event is dependent on the completion of the prior cell cycle event. This
allows
fidelity in the duplication and segregation of genetic material from one
generation of
cells to the next.
The term "cell cycle checkpoints" refers to the proteins, signals,
processes, and feedback controls that integrate discontinuous events during
cellular
replication, in order to maintain essential dependencies within the cell
cycle. The
present invention specifically relates to the cell cycle checkpoint that
ensures that
mitosis is delayed until the completion of DNA synthesis and/or the accurate
repair
of DNA damage occurs.
Failure of cell cycle checkpoints predisposes individuals to or directly
causes many disease states such as cancer, ataxia telangiectasia, embryo
abnormalities, and various immunological defects associated with aberrant B
and T
cell development. The latter are associated with pathological states such as
lupus,
arthritis and autoimmune diseases. Intense research efforts have therefore
focused on
identifying cell cycle checkpoints and the proteins essential for the function
of the
checkpoints.
Genetic analysis in the yeasts Schizosaccharomyces pombe and
Saccharomyces cerevisiae has identified a number of genes important for cell
cycle
arrest and DNA repair responses to ionizing radiation (IR). For a review, see
Carr
and Hoekstra, Trends in Cell Biology, 5: 32-40 (1995). One such gene,
identified in
both yeasts, is required for a DNA damage checkpoint which arrests the cell
cycle
at the G2 phase, as well as a related checkpoint which monitors the completion
of
DNA synthesis and arrests the cell cycle at the S phase. The gene is named
rad3+
in S. pombe [Seaton et al., Gene, 119: 83-89 (1992)], MECI/ESRI in S.
cerevisiae
[Kato et al., Nuc. Acids. Res., 22(15) : 3104-3112 (1994)), and is hereinafter
referred
to as rad3+. Cells having mutations in rad3+ fail to either sense or
appropriately
respond to DNA damage and subsequently lose viability more rapidly than wild
type
cells after exposure to clastogenic agents or events (e.g., IR, DNA damaging
agents,
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and mutations affecting chromosomal integrity). See Weinert et al., GENES &
DEVELOPMENT, 8: 652-665 (1994) and Al-Khodairy et al., EMBO J., 11(4) : 1343-
1350 (1992). This sensitivity to IR (radiosensitivity) can be caused by
defects in
checkpoint responses or defects in direct DNA repair reactions.
The product of the rad3+ gene is an approximately 270 kD protein that
falls into a growing family of high molecular weight PIK-related kinases. See
Hunter, Cell, 83: 1-4 (1995) for a discussion of this family of kinases. The
primary
structures of the catalytic domains found in members of this gene family are
closely
related to well characterized phosphatidylinositol kinases. This structural
relationship
initially suggested that these PIK-related kinases might be capable of
phosphorylating
lipids. When the substrate specificity of the PIK-related kinases is examined,
however, these enzymes appear to function as protein kinases and have yet to
be
demonstrated to phosphorylate phosphatidylinositides. Hartley et al., Cell,
82:
849856 (1995) reports that purified preparations highly active in protein
kinase assays
failed to show lipid kinase activity. Additional PIK-related kinases
identified include:
the TELI gene product from S. cerevisiae which affects telomere length
[Greenwell
et al., Cell, 82: 823-829 (1995)], and Mei41 + gene product from Drosophila
melanogaster which is important for a G2 checkpoint and meiotic development
[Hari
et al., Cell, 82: 815-821 (1995)], the DNA-PK gene product from mouse which is
important in immunoglobulin rearrangements and processing of DNA double strand
breaks, and the FRAP gene product which is important in the G 1/S transition
[Brown,
E. et al., Nature, 377:441-446 (1995)]. Mutations in the DNA-PK gene can
result
in the Severe Combined Immunodeficiency Syndrome (SCID) defect (Hartley et
al.,
supra).
In humans, less is known about the molecular components required for
checkpoint function. One component of the mammalian checkpoint machinery has
been identified through the analysis of the human disease syndrome ataxia-
telangiectasia (AT). Patients with AT show a diverse set of clinical symptoms,
including predisposition to a variety of tumor types. Fibroblasts from AT
patients are
radiosensitive and fail to undergo cell cycle arrest following treatment with
IR leading
to a phenomenon termed radioresistant DNA synthesis. This is reminiscent of
the S.
pombe rad3 defect where cells fail to sense or respond appropriately to DNA
damage.
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Interestingly, the locus responsible for AT, the Ataxia-Telangiectasia Mutated
(ATM)
gene, was recently described in Savitsky et al., Science, 268: 1749-1753
(1995) and
the partial cDNA encodes a protein with amino acid similarity to the rad3+
gene.
Savitsky et al., Human Molecular Genetics, 4(11):2025-2032 (1995) describes
isolation of a cDNA encoding full length ATM. The increased radiosensitivity
of
rad3+ yeast mutants and of mammalian cells lacking functional ATM suggests
that
these proteins may comprise a family of checkpoint proteins.
Kuerbitz et al., Proc. Nail. Acad. Sci. USA, 89: 7492-7495 (1992)
establishes that the tumor suppressor p53 is required for a GI checkpoint and
cell
cycle arrest observed following DNA damage. Irradiation of cells results in
increased
levels of p53 leading to the transcriptional activation of p53 responsive
genes. One
such p53-induced target is the product of the WAFI gene (also called p2I,
CIP1, and
sdil). WAF1 is a member of an expanding class of cell cycle regulators termed
cyclin-dependent kinase inhibitory proteins. The activities of cyclin-
dependent kinases
control transit through the cell cycle. Transcriptional activation of WAFI
thus
provides a direct link between DNA damage-dependent induction of p53 and the
inhibition of kinases essential for cell cycle progression. See Elledge and
Harper,
Current Opinion in Cell Biology, 6: 847-852 (1994). Mutations in the p53 gene
are
one of the most common genetic alterations in human cancers. For example,
Baker
et al., Science, 244:217-221 (1989) reports that approximately 70% of human
colorectal carcinomas contain deletions or mutant copies of the p53 gene. In
addition, Fearon et al., Cell, 61: 759-767 (1990) reports that breast, lung,
bladder
and brain tumors have been associated with loss of chromosome 17p, the region
to
which the p53 gene localizes.
At present there is relatively little known about the molecular
components of the G2 checkpoints in mammalian cells. Caffeine is a chemical
entity
which abrogates G2 checkpoint control. Russell et al., Cancer Res., 55: 1639-
1642
(1995) and Powell et al., Cancer Res., 55: 1643-1648 (1995) report that
analysis of
cell lines which differ only by the presence or absence of functional p53
demonstrated
preferential caffeine-enhanced sensitization to IR in those cells lacking the
p53-
dependent G 1 checkpoint. Thus, the conversion of potentially lethal damage
into
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lethal damage is greater in cells lacking the GI and G2 checkpoints in
comparison to
cells containing an intact GI checkpoint.
While certain cells undergo DNA damage-dependent cell cycle arrest,
other cells appear to respond to DNA damage by initiating an intrinsic suicide
program termed apoptosis or programmed cetl death. The factors determining
which
process occurs are not fully understood. Recent work has demonstrated an
important
role for p53 both in the regulation of G1 cell cycle transitions and
apoptosis.
Symonds et al., Cell, 78: 703-711 (1994) describe p53-dependent apoptosis as
suppressing tumor growth and progression in vivo.
High doses of radiation and chemotherapy are used to treat tumor cells
in order to damage DNA so severely that the cells will die. However, even
though
tumor cells having mutations in the p53 gene are defective in a G 1
checkpoint, they
can still repair DNA damaged induced by radiation or chemotherapy. The present
invention contemplates, for example, that inhibition of the G2 checkpoint in
tumor
cells should lead to a state in which tumor cells are incapable of repairing
DNA
damage therefore sensitizing the tumor cells to DNA damaging agents. Normal
cells,
containing intact G 1 and G2 checkpoints, should still be able to repair DNA
damage
in the presence of a G2 checkpoint-specific inhibitor. Thus, treatment of
tumors with
a G2 checkpoint-specific inhibitor followed by radiation or chemotherapy
should
increase the efficacy of cell killing and thereby decrease the required doses
of toxic
DNA-damaging agents.
There thus exists a need in the art for identification of the mammalian
proteins that are involved in the cell cycle checkpoints in order to develop
therapies
for the human disease states associated with defective cell cycle checkpoints
and for
the isolation of the genes encoding those proteins which in themselves may be
useful
as therapeutics or which would enable the development of therapeutically
useful
modulators of the proteins encoded by the genes.
SUMMARY OF THE IIWENTION
The present invention provides novel human PIK-related kinases
essential for a cell cycle checkpoint that responds in the G2 phase of the
cell cycle
to both damaged and unreplicated DNA.
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In one of its aspects, the present invention provides purified and
isolated polynucleotides (e. g. , DNAs and RNAs, both coding and non-coding
strands
thereof) encoding the cell cycle checkpoint PIK-related kinase MCCSI and
polynucleotides encoding other cell cycle checkpoint PIK-related kinases that
exhibit
about 50, about 60, or about 65 % nucleotide identity to the MCCS 1
polynucleotide
region encoding the MCCS I kinase domain (MCCS I a nucleotides 6579 to 7562 of
SEQ ID NO: 30 or MCCSlO nucleotides 6457 to 7440 of SEQ ID NO: 32).
Alternatively, the MCCS 1-like PIK-related kinases exhibit about 40 %, about
45 %,
or about 50% amino acid identity to the MCCS I kinase domain (MCCS I a amino
acids 2083 to 2410 of SEQ ID NO: 31 or MCCS1/3 amino acids 2152 to 2480 of SEQ
ID NO: 33). Polynucleotides contemplated by the invention include genomic
DNAs,
RNAs, cDNAs and wholly or partially chemically synthesized DNAs. Preferred
polynucleotides of the invention comprise the MCCSla DNA sequence set out in
SEQ ID NO: 30, the partial MCCS 1 a DNA sequence set out in SEQ ID NO: 3, the
full length MCCS 10 DNA sequence set out in SEQ ID NO: 32, and DNA sequences
which hybridize to the noncoding strands thereof under stringent conditions or
which
would hybridize but for the redundancy of the genetic code. Exemplary
stringent
hybridization conditions are as follows: hybridization at 65 C in 3X SSC,
20mM
NaPO4 pH 6.8 and washing at 65 C in 0.2X SSC. It is understood by those of
skill
in the art that variation in these conditions occurs based on the length and
GC
nucleotide base content of the sequences to be hybridized. Formulas standard
in the
art are appropriate for deternlining exact hybridization conditions. See
Sambrook et
al., 9.47-9.51 in Molecular Cloning, Cold Spring Harbor Laboratory Press, Cold
Spring Harbor, New York (1989). The MCCSIa DNA of SEQ ID NO: 30 was
deposited with the American Type Culture Collection (ATCC), 12301 Parklawn
Drive, Rockville, Maryland 20852, on November 3, 1995 as an insert in plasmid
pBSHFB/HT2-27 in E. coli DH5a and was assigned ATCC Accession No. 69951.
The MCCS 10 DNA of SEQ ID NO: 32, was deposited with the ATCC on November
7, 1995 as an insert in plasmid 517 in E. coli DH5a and was assigned ATCC
Accession No. 69950.
The DNA sequence information provided by the present invention
makes possible the identification and isolation of DNAs encoding related
molecules
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by well-known techniques such as DNA/DNA hybridization as described above and
polymerase chain reaction (PCR) cloning. As one series of examples, knowledge
of
the sequence of a cDNA encoding MCCS 1 makes possible the isolation by
DNA/DNA hybridization of genomic DNA sequences encoding the kinase and
expression control regulatory sequences such as promoters, operators and the
like.
Similarly, knowledge of a partial cDNA sequence encoding MCCS 1 J3 make
isolation
of a complete cDNA possible. DNA/DNA hybridization procedures carried out with
DNA sequences of the invention under stringent conditions are likewise
expected to
allow the isolation of DNAs encoding allelic variants of the PIK-related
kinase; non-
human species enzymes homologous to the PIK-related kinase; and other
structurally
related proteins sharing one or more of the enzymatic activities, or abilities
to interact
with members or regulators, of the cell cycle checkpoint pathway in which
MCCSI
participates. Polynucleotides of the invention when detectably labelled are
also useful
in hybridization assays to detect the capacity of cells to synthesize MCCS 1.
The
DNA sequence information provided by the present invention also makes possible
the
development, by homologous recombination or "knockout" strategies [see,
Capecchi,
Science, 244: 1288-1292 (1989)], of rodents that fail to express functional
MCCSI
or that express a variant of MCCS 1. Such rodents are useful as models for
studying
the activities of MCCS 1 and MCCS 1 modulators in vivo. Polynucleotides of the
invention may also be the basis for diagnostic methods useful for identifying
a genetic
alteration(s) in the MCCSI locus that underlies a disease state or states.
Also made
available by the invention are anti-sense polynucleotides relevant to
regulating
expression of MCCS 1 by those cells which ordinarily express the same.
The invention also provides autonomously replicating recombinant
constructions such as plasmid and viral DNA vectors incorporating
polynucleotides
of the invention, especially vectors in which the polynucleotides are
functionally
linked to an endogenous or heterologous expression control DNA sequence and a
transcription terminator.
According to another aspect of the invention, host cells, especially
unicellular host cells such as procaryotic and eukaryotic cells, are stably
transformed
or transfected with DNAs of the invention in a manner allowing expression of
the
PIK-related kinase therein. Host cells of the invention are conspicuously
useful in
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methods for the large scale production of MCCS 1 wherein the cells are grown
in a
suitable culture medium and the desired enzymes are isolated from the cells or
from
the medium in which the cells are grown.
MCCS 1 products having part or all of the amino acid sequence set out
in SEQ ID NO: 31, SEQ ID NO: 4, or SEQ ID NO: 33 are contemplated. Use of
mammalian host cells is expected to provide for such post-translational
modifications
(e. g. , myristoylation, glycosylation, truncation, lipidation and tyrosine,
serine or
threonine phosphorylation) as may be needed to confer optimal biological
activity on
recombinant expression products of the invention. The enzyme products of the
invention may be full length polypeptides, fragments or variants. Variants
comprise
MCCSI products wherein one or more of the specified (i.e., naturally encoded)
amino acids is deleted or replaced or wherein one or more nonspecified amino
acids
are added: (1) without loss of the kinase activity specific to MCCS 1; or (2)
with
disablement of the kinase activity specific to MCCS1; or (3) with disablement
of the
ability to interact with members or regulators of the cell cycle checkpoint
pathway.
Substrates of MCCS 1 and proteins which interact with MCCS I may be identified
by
various assays.
Substrates of MCCS 1 may be identified by incorporating test
compounds in assays for kinase activity. MCCS1 kinase is resuspended in kinase
buffer and incubated either in the presence or absence of the test compound
(e.g.,
casein, histone H1, or appropriate substrate peptide). Moles of phosphate
transferred
by the kinase to the test compound are measured by autoradiography or
scintillation
counting. Transfer of phosphate to the test compound is indicative that the
test
compound is a substrate of the kinase.
Interacting proteins may be identified by the following assays.
A first assay contemplated by the invention is a two-hybrid screen.
The two-hybrid system was developed in yeast [Chien et al., Proc. Natl. Acad.
Sci.
USA, 88: 9578-9582 (1991)] and is based on functional in vivo reconstitution
of a
transcription factor which activates a reporter gene. Specifically, a
polynucleotide
encoding a protein that interacts with MCCS 1 is isolated by: ttansfotming or
transfecting appropriate host cells with a DNA construct comprising a reporter
gene
under the control of a promoter regulated by a transcription factor having a
DNA
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binding domain and an activating domain; expressing in the host cells a first
hybrid
DNA sequence encoding a first fusion of part or all of MCCS 1 and either the
DNA
binding domain or the activating domain of the transcription factor;
expressing in the
host cells a library of second hybrid DNA sequences encoding second fusions of
part
or all of putative MCCS 1 binding proteins and the DNA binding domain or
activating
domain of the transcription factor which is not incorporated in the first
fusion;
detecting binding of an MCCS 1 interacting protein to MCCS 1 in a particular
host cell
by detecting the production of reporter gene product in the host cell; and
isolating
second hybrid DNA sequences encoding the interacting protein from the
particular
host cell. Presently preferred for use in the assay are a lexA promoter to
drive
expression of the reporter gene, the lacZ reporter gene, a transcription
factor
comprising the lexA DNA binding domain and the GAL4 transactivation domain,
and
yeast host cells.
Other assays for identifying proteins that interact with MCCS1 may
involve immobilizing MCCS 1 or a test protein, detectably labelling the
nonimmobilized binding partner, incubating the binding partners together and
determining the amount of label bound. Bound label indicates that the test
protein
interacts with MCCS 1.
Another type of assay for identifying MCCS 1 interacting proteins
involves immobilizing MCCS 1 or a fragment thereof on a solid support coated
(or
impregnated with) a fluorescent agent, labelling a test protein with a
compound
capable of exciting the fluorescent agent, contacting the immobilized MCCS 1
with the
labelled test protein, detecting light emission by the fluorescent agent, and
identifying
interacting proteins as test proteins which result in the emission of light by
the
fluorescent agent. Alternatively, the putative interacting protein may be
immobilized
and MCCS I may be labelled in the assay.
Also comprehended by the present invention are antibody products
(e.g., monoclonal and polyclonal antibodies, single chain antibodies, chimeric
antibodies, CDR-grafted antibodies and the like) and other binding proteins
(such as
those identified in the assays above) which are specific for the MCCS 1
kinases of the
invention. Binding proteins can be developed using isolated natural or
recombinant
enzymes. The binding proteins are useful, in turn, for purifying recombinant
and
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naturally occurring enzymes and identifying cells producing such enzymes.
Specifically illistrating monoclonal antibodies of the invention are the
monoclonal
antibodies produced by hybridoma cell lines 224C and 224F which were deposited
with the American Type Culture Collection (ATCC), 12301 Parklawn Drive,
Rockville, MD 20852 on November 7, 1996 and assigned ATCC Accession Nos. HB
12233 and HB 12234, respectively. Assays for the detection and quantification
of
proteins in cells and in fluids may involve a single antibody substance or
multiple
antibody substances in a "sandwich" assay format. The binding proteins are
also
nianifestly useful in modulating (i.e.,blocking, inhibiting, or stimulating)
enzyme/substrate or enzyme/regulator interactions. Anti-idiotypic antibodies
specific
for PIK-related kinase binding proteins are also contemplated.
The invention contemplates that mutations in the MCCS 1 gene that
result in loss of normal function of the MCCS 1 gene product underlie human
disease
states in which failure of the G2 cell cycle checkpoint is involved. Gene
therapy to
restore MCCSI activity would thus be indicated in treating those disease
states (for
example, testicular cancer). Delivery of a functional MCCS 1 gene to
appropriate
cells is effected in vivo or ex vivo by use of viral vectors (e.g.,
adenovirus, adeno-
associated virus, or a retrovirus) or ex vivo by use of physical DNA transfer
methods
(e.g., liposomes or chemical treatments). For reviews of gene therapy
technology see
Friedmann, Science, 244: 1275-1281 (1989); Verma, Scientific American: 68-84
(1990); and Miller, Nature, 357: 455-460 (1992). Alternatively, it is
contemplated
that in other human disease states preventing the expression of or inhibiting
the
activity of MCCS1 will be useful in treating the disease states. It is
contemplated that
antisense therapy or gene therapy could be applied to negatively regulate the
expression of MCCS1. Antisense nucleic acids (preferably 10 to 20 base pair
oligonucleotides) capable of specifically binding to MCCS 1 expression control
sequences or MCCS 1 RNA are introduced into cells (e. g. , by a viral vector
or
colloidal dispersion system such as a liposome). The antisense nucleic acid
binds to
the MCCS 1 target sequence in the cell and prevents transcription or
translation of the
target sequence. Phosphothioate and methylphosphate antisense oligonucleotides
are
specifically contemplated for therapeutic use by the invention. The antisense
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oligonucleotides may be further modified by poly-L-lysine, transferrin
polylysine, or
cholesterol moieties at their 5' end.
Moreover, for example, if a particular form of cancer results from a
mutation in a gene other than MCCS I such as the p53 gene, an agent which
inhibits
the transcription or the enzymatic activity of MCCS l and thus the G, cell
cycle
checkpoint may be used to render cancerous cells more sensitive to
chemotherapy or
radiation therapy. The therapeutic value of such an agent lies in the fact
that current
radiation therapy or chemotherapy in most cases does nothing to overcome the
ability
of the p53 mutant cancerous cell to sense and correct the DNA damage imposed
as
a result of the treatment. As a result, a cancer cell can simply repair the
DNA
damage. Modulating agents of the invention may therefore be chemotherapy and
radiation adjuvants or may be directly active as chemotherapeutic drugs
themselves.
Agents that modulate MCCS I kinase activity may be identified by
incubating a test compound with MCCSI immunopurified from cells naturally
expressing the PIK-related kinase, with MCCS 1 obtained from recombinant
procaryotic or eukaryotic host cells expressing the enzyme, or with purified
MCCS 1,
and then determining the effect of the test compound on MCCSI activity. The
activity of the PIK-related kinase can be measured by determining the moles of
3zP-phosphate transferred by the kinase from gamma-32P-ATP to either itself
(autophosphorylation) or to an exogenous substrate such as a lipid or protein.
The
amount of phosphate incorporated into the substrate is measured by
scintillation
counting or autoradiography. An increase in the moles of phosphate transferred
to
the substrate in presence of the test compound compared to the moles of
phosphate
transferred to the substrate in the absence of the test compound indicates
that the test
compound is an activator of said MCCS1 kinase. Conversely, a decrease in the
moles of phosphate transferred to the substrate in presence of the test
compound
compared to the moles of phosphate transferred to the substrate in the absence
of the
test compound indicates that the modulator is an inhibitor of said MCCS 1
kinase. In
another aspect, agents that modulate both MCCSI and ATM or modulate one of the
enzymes are also contemplated. Agents which modulate MCCS 1 are screened in a
kinase assay as described above in which ATM is the phosphorylating enzyme.
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In a presently preferred assay, a MCCSI-specific antibody linked to
agarose beads is incubated with a cell lysate prepared from host cells
expressing the
kinase. The beads are washed to remove proteins binding nonspecifically to the
beads
and the beads are then resuspended in kinase buffer. The reaction is initiated
by the
addition of gamma-32P-ATP and an appropriate exogenous substrate such as lipid
or
peptide. The activity of the kinase is measured by determining the moles of
32P-
phosphate transferred either to the kinase itself or the added substrate. In a
preferred
embodiment the host cells lack endogenous MCCS 1 and/or ATM kinase activity.
The
selectivity of a compound that modulates the kinase activity of MCCS 1 can be
evaluated by comparing its activity on MCCSI to its activity on other known
PIK-
related kinases. The combination of the recombinant MCCSI products of the
invention with other recombinant PIK-related kinase products in a series of
independent assays provides a system for developing selective modulators of
MCCS 1.
Furthermore, combinatorial libraries, peptide and peptide mimetics,
defined chemical entities, oligonucleotides, and natural product libraries may
be
screened for activity as modulators in assays such as those described below.
For example, an assay for identifying modulators of MCCS 1 kinase
activity involves incubating an MCCS 1 kinase preparation in kinase buffer
with
gamma-32P-ATP and an exogenous kinase substrate, both in the presence and
absence
of a test compound, and measuring the moles of phosphate transferred to the
substrate. An increase in the moles of phosphate transferred to the substrate
in
presence of the test compound compared to the moles of phosphate transferred
to the
substrate in the absence of the test compound indicates that the test compound
is an
activator of said MCCSI kinase. Conversely, a decrease in the moles of
phosphate
transferred to the substrate in presence of the test compound compared to the
moles
of phosphate transferred to the substrate in the absence of the test compound
indicates
that the modulator is an inhibitor of said MCCS I kinase.
Moreover, assays for identifying compounds that modulate interaction
of MCCS 1 with other proteins may involve: transforming or transfecting
appropriate
host cells with a DNA construct comprising a reporter gene under the control
of a
promoter regulated by a transcription factor having a DNA-binding domain and
an
activating domain; expressing in the host cells a first hybrid DNA sequence
encoding
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a first fusion of part or all of MCCS I and the DNA binding domain or the
activating
domain of the transcription factor; expressing in the host cells a second
hybrid DNA
sequence encoding part or all of a protein that interacts with MCCS1 and the
DNA
binding domain or activating domain of the transcription factor which is not
incorporated in the first fusion; evaluating the effect of a test compound on
the
interaction between MCCS 1 and the interacting protein by detecting binding of
the
interacting protein to MCCS I in a particular host cell by measuring the
production
of reporter gene product in the host cell in the presence or absence of the
test
compound; and identifying modulating compounds as those test compounds
altering
production of the reported gene product in comparison to production of the
reporter
gene product in the absence of the modulating compound. Presently preferred
for use
in the assay are a lexA promoter to drive expression of the reporter gene, the
lacZ
reporter gene, a transcription factor comprising the lexA DNA binding domain
and
the GAL4 transactivation domain, and yeast host cells.
Another type of assay for identifying compounds that modulate the
interaction between MCCS 1 and an interacting protein involves immobilizing
MCCS 1
or a natural MCCS 1 interacting protein, detectably labelling the
nonimmobilized
binding partner, incubating the binding partners together and determining the
effect
of a test compound on the amount of label bound wherein a reduction in the
label
bound in the present of the test compound compared to the amount of label
bound in
the absence of the test compound indicates that the test agent is an inhibitor
of
MCCS 1 interaction with protein. Conversely, an increase in the bound in the
presence of the test compound compared to the amount label bound in the
absence of
the compound indicates that the putative modulator is an activator of MCCS 1
interaction with the protein.
Yet another method contemplated by the invention for identifying
compounds that modulate the binding between MCCS I and an interacting protein
involves immobilizing MCCS 1 or a fragment thereof on a solid support coated
(or
impregnated with) a fluorescent agent, labelling the interacting protein with
a
compound capable of exciting the fluorescent agent, contacting the immobilized
MCCS 1 with the labelled interacting protein in the presence and absence of a
test
compound, detecting light emission by the fluorescent agent, and identifying
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modulating compounds as those test compounds that affect the emission of light
by
the flourescent agent in comparison to the emission of light by the
fluorescent agent
in the absence of the test compound. Alternatively, the MCCS1 interacting
protein
may be immobilized and MCCSI may be labelled in the assay.
The present invention further provides a cell-based complementation
assay for identifying compounds which modulate the activity of MCCS 1 or ATM.
The assay involves complementation of a phenotypic trait associated with a
genetic
alteration in the cell. For example, the genetic alteration identified as esrl-
1 results
in cellular sensitivity to DNA damage in yeast cells [Kato et al., Nuc. Acids.
Res.,
22(15): 3104-3112 (1994)]. esrl-1 cells fail to either sense or appropriately
response
to DNA damage after exposure to DNA damaging agents such as ionizing radiation
or clastogenic agents. The phenotypic trait of the genetically altered cell is
complemented by transforming and expressing MCCS 1 or ATM in the cell. The
transformed cells are exposed to DNA damaging treatment (e.g. ionizing
radiation)
in the presence and absence of a test compound and sensitivity of the cells to
DNA
damage is measured. Agents that affect the cell sensitivity to DNA damaging
activity
of MCCS I and/or ATM are identified as modulators.
Modulators of MCCS 1 may affect its kinase activity, its localization
in the cell, and/or its interaction with members of the cell cycle checkpoint
pathway.
MCCS I modulators may be formulated in compositions comprising
pharmaceutically
acceptable carriers. Such compositions may additionally include
chemotherapeutic
agents. Dosage amounts indicated would be sufficient to result in modulation
of
MCCS 1 activity in vivo. Selective modulators may include, for example,
polypeptides
or peptides which specifically bind to MCCSI or MCCSI nucleic acid,
oligonucleotides which specifically bind to the PIK-related kinase or PIK-
related
kinase nucleic acid, and/or other non-peptide compounds (e.g., isolated or
synthetic
organic molecules) which specifically react with MCCSI or MCCSI nucleic acid.
Mutant forms of MCCS 1 which affect the enzymatic activity or cellular
localization
of wild-type MCCSI are also contemplated by the invention. Presently preferred
regions of the PIK-related kinases which are targets for the development of
selective
modulators include, for example, the following four regions: the MCCSIa amino
terminal effector domain (amino acids I to 1081 of SEQ ID NO: 31), the MCCS 10
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amino terminal effector domain (amino acids I to 1150 of SEQ ID NO: 33), the
MCCSIa rad3+ domain (amino acids 1082 to 2082 of SEQ ID NO: 31), the
MCCS1(3 rad3+ domain (amino acids 1151 to 2151 of SEQ ID NO: 33), the
MCCS 1 PIK domain (amino acids 2083 to 2410 of SEQ ID NO: 31), and the
MCCS1 j3 PIK domain (amino acids 2152 to 2480 of SEQ ID NO: 33).
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DETAILED DESCRIPTION
The present invention is illustrated by the following examples.
Example 1 details the isolation of cDNAs encoding MCCS 1 kinases. Example 2
describes mapping of the human MCCS1 gene to human chromosome 3. The
recombinant expression of MCCS 1 in E. coli and insect cells is respectively
described
in Examples 3 and 4. Example 4 also presents assays for measuring MCCS I
kinase
activity. Example 5 describes the production of MCCS 1-specific polyclonal and
monoclonal antibodies. Example 6 reports the immunoprecipitation of MCCS 1
kinase
associated activity from mouse testes. Example 7 examines the expression of
MCCS 1
mRNA in various human tissues and cancer cell lines. Example 8 describes
analyses
of MCCS I mRNA and protein expression in mouse testes. Example 9 describes
analyses of MCCS1 protein expression in meiotic cells. Assays for substrates
and
interacting proteins of MCCS ] are described in Example 10. Example 11
describes
modulators and assays for modulators of the kinase activity of MCCS 1. Example
12
describes the cell-based complementation assay for identifying modulators of
MCCS 1
and/or ATM and Example 13 describes the kinase activity of ATM.
Example 1
cDNAs encoding the PIK-related kinase MCCSI were isolated by a
series of PCR reactions.
An alignment of the amino acid sequences of S. pombe rad3+ (Hari
et al., supra) and S. cerevisiae MEC1 (Kato et al., supra) was the basis for
design
of seven degenerate oligonucleotides that encoded (or were complementary to)
the
regions of highest homology/lowest degeneracy between the sequences and
contained
convenient restriction sites to facilitate cloning of amplification products.
The
oligonucleotides were then used in a PCR-based assay to isolate a related
human
sequence.
Initially, PCR amplifications were performed on cDNA preparations
from rat T-cells, human peripheral blood mononuclear cells (PBMC), and S.
cerevisiae genomic DNA. Five oligonucleotide pairs were used (oDHl5a/oDHl6,
oDH l5b/oDH 16, oDH 17a/oDH 16, oDH 15a/oDH 17b, and oDH 15b/oDH 17b) for the
primary amplifications. The sequences of the oligonucleotide priiners included
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inosines and are set out below in IUPAC nomenclature for degenerate nucleotide
positions.
oDH15a (SEQ ID NO: 5)
5' GCA GAC GGA TCC GGI WCI GAY GGI AAY HTI TAY 3'
oDH15b (SEQ ID NO: 6)
5' GCA GAC GGA TCC GGI WCI GAY GGI AAY 3'
oDH 16 (SEQ ID NO: 7)
5' GCA GAC GAA TTC RCA RTY RAA RTC IAC RTG 3'
oDH 17a (SEQ ID NO: 8)
5' GCA GAC GGA TCC AAR TTY
CCI CCI RTI YTI TAY SAR TGG TT 3'
oDH17b (SEQ ID NO: 9)
5' GCA GAC GAA TCC AAC CAY
TSR TAI ARI AYI GGI GGR AAY TT 3'
PCR was performed on reaction mixtures of IX PCR buffer (Perkin Elmer Cetus,
Emeryville, California), 2-3 M oDH primers, 1.5mM MgCl2, 200,uM dNTPs, and
0.5 l Amplitaq polymerase. The reaction was performed in a Perkin-Elmer Cetus
Thermocycler Model 480 under the following conditions: denaturation at 94 C
for
1 minute, annealing at 64 C for 2 minutes, and elongation at 72 C for 1 minute
for
3 cycles. The procedure was then repeated using 60 C annealing temperature
for 3
cycles, 56 C annealing for 3 cycles, and finished with denaturation at 94' C
for 1
minute, annealing at 54 C(2 minutes, and elongation at 72 C for 1 minute
for 30
cycles. PCR products were separated on 2 or 4% Tris Acetate EDTA (TAE) agarose
gels, stained with ethidium bromide, and DNA products were visualized by UV
fluorescence.
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From the primary amplifications of yeast genomic DNA, rat T-cell
cDNA, and human PBMC cDNA, only a single reaction with yeast genomic DNA
(oDH17a/oDH16) gave a visible amplification product, resulting in a product
that was
the expected size for the region of the S. cerevisiae MECI gene between these
primers. Further analysis of the oDH17a/oDH16 amplifications that utilized rat
T-
cell and PBMC cDNA was therefore performed. To remove oligonucleotides and
"primer dimers" that might interfere with subsequent PCR, primary reactions
were
purified prior to reamplification.
A "nested" PCR strategy was employed, and amplifications were
repeated with primer pairs oDH18a/oDHl6 and oDH18b/oDH16 under reaction
conditions described above with cycle times of denaturation of 94 C for 1
minute,
annealing at 55"C for 1 minute, and elongation at 72"C for 30 seconds for 30
cycles.
The sequences of the oDH18a and oDH18b oligonucleotide primers included
inosines
and are set out below in IUPAC nomenclature for degenerate nucleotide
positions.
oDH18a (SEQ ID NO: 10)
5' GCA GAC GGA TCC YTI GGI YTI GGI GAY CGI CA 3'
oDH 18b (SEQ ID NO: 11)
5' GCA GAC GGA TCC YTI GGI YTI GGI GAY AGR CA 3'
An approximately 90 base pair (bp) product (the expected size amplification
product
for these primers) was seen in the reamplifications of the yeast genomic and
human
PBMC cDNA primary reactions. No 90 bp product was seen in the reamplification
of the primary reaction on rat T-cell cDNA and this reaction was not analyzed
further.
In addition to the approximately 90 bp product, several other non-
specific bands were also present, though significantly fewer than were
observed when
the primary reactions were reamplified with oDH17a/oDH16. While the
approximately 90 bp product was present in both the oDH18a/oDH16 and
oDHl8b/oDH16 reamplifications of the yeast genomic DNA primary reactions, only
the oDH18a/oDHl6 reaction yielded the appropriate size fragment during
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reamplification of the human PMBC cDNA primary reaction. This was presumed to
reflect codon usage in the human gene (compare primers oDH 18a and oDH l 8b).
The
approximately 90 bp product from the oDHI8a/oDH16 reamplification of the human
PMBC cDNA primary reaction was gel purified and subcloned into the pBluescript
SKII+ cloning vector (Stratagene, La Jolla, California) and sequenced.
Analysis of the sequence encoded by the 90 bp product indicated that
the deduced amino acid sequence was similar to both S. cerevisiae MECI and S.
pombe rad3+, but was not identical to either. To identify a larger region of
coding
sequence and extend the sequence comparison, a non-degenerate oligonucleotide,
oDH23 5' GACGCAGAATTCACCAGTCAAAGAATCAAAGAG 3' (SEQ ID NO:
12), was synthesized for use in additional amplification reactions.
Reamplification
of the purified PBMC cDNA primary reaction with oDH17a/oDH23 led to the
production of an amplification product of 174 bp. This fragment was then
purified,
subcloned and sequenced as described above. Computer analysis of the
conceptual
translation product confirmed its relationship (similar but not identical) to
MECl and
rad3+. This PCR fragment was then used as a probe to screen a plasmid library
containing macrophage cDNA using the following hybridization conditions:
incubation of nitrocellulose filters with radiolabelled probes in 3X SSC, 5X
Denhardt's, 0.1 % sarcosyl, 20mM NaPO4 pH 6.8, 100 ug/ml single stranded
salmon
sperm DNA, for 18 to 24 hours at 65 C. Washes were done 3 times in 0.2X SSC,
0.1 % SDS at 65 C for 30 minutes (with changes of wash buffer). Four
positive
clones were isolated, and the nucleotide sequence of each was determined.
Computer
analysis of the four sequences demonstrated that they were overlapping clones
derived
from a locus with homology to the rad3+ gene from S. pombe. Clone 517 (ATCC
69950) contained a 2.8 kbp insert and its DNA and deduced amino acid sequence
are
set out in SEQ ID NOs: 3 and 4, respectively. The clone contained an open
reading
frame encoding an amino tetminal truncated protein product of 870 amino acids
which were 39% identical to the COOH-terminus of rad3+. The protein product of
the cDNA insert was named MCCS1O.
The sequence of clone 517 was used to design the oligonucleotides,
mo3 5'-CTACAGAGCCAAGGAG-3' (SEQ ID NO: 13) and mo6 5'-
TCGAGCTATGCTACTAGTGGGC-3' (SEQ ID NO: 14), which were used to
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generate a probe using a gel purified EcoRI fragment derived from clone 517 as
a
template. The PCR conditions were as follows: 50 ng DNA fragment, IX PCR
buffer (Perkin-Elmer Cetus), 1.5mM MgC12, 20014M dATP, dGTP, and TTP, lAM
dCTP, 50 Ci a32P-dCTP, l Ong/ml each oligonucleotide, I U AmpliTaq (Perkin-
Elmer
Cetus). The reaction was performed in a Perkin-Elmer Cetus Thermocycler Model
480 for an initial denaturing cycle at 94 C for 4 minutes followed by 20
cycles of
94 C for 15 seconds, 60 C for 15 seconds, 72 C for 30 seconds.
Unincorporated
nucleotides were removed using a Stratagene Nuc-trap Push Column.
Since Northern blot analyses showed that the expression of the niRNA
corresponding to clone 517 was highest in testis, one million clones from a
human
testis cDNA library (Stratagene #939202) were screened with the PCR-generated
probe and eleven clones were obtained. The two longest clones, HT2 and HT9,
were
chosen for analysis. HT2 contained a 4.7 Kb insert (corresponding to
nucleotide
2974 of SEQ ID NO: 30 and extending further downstream than SEQ ID NO: 1) and
HT9 contained a 5485 bp insert (corresponding to nucleotides 2152 to 7624 of
SEQ
ID NO: 30). Nucleotide sequence analysis revealed that in the region common to
both cDNA clones there was a single base pair insertion of a T at nucieotide
3233 in
HT9. This nucleotide insertion causes the predicted amino acid reading frame
to shift
and then terminate and is believed to be an error introduced by reverse
transcriptase
in clone HT9.
In order to isolate a clone containing an additional 2.5 Kb, one million
clones from each of three additional cDNA libraries were screened: a human
fetal
brain cDNA library (Stratagene #93206), a human heart cDNA library (Stratagene
#
936207), and a human aorta cDNA library (Clontech Laboratories #HL1136a, Palo
Alto, California). The sequence of the most 5' region of HT9 was utilized to
design
and synthesize two oligonucleotides, oHT9-1 5'-CCTAGTCCAGTAA.AACTTGC-3'
(SEQ ID NO: 15) and oHT9-4 5'-TTTGCGGCCCTTCCAATATC-3' (SEQ ID NO:
16) which were used to generate a 317 bp PCR probe under conditions described
for
generating the probe above. While no positive clones were isolated from the
heart
or aorta cDNA libraries, two positive clones were obtained from the fetal
brain
library. One of these clones, HFB2, included a cDNA 4.5 Kb insert which
included
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approximately 2300 bp of additional sequence. The HFB2 insert corresponds to
nucleotides 1 to 3194 of SEQ ID NO: 30.
A composite cDNA encoding MCCS 1 a was constructed from clones
HFB2, HT9 and HT2. The three clones were joined together by digesting HFB2
with
the restriction enzymes KpnI and SaII to generate a fragment to comprise the
5' end
of the composite clone, digesting HT9 with Kpnl and Noti to generate a
fragment to
comprise the 3' end of the composite clone, and then ligating isolated
fragments to
the vector pBS SK- (Stratagene) that had been digested with SaII and NotI. The
region of the HT9 fragment containing the one nucleotide insertion was
replaced with
an EcoRV fragment containing nucleotides 3174 to 5282 of clone HT2. The final
plasmid containing a 7621 bp insert was named pBSHFB2HT2-27 (ATCC 69951).
The DNA and deduced amino acid sequence of the insert are presented in SEQ ID
NOs: 1 and 2, respectively. The coding domain of the cDNA initiates with an
ATG
at nucleotide 333 and ends with a termination codon at nucleotide 7560
predicting a
coding sequence of 2409 amino acids and protein of 265 kD. The protein product
of
the cDNA insert was named MCCSIa. Subsequent sequence analysis of the insert
in plasmid pBSHFB2HT2-27 (ATCC 69951) revealed sequencing errors in SEQ ID
NO: 1. Corrected DNA and deduced amino acid sequences of the insert are set
out
in SEQ ID NOs: 23 and 24, respectively. Even further sequence anaysis of
insert
in plasmid pBSHFB2HT2-27 revealed sequencing error in SEQ ID NO: 23. At
nucleotide position 6317 (SEQ ID NO: 23) a "G" was erroneously included and
between positions 6338 and 6339 the sequence was missing an "A". The corrected
sequences of MCCS I a are provided in SEQ ID NOs: 30 and 31.
Comparison of the predicted amino acid sequence of MCCS 1 a with the
partial amino acid sequence of MCCS1(3 predicted from clone 517 revealed the
presence of a seventy amino acid deletion in the MCCS 1 a product. The MCCS
1(3
clone 517 amino acid sequence corresponds to MCCSIa amino acids 1611 to 2410
of SEQ ID NO: 31. The seventy amino acid deletion in MCCS 1 a(1. e. , where
the
seventy amino acids would be inserted to generate a product identical to
MCCS1O)
occurs between amino acids 2065 and 2066 in SEQ ID NO: 31, seventeen amino
acids upstream from the kinase domain. Since both clones maintain an open
reading
frame, cDNA clone pBSHFB2HT2-27 was apparently generated from alternatively
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spliced mRNA. The carboxyl terminal domains containing the kinase domains are
identical in MCCS 1 a(amino acids 2083 to 2410 of SEQ ID NO: 31) and MCCS 1 a
clone (amino acids 543 to 870 of SEQ ID NO: 4).
A composite clone containing the complete coding sequence of
MCCS 10 (with the seventy amino acid insert) is presented in SEQ ID NO: 32.
The
amino acid sequence deduced from the clone is presented in SEQ ID NO: 33. This
clone is constructed by replacing the sequence between the BSTXI site, which
cleaves
after nucleotide 3229, and the NotI site in the polylinker sequence at the 3'
end of
pBSHFB2HT2-27 (SEQ ID NO: 1) with the sequence contained in HT2 between the
BstXl site and the Notl site at the 3' end of HT2. Thus this clone contains
sequences
that are identical to MCCS 1 a nucleotides 1 to 5159 of SEQ ID NO: 1(encoding
amino acids 1 to 1609 of SEQ ID NO: 2) linked to sequences that are identical
to
clone 517 nucleotides 1 to 2610 of SEQ ID NO: 3 (encoding amino acids 1 to 870
of SEQ ID NO: 4). As noted above, subsequent sequence analysis revealed errors
in nucleotides 1 to 5159 of SEQ ID NO: 1. Corrected MCCS 10 DNA and deduced
amino acid sequences that include the same corrections that appear in MCCS 1 a
SEQ
ID NOs: 23 and 24 are set out in SEQ ID NOs: 25 and 26. The SEQ ID NO: 25
clone represents a cDNA encoding a full length MCCS 1/3 kinase. Further
sequences
for MCCS10 including corrections of errors identified in resequencing the
MCCS1a
clone are presented in SEQ ID NOs: 32 and 33.
The MCCS 1 products can be divided into three regions based on
sini ilarity to other PIK-related kinases: an amino terminal domain (MCCSIa
amino
acids 1 to 1081 of SEQ ID NO: 31 and MCCSIO amino acids I to 1150 of SEQ ID
NO: 33), a region with similarity to rad3+ (MCCSIa amino acids 1082 to 2082 of
SEQ ID NO: 31 and MCSS 1(3 amino acids 1151 to 2151 of SEQ ID NO: 33) and a
PIK domain (MCCSIa amino acids 2083 to 2410 of SEQ ID NO: 31 and MCCS1/3
amino acids 2152 to 2480 of SEQ ID NO: 33) including a kinase domain. The
amino
terminal region and rad3+ region are regulatory domains that modulate the
kinase
activity of the enzyme and are involved in interactions with associated
proteins.
Results of comparisons of the nucleotide and amino acid sequence of
MCCS 1 a and MCCS 1 Q to the sequences of other PIK-related and non-PIK-
related
kinases are shown in Table 1. Specifically, the 3' end of MCCS 1 a(nucleotides
6579
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to 7562 of SEQ ID NO: 30 encoding the kinase domain), the 3' end of MCCS1(3
(nucleotides 1627 to 2379 of SEQ ID NO: 32 encoding the kinase domain), the
rad3+ domain of MCCS1 (nucleotides 3576 to 6578 of SEQ ID NO: 30), and the
rad3+ domain of MCCS1(3 (clone 517 nucleotides 1 to 1626 of SEQ ID NO: 3)
were compared to the analogous region in human ATM [Savitsky et al., supra],
human DNA-PK [Huntley et al., Cell, 82: 849-856 (1995)], human FRAP [Brown
et al., supra], human p110 [Hu et al., Mol. Cell. Biol., 13(12): 7677-7688
(1993)],
S. cerevisiae MEC1 [Weinert et al., Genes Dev., 8(6): 652-665 (1994), S. pombe
rad3+ [Seaton et al., supra and Hari et al., Cell, 82: 815-821 (1995)] and an
cAMP-
dependent protein kinase (PKA) [Beebe et al., Mol. Endocrinol., 4(3): 465-475
(1990)]. Percent identity of nucleotides is shown in the top line, percent
identity of
amino acids is shown in the middle line, and percent similarity of amino acids
(i. e. ,
including identical amino acids and conservative variations in amino acids) is
shown
in the bottom line for each kinase in Table 1. Conservative variation as used
herein
denotes biologically similar residues. Examples of conservative variations
include the
substitution of one hydrophobic residue such as isoleucine, valine, leucine or
methionine for another, or the substitution of one polar residue for another,
such as
the substitution of arginine for lysine, glutamic for aspartic acids, or
glutamine for
asparagine, and the like. In the Table, "ND" indicates a value was not
determined
either because the nucleotide sequence encoding the kinase (i. e. , rad3 +)
was not
publically available or because the kinase (i. e. , FRAP, p 110,Q, or PKA)
lacks the
particular domain being compared.
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Table I
Protein Kinase MCCSIa/MCCS1,6 MCCSIa MCCS1o
Kinase rar13+ rad3+
Domain Domain Domain
S. pombe rad3 + ND ND ND
56 22 30
72 46 53
S. cerevisiae 51 42 44
MECI 45 21 24
63 46 49
Human ATM 50 41 41
38 22 24
60 46 47
Human DNA-PK 43 39 43
29 19 20
53 45 49
Human FRAP 45 ND ND
37 ND ND
61 ND ND
Human p110Q 45 ND ND
24 ND ND
54 ND ND
Human PKA 39 ND ND
16 ND ND
39 ND ND
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Example 2
The MCCSI gene was mapped to chromosome 3 by a PCR-based
assay. Human/rodent somatic cell hybrids containing various human chromosome
panels available from the NIGMS Human Genetic Mutant Cell Repository [Drwinga
et al., Genomics, 16: 311-314 (1993)] were used as templates.
Two oligonucleotide primers oDH23 (SEQ ID NO: 12) and oDH26 5'
TGG'ITTCTGAGAACATTCCCTGA 3' (SEQ ID NO: 19) based on the MCCS 1 a
cDNA sequence were utilized to amplify a portion of the gene. The primers
generate
237 bp PCR products. PCR conditions consisted of 50 ng genomic DNA, 0.5 g of
each primer, 200 M dNTPs, 1.5mM MgC12, 1X PCR buffer (Perkin Elmer-Cetus),
and 1 unit of Amplitaq polymerase (Perkin-Elmer Cetus) in a 25 pl reaction
volume.
The samples were denatured for 4 minutes and then cycled 35 times with
denaturing,
annealing, and extension times of 45 seconds, 30 seconds, and 45 seconds,
respectively, in a Model 480 Cetus Thecmocycler. Five Fcl of the resulting PCR
product was electrophoresed on a 3% agarose gel and stained with ethidium
bromide.
DNA corresponding to the human/rodent chromosome 3 hybrid yielded a positive
amplification product.
In a second set of amplification reactions, the same oligonucleotide
primers were used to sublocalize the MCCS 1 gene to a specific region on
chromosome 3. The templates for these amplifications consisted of DNA samples
from patients with chromosome 3 truncations [Leach et al., Genomics, 24: 549-
556
(1994)]. Amplifications were performed as described in the foregoing
paragraph.
The pattern of positive amplification products narrowed the localization to
the interval
between q21 and q25.1.
Example 3
Polynucleotides encoding carboxyl terminal portions of the PIK-related
kinase MCCS 1/3 were expressed by recombinant techniques in E. coli.
Two E. coli expression plasmids were constructed that expressed either
the COOH-terminal 423 or 571 amino acid residues of the kinase in the Pinpoint
fusion protein expression/purification system (Promega, Madison, Wisconsin).
Briefly, DNA sequences encoding the COOH-terminal portion of the kinase
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(nucleotides 1339 to 2630 or nucleotides 898 to 2630 of SEQ ID NO: 3) were
fused
in frame to the COOH-terminus of a 13 kD peptide derived from the
transcarboxylase
complex from propionibacterium shermanii. This region undergoes biotination in
E.
coli, and thus provides a means for monitoring expression and purification of
the
fusion proteins. Expression was driven from the tac promoter in pinpoint W.
Fusion protein expression was induced with 0.1mM IPTG and confirmed using
streptavidin alkaline phosphatase in a pseudo-Western format as described by
the
manufacturer.
Example 4
Recombinant versions of MCCS I may also expressed in yeast or in
SF9 insect cells using a baculovirus expression system. The FRAP kinase has
been
expressed, purified and is enzymaticaliy active after expression in the
baculovirus
system [Brown et al., supra].
The coding region of MCCSI is fused at the amino terminus to a
heterologous peptide sequence, such as the FLAG tag MDYKDDDDK (SEQ ID NO:
20) or a six-histidine tag, and reconstructed into the appropriate vectors.
Once
expressed in insect cells, a monoclonal antibody that recognizes the FLAG tag
(Eastman Kodak, Rochester, New York) is used to purify large quantities of the
FLAG-PIK-related kinase fusion protein. Infected insect cells are incubated
for 48
hours and lysed in lysis buffer (25mM 2-glycerolphosphate, 50mM sodium
phosphate
pH 7.2, 0.5% Triton-X 100, 2mM EDTA, 2mM EGTA, 25 mM sodium fluoride,
100 M sodium vanadate, 1mM PMSF, l g/ml leupeptin, 1 g/ml pepstatin, 1mM
benzamidine, and 2mM DTT). Expressed FLAG fusion proteins are purified over
a column containing anti-FLAG antibody M2 affinity resin (Eastman Kodak). The
column is washed with 20 column volumes of lysis buffer, then 5 column volumes
of 0.5M lithium chloride, 50mM Tris pH 7.6, 1 mM DTT, and then eluted either
with
0.1M glycine pH 3.0 followed by immediate neutralization or by competitive
elution
with the FLAG peptide. For six-histidine tagged proteins, Ni-NTA agarose
(Qiagen)
is used for protein purification.
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Shortly after the filing of parent application U.S.S.N. 08/558,666, a
gene identified as ATR was described by Antony M. Carr and co-workers
(personal
communications). ATR appears to encode the same or a closely related protein
to
MCCS I based on a comparison of amino acid sequences between ATR and MCCS 1.
The DNA and deduced amino acid sequences of ATR are presented in SEQ ID NOs:
28 and 29, respectively. The sequence differences between ATR and MCCS1(.3 are
as follows. ATR includes an additional 98 amino acid residues at the N-
terminus.
At nucleotide position 1284 (SEQ ID NO: 32) there is a conservative base
change
from "A" in MCCS1/3 to "T" in ATR and at nucleotide position 4176, there is an
additional conservative base change from "C" in MCCS1/3 to "T" in ATR.
The FLAG tag was fused at the amino-terminus of a truncated ATR
molecule which lacked the first sixty-six ATR amino acids. The FLAG tag was
added by PCR as follows. The oligos FLAG-ATR
(5'-CGGGATCCGCCATGGACTACAAGGACGATGACAAGATGTTGCTTGA17TC-3').
And HFB24 (5'CTTAAGCCGCATGAGCACACCGTC-3') were used in the
following PCR reaction: 100ng of pcDNAATR (obtained from Antony M. Carr) as
template; IX PCR buffer (Perkin-Elmer Cetus); 1.5 mM MgCIZ, 200 M each of
dATP, dGTP, dCTP, and TTP, 10 ng/ l of each primer; lU AmpliTaq (Perkin-
Elmer Cetus). The reaction was denatured at 94 C for 4 minutes followed by 30
cycles of 94 C for 30 seconds, 60 C for 30 seconds and 72 C for 30 seconds.
The
resulting approximately 800 bp PCR product was digested with BamHI and Nhel
and
was ligated to the 10kb fragment of the mammalian ATR expression plasmid,
pcDNAATR digested with BamHI and BstXI along with the remainder of the ATR
coding sequences contained on a 2.5 kb BstXI to NheI fragment. Sequence
analysis
confirmed the addition of the FLAG tag. The insert contained within this
plasmid
was then used to construct a baculovirus expression plasmid that would express
the
FLAG tagged ATR truncate. The 5' end of ATR contained on a BamHI to BstXI
fragment and the 3' end of ATR contained on a BstXI to SaII fragment derived
from
pBTM ATR were ligated to the baculovirus expression vector, pFB (Gibco/BRL)
that
had been digested with BamHI and SaII. This plasmid was designated
pFMBCCS(3FLAG.
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The full coding region of ATR was fused at the amino terminus to the
six histidine tag by PCR. Oligonucleotides MCCS6his
(5'-CGGGATCCAGCATGCATCACCATCACCATCACATGGGGGAACATGGGC-3')
and Frp1R ("5'-CATGACCACTGGCCATTCCACACG-3') were used in a PCR
reaction to add the six histidine tag to sequences encoding the amino-terminus
of
ATR. PCR conditions were as follows: 100 ng of PstA 12ATR (obtained from
Antony M. Carr) was used as template; 1X PCR buffer (Perkin-Elmer Cetus); 1.5
mM MgCIZ, 200liM each of dATP, dGTP, dCTP, and TTP, 10 ng/ l of each primer;
IU AmpliTaq (Perkine-Eimer Cetus). The reaction was denatured at 94 C for 4
minutes followed by 25 cycles of 94 C for 30 seconds, 60 C for 30 seconds and
72 C for 30 seconds. The approximately 800 bp PCR product was digested with
BamHI and Mscl and ligated to two other fragments: a 10kb fragment from
pcDNAATR digested with BamHI and BstXI and an approximately 3 kb Mscl to
BstXI fragment containing the remainder of the ATR coding sequence. The
addition
of the six histidine tag was verified by sequence analysis. The resulting
plasmid
encoding a six-histidine tagged full length ATR molecule was designated
pcDNA6his
ATR.
To construct a baculovirus expression plasmid that expressed the entire
coding sequence of ATR, the 1.2 kb BamHI to Agel fragment from
pFBMCCS/3FLAG was ligated to the BamHI to Agel fragment from pcDNA6his
ATR. The resulting plasmid, designated pFB/HisX6MCCS-1 plasmid was
transformed into the E.coli strain, DH5a (Gibco/BRL) for screening of
recombinants.
This plasmid was purified by using the Promega "Wizard" mini-prep kit, then
transformed into E. coli aSF9 cells (Invitrogen) using the Cellfectin protocol
described by Gibco/BRL.
Forty eight hours after transfection, the SF9 cell pellet and baculovirus
produced by the transfected cells were harvested. The virus was stored at 4 C
in
Grace's Complete media containing 10% FBS, Pennicillin-Streptomycin, and
Gentamicin. This viral prep was used to make a high titer (P2) virus stock.
The P2
virus stock was used to infect a 50 ml culture of SF9 cells. The cells were
collected
48 hours after infection and centrifuged at low speed to pellet the cells
without lysis.
The cell pellet was stored at -20 C for 24 hours before lysis. The cells were
lysed
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in 5 ml of lysis buffer (50 mM Tris, pH 8.0; 500 mM NaCI; 1% NP40; 100 m
PMSF). Expression of ATR was confirmed by immunoblot using the polyclonal
antibody anti-AgDH2 as a probe. The FBHisX6 ATR baculovirus produced an
approximately 300 kDa protein that was immunoreactive with anti-AgDH2
antibodies
and comigrated with a protein in a mouse testes cell extract.
The P2 virus stock was also used to infect a 2 liter culture of SF9 cells.
The cells were collected 48 hours after infection, centrifuged at low speed to
pellet
the cells without lysis and stored at -20 C. A cell pellet from 150 mis of
this culture
was lysed in 7.5 ml of lysis buffer (50mM NaPO1 pH7.2; 0.5% NP-40; 10mM
imidazole, 25mM NaF, 100 M Na3VO4; 0.5mM AEBSF; 1 g/ml leupeptin; l g/ml
pepstatin A) and incubated on ice for 15 minutes. The lysate was then
centrifuged
for 30 minutes at 10,000 x g. The supernatant was removed and any DNA in the
lysate resulting from broken nuclei was sheared by aspirating through an 20
gauge
needle. Particulate matter was then removed by filtering through a 0.8 micron
filter
followed by a 0.2 micron filter. This cleared lysate was adjusted to contain 5
mM
0-mercaptoethanol and 0.4 M NaCI. A 1 ml Ni-NTA-agarose column (Qiagen) was
equilibrated in Buffer A (0.4 M NaCI; 5 mM 0-mercaptoethanol; 0.1 % Triton X-
100; 50 mM NaPO4 10 mM imidazole; 25 mM NaF, 100 M Na3VO4; 0.5 mM
AEBSF; 1 g/ml leupeptin; 1 g/ml pepstatin A) prior to loading the cleared
lysate.
The sample was loaded at a flow rate of 0.25 ml/minute, washed 5 ml of Buffer
A
and then eluted in 10 ml of a gradient of 50 to 500 mM imidazole in Buffer A.
One
half ml fractions were collected and was assayed for kinase activity as
follows. Five
l of each fraction was incubated in kinase buffer, 10 Ci 32PyATP, 10 M ATP,
and 5Ag of substrate PHAS-1 (Stratagene) and incubated at 37 C for 20 minutes.
The reaction was then spotted onto phosphocellulose spin columns and
centrifuged at
2500x g, washed twice with 0.5 ml of 75 mM phosphoric acid and once with 0.5
ml
absolute ethanol. The phosphocellulose disks were then transferred to
scintillation
vials and the counts per minutes incorporated into the PHAS-1 proteins were
recorded. Fractions 4 through 9 were found to contain activity toward PHAS-1
and
immunoblot analysis confirmed that ATR was also present in the same fractions.
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MCCS 1 encoding plasmid DNA was transformed into an esrl-1 diploid
yeast strain (Mata 1eu2-1 his4-4canl ura3 cyh2 ade6 ade2 esrl-1/MATa leu2-
27his4
trpl met2 ade2 esrl-1), and cells were grown to mid-log phase in either
galactose or
glucose containing medium. Cells were pelleted, washed and all steps
perfornned at
4 C. Cell pastes were resuspended in buffer (20 mM Tris at pH 8.0, 300 mM
NaCI,
10% glycerol, 0.1 mM PMSF, 0.25 mg/ml pepstatin, leupeptin, and aprotinin) and
lysed in a French Press or using glass beads. Lysis was verified by microscopy
following a low-speed (10K) spin and a high-speed spin (100K), and the
supernatant
was loaded onto a 1.5 ml Ni-NTA agarose (Qiagen, Inc., Chatsworth, CA) column
prewashed in 1 x buffer. The column was washed with six column volumes of
buffer.
The column was eluted stepwise with 8 ml of 10 mM, 50 mM, 100 mM, and 250
mM imidazole in buffer. Fractions were collected and Western analysis was
performed using 15 IAl of each elution peak. Kinase activity was measured as
described above.
Example 5
Polyclonal and monoclonal antibodies specific for MCCS l were
generated by standard techniques in the art.
Two different bacterial expression plasmids, pGEX 1-MEC and pGEX3-
MEC, were constructed for the recombinant production of portions of the MCCS1
polypeptide as fusions to the COOH-terminus of glutathione S-transferase
(GST).
Both plasmids were used for the generation of antigens AgDH-2 and AgDH-3, from
pGEXl-MEC and pGEX3-MEC respectively for use in a standard immunization
protocol. pGEXI-MEC contains an EcoRI fragment encoding amino acid residues
566 to 870 of SEQ ID NO: 4 fused to GST in the pGEXI vector (Pharmacia
Biotech,
Milwaukee, Wisconsin); pGEX3-MEC contains an Eco RI fragment encoding amino
acid residues 118 to 567 of SEQ ID NO: 4 fused to GST in the pGEX3 vector
(Pharmacia Biotech). Induction of the pGEX tac promoter with 0.1mM IPTG led to
high level expression of each fusion protein in an insoluble form (inclusion
bodies).
Following lysis of induced cultures with a French pressure cell, AgDH-2 and
AgDH-
3 extracts were centrifuged through a 35% sucrose solution containing 0.1M
NaCI,
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O.O1M Tris pH7.5, and 0.OOIM EDTA (STE). Pellets were then washed twice and
resuspended in STE.
For the generation of polyclonal antisera in rabbits, AgDH-2 and
AgDH-3 were further purified using preparative SDS polyacrylamide gel
electrophoresis and electroelution of each antigen from gel slices. Primary
immunization of female New Zealand White rabbits was with 200 g of each
antigen
mixed with complete Freund's adjuvant injected at multiple sites
subcutaneously.
Subsequent immunizations were with 100,ug antigen mixed with incomplete
Freund's
adjuvant at approximately 21 day intervals, and test bleeds were taken after
itnmunizations 3, 4 and 5. Western blot analysis of extracts of human testis
tissue
demonstrates antibody reactivity against an approximately 270 kD protein in
immune
but not preimmune antisera. In addition, the immune sera showed reactivity
against
the MCCS I pinpoint fusion proteins described in Example 3, providing evidence
of
the generation of MCCS 1-specific antibodies.
The MCCS 1-specific antibodies were purified as follows. Inclusion
body preparations of AgDH-2 and AgDH-3 were coupled to cyanogen bromide
(CNBr)-activated Sepharose (Pharmacia, Alameda, CA). Two mg of antigen were
solubilized in 1% SDS (4.5 ml final volume) and dialyzed overnight against
Coupling
Buffer (0.1M NaHCO3/0.1 % SDS). 0.5 ml of 5M NaCl were added to each antigen
preparation prior to incubation with the CNBr Sepharose. 0.4 gm of freeze-
dried
CNBr Sepharose (per antigen) were resuspended in 1 mM HC 1 and washed in a
scintered glass funnel with 250 ml 1 mM HCI added in several aliquots over 15
minutes. The HCI-washed CNBr Sepharose was then removed to a 15 mi snap cap
tube and washed twice with 5 ml of Coupling Buffer. Dialyzed antigen preps
were
added to the washed Sepharose and then incubated at room temperature for 1.5
hours
on a slowly rotating wheel. The Sepharose was washed once with 5 ml of
Coupling
Buffer, once with 10 mJ of 0.1M Tris pH8.0, and then incubated in 10 ml 0.1M
Tris
8.0 for 2 hours at room temperature to block any remaining reactive groups on
the
resin. Coupling efficiency was 60-80% as judged by SDS-PAGE analysis. The
antigen columns were then washed with 15 ml of 6M Guanidine HCI (to remove
uncoupled antigen), 25 ml of Buffer A(50mM Tris pH 7.4), 15 ml of Buffer B
(4.5M MgClZ/lmg/ml BSA/50mM Tris 7.4), and then 50 ml of Buffer A. Thirty ml
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of rabbit serum from immunized animals (rabbit 4747 immunized with AgDH-3 and
rabbit 4779 immunized with AgDH-2) were passed over the appropriate antigen
column over the course of 3 hours. The columns were then washed with 20 ml of
Buffer A, 40 ml of 1M Guanidine HCI, and then equilibrated with an additional
20
ml of Buffer A. Anti-AgDH-3 or Anti-AgDH-2 antibodies were then eluted off the
antigen columns with 10 ml of Buffer B. One ml fractions were collected, IgG-
containing fractions were pooled and dialyzed against I L of phosphate
buffered
saline (PBS) for 3 hours, and then overnight against 1 L of PBS containing 35
%
glycerol.
Antipeptide antibodies were generated against the human ATM protein
by coupling a 15-amino-acid peptide (residues 1359-1373) to Keyhole Limpet
Hemocyanin-using EDC as described by the manufacturer (Pierce), followed by
injection of the coupled immunogen into rabbits. The antibodies were first
precipitated from the serum (#6076) with an equal volume of saturated ammonium
chloride followed by resuspension and dialysis against PBS. Affinity
purification was
carried out using a peptide column prepared by coupling the antigenic peptide
to
CNBr-activated Sepharose (Phannacia) as described by the manufacturer. The
antibodies were then bound to the peptide column and washed with 2 m KCI-PBS.
Elution was carried out with 20 ml S m Nal (in 1 mM sodium thiosulfate), which
was
dialyzed immediately against PBS.
To generate monoclonal antibodies, female Balb/c mice were
immunized with 50 ug AgDH-2 or AgDH-3. Additional mice were immunized with
to 50 ug AgDH-2 or AgDH-3 that had been combined with an equal molar ratio
of mAb 61F3B, a monoclonal antibody with specific reactivity to GST. A third
25 group of mice were immunized with SDS polyacrylamide gel slices containing
AgDH-2 or AgDH-3. The immunogen for each group of mice was prepared in
complete Freund's adjuvant, with subsequent boosts (25 ug antigen in
incomplete
Freund's) at about 21 day intervals. Cell lines producing monoclonal
antibodies were
isolated as follows. Briefly a single cell suspension was formed by grinding
immunized mouse spleen in serum free RPMI 1640, supplemented with 2mM L-
glutamine, 1mM sodium pyruvate, 100 units/ml penicillin, and 100 g/ml
streptomycin (RPMI) (Gibco, Canada). The cell suspension was filtered through
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sterile 70-mesh Nitex cell strainer (Becton Dickinson, Parsippany, New
Jersey), and
washed twice by centrifuging at 200 g for 5 minutes and resuspending the
pellet in
20 mi serum free RPMI. Thymocytes taken from three naive Balb/c mice were
prepared in this manner.
NS-1 myeloma cells kept in log phase in RPMI with II % fetal bovine
serum (FBS) (Hyclone Laboratories, Inc., Logan, Utah) for three days prior to
fusion, were centrifuged at 200 g for 5 minutes, and the pellet was washed
twice as
described in the foregoing paragraph. After washing, each cell suspension was
brought to a final volume of 10 ml in serum free RPMI, and 10 l was diluted
10:100. Twenty l of each dilution was removed, mixed with 20 gl 0.4% trypan
blue stain in 0.85% saline (Gibco), loaded onto a hemacytometer and counted.
Two x 108 spleen cells were combined with 4 x 10' NS-1 cells,
centrifuged, and the supematant was aspirated. The cell pellet was dislodged
by
tapping the tube and 2 ml of 37 C PEG 1500 (50% in 75mM Hepes, pH 8.0)
(Boehringer Mannheim) was added with stirring over the course of 1 minute,
followed by adding 14 ml of serum free RPMI over 7 minutes. An additional 16
mi
RPMI was added and the cells were centrifuged at 200 g for 10 minutes. After
discarding the supernatant, the pellet was resuspended in 200 ml RPMI
containing
15% FBS, 100 M sodium hypoxanthine, 0.4 M aminopterin, 16 M thymidine
(HAT) (Gibco), 25 units/ml IL-6 (Mallinckrodt, Folcrost, Pennsylvania), and
1.5 x
106 thymocytes/ml. The suspension was dispensed into ten 96-well flat bottom
tissue
culture plates at 200 141/well. Cells in plates were fed 3 to 4 times between
fusing
and screening by aspirating approximately half the medium from each well with
an
18 G needle and replenishing plating medium described above except containing
10
units/ml IL-6 and lacking thymocytes.
Fusions were screened when cell growth reached 60-80% confluency
(day 7 to 9) by ELISA on AgDH2 versus AgDH3. Immunlon 4 plates (Dynatech,
Cambridge, MA) were coated at 4`C overnight with 100 ng/well protein in 30mM
carbonate buffer, pH 9.6. Plates were blocked with 100 g/well 0.5% fish skin
gelatin in PBS for one hour at 37 C, washed 3 times with PBS, 0.05% Tween 20
(PBST) and 50 l culture supernatant is added. After incubation at 37 C for
30
minutes, and washing as described above, 50 l of horseradish peroxidase
conjugated
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goat anti-mouse IgG(fc) (Jackson ImmunoResearch, West Grove, PA) diluted
1:10,000 in PBST was added. Plates were incubated as above, washed 4 times
with
PBST and 100 tcl substrate consisting of 100 g/ml of tetramethylbenzidine and
0.15
l/m1 H,O., in 100mM sodium acetate, pH 5.5, was added. The color reaction was
stopped in 5-10 minutes with the addition of 50 ul of 15 % H,SOa. A49o was
read on
a plate reader.
Fifty three pools of hybridomas that were positive in an ELISA were
screened for the ability to immunoblot or immunoprecipitate MCCS from a mouse
testes cell lysate. Immunoblot analysis using the mouse testes extract is
described in
Example 6. Immunoprecipitations was performed as follows. A six percent SDS
polyacrylamide gel was run and transferred to Immobilon-PVDF in 192 mM
glycine,
25 mM Tris base, 0.1 % SDS, 20% methanol, then blocked for 1 hour in 5%
powdered nonfat milk, 20 mM Tris ph 7.5, 100 mM NaCI 0.1 % Tween 20, and cut
into the appropriate number of strips. The primary antibody (well supematant)
was
diluted in the above block solution and incubated for one hour at room
temperature,
washed four times in block minus milk, incubated in goat anti-mouse IgG (H+L)
HRP (BioRad #170-6516), washed again in block solution minus milk, transfered
to
NEN Renaissance ECL reagent and developed for 5 minutes.
Immunoprecipitation was performed as follows. Fifty ttl of hybridoma
supematant was incubated for one hour on ice with 300 g of testes cell lysate
prepared as described in Example 6. Thirty l of a 50% slurry of protein A
agarose
(Pierce, Rockford, IL), prebound to a rabbit anti-mouse bridging antibody (5
tcg/reaction) (Pierce) was added and incubated at 4 C with rocking. The immune
complexes were washed three times in lysis buffer and the antigen/antibody
complex
eluted by boiling in SDS sample buffer (2% SDS, 20 mM Tris pH 6.8, 20%
glycerol,
0.001 % bromphenol blue). The resulting supernatant was separated on a 6% SDS
polyacrylamide gel and transferred to Immobilon-PVDF (Millipore) and an
immunoblot was performed using affinity purified rabbit anti-Ag DH2 polyclonal
antiserum. Four hybridomas were cloned and characterized in immunoblots,
immunoprecipitations and in immunoprecipitation/kinase assays as described in
Example 6. The four hybridoma cell lines were designated 224B, 224C (ATCC HB
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12233), 224F (ATCC HB 12234) and 224G. All four monoclonal antibodies
recognized MCCS 1 by immunoblot and immunoprecipitation.
Example 6
MCCS 1 associated protein kinase activity was immunoprecipitated
using the MCCS1-specific polyclonal antibodies described in Example 5.
Extracts were made from fresh testes tissue isolated from Balb/c mice.
Minced testes were homogenized on ice with 10-15 strokes of a tight fitting
dounce
homogenizer in Lysis Buffer (50 mM NaPO4, pH 7.2; 0.5% TritonX-100; 2 mM
EDTA; 2 mM EGTA; 25 mM NaF; 25 mM 2-glycerophosphate; 1 mM
phenylmethylsulfonyl fluoride [PMSF]; I g/ml leupeptin; 1 g/m1 pepstatin A;
2 mM
DTT) and incubated on ice for 30 minutes. The lysate was centrifuged at
13,000xg
rpm for 10 minutes at 4 C in a TL-100 table-top ultracentrifuge (Beckman) to
remove unbroken cells and other insoluble material. Aliquots of cell lysate
were snap
frozen in liquid N2 and stored at -70 C. Five hundred ug of testes extract
was
incubated with either 5 ug of affinity purified anti-AgDH-2 polyclonal
antibody or 5
ug purified rabbit IgG (Zymed, So. San Francisco, CA) in 1 ml of Lysis buffer
for
one hour on ice in microcentrifuge tubes. Thirty l of protein A sepharose
beads
(Repligen, Cambridge, MA) (washed in Lysis buffer) were added to the extracts,
and
then incubated for an additional 30 minutes at 4 C on a rocking platform. The
immune complex/Protein A sepharose beads were washed four times with 1 ml of
Lysis buffer, one time with 1 mi Kinase Buffer (25 mM Hepes pH 7.7; 50 mM KCI;
10 mM MgC12; 0.1 % NP-40; 2% glycerol; 1 mM DTT), and then incubated in 20
ul Kinase Buffer with 10 ttCi ATP [50 Ci/mmol]) for 20 minutes at 37 C. The
kinase reactions were stopped with 20 t4l 2X SDS sample buffer and heated to
100
C prior to separation on 6% polyacrylamide gels. Gels were fixed in 20%
methanol/7% Acetic acid, and then dried onto Whatman 3NIM paper prior to
autoradiography. While little or no phosphorylation was evident in control
immunoprecipitations, immunoprecipitations using anti-AgDH-2 antibody
contained
two major phosphorylated bands at approximately 300 kD and approximately 180
kD.
In addition, there were several minor phosphorylation products, including one
which
comigrated with the MCCS 1 protein itself as demonstrated by Western blot
analysis
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(see Example 8 for Western blot description.) Phosphoaminoacid analysis of the
approximately 300 kD protein identified the presence of phosphoserine
residues.
Addition of 5 ug of AgDH-2 (but not AgDH-3) dramatically reduced or eliminated
the MCCS1-associated kinase activity found in the immunoprecipitates.
Example 7
The expression pattern of MCCSI in various human tissues was
examined by Northern blot hybridization.
Nylon membranes containing 2gg of size-fractionated polyA+ RNA
from a variety of human tissue sources were obtained from Clontech
Laboratories,
Inc., and the hybridization protocol supplied by the manufacturer was followed
precisely, except that the final wash was performed at 55 C, rather than 50'
C, to
minimize the possibility of cross-hybridization to related sequences. The 32P-
labelled
DNA hybridization probe used was generated by PCR. A DNA encoding the COOH-
terminal 30 % of MCCS 1 a was used as a template to amplify a 1. 3 kb fragment
in
the presence of'ZP-dCTP using primers 279-3 5'TGGATGATGACAGCTGTGTC 3'
(SEQ ID NO: 21) and 279-6 5'TGTAGTCGCTGCTCAATGTC3' (SEQ ID NO: 22).
Results of the Northern blots show that MCCS 1 is expressed as an
approximately 9 kb mRNA in a wide variety of human tissues. Testis tissue
contains
the highest level of MCCSI mRNA, though the transcript is also expressed in
small
intestine, ovary, prostate, thymus, spleen, heart, peripheral blood
lymphocytes, colon,
brain, placenta, skeletal muscle, kidney and pancreas.
Expression of MCCS I mRNA in human cancer cell lines was also
examined using a human cancer cell line RNA blot obtained from Clonetech. The
RNA blot contained RNA from the cell lines HL-60 (promyelocytic leukemia),
HeLa
(cervical carcinoma), K-562 (chronic myelogenous leukemia), MOLT-4
(lymphoblastic leukemia), Raji (Burkitt's lymphoma), SW480 (colorectal
adenocarcinoma), A549 (lung carcinoma), and G361 (melanoma). Northern blot
analysis was performed as directed by the manufacturer with hybridization
being
carried out at 65'C using a 2.0kb Kpn!-Sall fragment of the MCCS1 partial
clone
HFB2. Expression was observed in the HL-60, HeLa, K-562, Raji, SW480, and
G361 cell lines with the highest level of expression occurring in the G361
cell line.
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Detectable but low levels of expression were observed in the MOLT-4 and A549
cell
lines.
Example 8
The expression of MCCS 1 mRNA and protein in normal and irradiated
mouse testes and in mouse embryos was examined by in situ hybridization,
immunostaining and/or immunoblotting.
In situ Hybridization
Normal and irradiated mouse testes were harvested from male Balb/c mice.
The tissues were sectioned at 61.cm thickness, picked up on Superfrost Plus
(VWR
Scientific) slides and allowed to air-dry at room temperature ovelnight.
Sections were
stored at -70o C if not immediately used. The tissue sections were fixed in 4%
paraformaldehyde (Sigma) in PBS for 20 minutes at 4c) C, dehydrated (70%, 95%,
100% ethanol) for 1 minute at 4o C in each grade, then allowed to air dry for
30
minutes at room temperature. The slides were acetylated in a solution of 0.25
% (v/v)
acetic anhydride (Sigma)/0.1M triethanolamine pH 8.0 for 10 minutes at room
temperature with stirring, rinsed in 0.2X SSC for 10 minutes at room
temperature
with stirring, and dehydrated and air dried as described above. The tissues
were
hybridized in situ with digoxigenin-labeled single-stranded mRNA generated
from
murine MCCSI DNA by in vitro RNA transcription incorporating digoxigen-UTP
(Boehringer Mannheim). The labeled riboprobes (see sequence in SEQ ID NO: 27)
( I gg/section) and diethylpyrocarbonate (depc)-treated water were added to
hybridization buffer with a final concentration of 50% formamide, 0.3 M NaCI,
20
mM Tris pH 7.5, 10% dextran sulfate, 1X Denhardt's solution, 100 mM
dithiothreitol (DTT) and 5 mM EDTA, and 20 g1 of the solution was applied to
each
section and covered with a sterile, RNase-free 22 x 22 cover slip. The mRNA in
both the section and the probe solution was denatured by heating the slides to
85 C
for 10 minutes in an oven. Hybridization was carried out overnight (12-16
hours) at
50 C.
After hybridization, sections were washed for 1 hour at room
temperature in 4X SSC/10 mM DTT, then for 30 minutes at 50 C in 50%
formamide/2X SSC/10 mM DTT, 30 minutes at 37 C in a solution of 500 mM
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NaCI, 10 mM Tris-HC 1, 1 mM EDTA, pH 7.5 (NTE buffer), 30 minutes at 37 C
in a bath of 10 g/mL RNase A (Boehringer Mannheim) in NTE buffer, 15 minutes
at 37 C in NTE buffer, 15 minutes at room temperature in 2X SSC, 15 minutes
at
room temperature in 0.1X SSC, and 2 minutes at room temperature in 100 mM Tris-
HC 1, 150 mM NaCI, pH 7.5 (Buffer 1). To detect the labeled riboprobes, the
sections were blocked for 30 minutes at room temperature in a solution of 5 %
normal
sheep serum (Harlan Bioproducts for Science, Indianapolis, IN) and 0.3% Triton
X-
100 (Sigma) in Buffer I with gentle stirring, after which 150 I/section of
sheep
aDigoxigenin-gold conjugate (Goldmark Biologicals, Philipburg, Pa) was applied
to
the tissues and incubated for 2 hours at room temperature. The slides were
then
washed three times for 5 minutes in Buffer 1, five times for 3 minutes in
sterile
deionized water, the excess liquid blotted off the slide and 2 drops each of
silver
enhancing and initiating solution (Goldmark Biologicals) applied to each
section. The
chemical reaction was allowed to proceed for 23 minutes at room temperature,
then
the sections were rinsed thoroughly in sterile deionized water, counterstained
in
Nuclear Fast Red (Vector), rinsed again in sterile deionized water, air dried
overnight
at room temperature and mounted with Cytoseal 60 (VWR).
In both normal and irradiated mouse testes signal was observed in the
cytoplasm of spermatogonia and spermatocytes. The expression level in
irradiated
testis was not increased over that seen in normal testis.
Immunostaining
Testis tissue from nonnal male Balb/c mice was sectioned at 6 m
thickness, picked up on Superfrost Plus (VWR Scientific) slides and allowed
to air-
dry at room temperature overnight. Sections were stored at -70 C if not
immediately used. The sections were fixed in cold (4 C) acetone for 10
minutes at
room temperature; once the slides were removed from the acetone the reagent
was
allowed to evaporate from the sections. Each tissue section was blocked with
150 l
of a solution of 30% normal rat serum (Harlan Bioproducts), 5% normal goat
serum
(Vector Laboratories) and 1% bovine serum albumin (BSA) (Sigma) in IX TBS for
30 minutes at room temperature. After blocking, the solution was gently
blotted from
the sections and anti-AgDH-3 and anti-AgDH-2 polyclonal antibodies and
preimmune
sera from the same rabbits were diluted 1:50 and 1:100 in the blocking
solution and
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100 tcl applied to each tissue section and incubated for 30 minutes at 37 C.
The
antibody solution was blotted gently from the sections and unbound antibody
removed
from the sections by washing the slides 3 times for 5 minutes each in 1X TBS.
The
excess TBS was blotted from the slide and 100 l of the biotinylated goat anti-
rabbit
antibody contained in the Elite Rabbit IgG Vectastain ABC kit (Vector),
prepared
according to the product insert, were applied to each section and incubated
for 15
minutes at 37 C. After incubation, the slides were washed 2 times in 1X TBS
for
5 minutes in each wash. Next, 100 l of streptavidin-gold conjugate (Goldmark
Biologicals) diluted 1:100 in a solution containing 5% normal rat serum and 1%
BSA
was applied to each section and incubated for 1 hour at room temperature. The
slides
were then washed 3 times in 1X TBS for 5 minutes each wash, and 100 141 of 1%
glutaraldehyde (Sigma) in TBS buffer was applied to the slides for 5 minutes
at room
temperature. The slides were then washed 3 times for 5 minutes each in TBS,
then
4 times in sterile deionized water for 3 minutes each. The excess liquid was
blotted
from each slide and 2 drops each of silver enhancing and initiating solution
(Goldmark Biologicals) were applied to each section. The chemical reaction was
allowed to proceed for 13 minutes at room temperature, then the sections were
rinsed
thoroughly in sterile deionized water, counterstained in Nuclear Fast Red
(Vector),
rinsed again in sterile deionized water, air dried overnight at room
temperature and
mounted with Cytoseal 60 (VWR).
Signal was detected in the spermatogonia and primary spermatocytes
with both of the polyclonal antibodies, but not with the preimmune sera from
the
same animals.
ImmunoblottinQ
Freshly obtained mouse testicles were minced with razor blades in cold
PBS, and a cell suspension was generated using a loose fitting dounce
homogenizer.
This cell suspension was then boiled with an equal volume of 2X SDS sample
buffer.
Fifty ug aliquots of each extract were separated on 6% polyacrylamide gels,
transferred onto Immobilon membranes (Millipore, Bedford, MA) and analyzed for
anti-MCCS 1-reactivity using the affinity purified antibodies in Example 5,
and HRP-
conjugated goat anti-rabbit secondary antibody and the Renaissance Enhanced
Chemiluminescence kit (Dupont/NEN, Boston, MA). Extracts prepared from fresh
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lnouse testis contain a high molecular weight species (about 294 kD) that was
recognized by both affinity-purified antiserum. No reactivity against this
protein was
seen with either of the preimmune sera. Importantly, the signal obtained from
each
affinity purified sera was specifically blocked after pre-incubation of the
antibody with
the corresponding immunogen.
In summary, high levels of MCCS I mRNA and protein are detected in mouse
testis in the spermatogonia and primary spermatocytes, cells that are in the
early
stages of meiosis. This suggests that MCCSI plays an important role in meiotic
cell
division. Meiosis is a specialized form of cell division that produces germ
cells in
higher eukaryotes. There are two major characteristics of meiosis that
distinguish it
from mitosis. Whereas mitotic cell division results in genetically identical
cells
containing two of each chromosome, meiotic cell division results in cells
containing
one of each chromosome. Early in meiosis, during the "reduction division"
process,
sister chromatids pair and undergo reciprocal recombination at some regions.
During
this process, these cells are exposed to DNA strand breaks. It is likely that
the
cellular response to the DNA strand breaks during meiosis is similar to the
cellular
response found in non-germ cells in response to IR-induced DNA damage. This
interpretation is further substantiated by studies that demonstrate the MECI
is
upregulated 10 to 20 fold during sporulation, indicating an important role for
MCCS 1
during meiosis in addition to its role in DNA repair.
Example 9
In order to identify the cells within the developing mouse testis that
express MCCS1, Western blot analysis of MCCSI expression within populations of
meiotic cells was performed. Extracts of purified pachytene spermatocytes,
round
spermatids, condensing spermatids, and epididymal sperm cells were examined
for
MCCS 1 expression as described above in Example 8.
Pachytene spermatocytes, round, and condensing spermatids were
prepared from decapsulated testes of adult mice by sequential dissociation
with
collagenase and trypsin-DNase 1. The cells were separated into discrete
populations
by sedimentation velocity at unit gravity in 2-4% BSA gradients in Enriched
Krebs
Ringer Bicarbonate Medium (EKRB). The pachytene spermatocyte and round
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spermatid populations were each at least 85 % pure, while the condensing
spermatid
population was about 40-50% pure (contaminated primarily with enucleated
residual
bodies and some round spermatids). Sperm were obtained from the cauda
epididymides. Purified populations of spermatogenic cells were dissolved
directly in
SDS-sample buffer containing 40 mM DTT, heated to 100 C for 5 minutes, and
the
amount of protein in each sample determined by the Amido-Black procedure.
The highest levels of MCCS 1 protein were found in pachytene
spermatocytes, with the level dropping significantly in round spermatids.
MCCSI
protein levels were barely detectable lower in the condensing spermatid
population,
and this may reflect the presence of round spermatids in the preparation (see
above).
No MCCS1 protein was detected in epididymal sperm. The Western analysis thus
corroborates the immunocytochemical data, and suggests a role for MCCS 1 in
meiotic
cells.
Example 10
Substrates of MCCS 1 and proteins that interact with MCCS 1(for
example, members of the cell cycle checkpoint pathway and proteins that
localize
MCCSI in cells) may be identified by various assays.
A. Identification of Substrates
Substrates of MCCS 1 may be identified by incorporating test
compounds in assays for kinase activity. MCCSI kinase is resuspended in 20 l
kinase buffer (25mM Hepes pH7.4, 25mM KCI, 10mM MgC12, 1 mM DTT, 2%
glycerol, 0.1 % NP40, 0.5mM ATP, 10 uCI gamma 32P-ATP) and incubated for 30
minutes, either in the presence or absence of 4 g test compound (e.g.,
casein,
histone H 1, or appropriate substrate peptide). Reactions are separated on 12
% PAGE
gels and dried onto Whatman paper prior to autoradiography. Moles of phosphate
transferred by the kinase to the test compound are measured by autoradiography
or
scintillation counting. Transfer of phosphate indicates that the test compound
is a
substrate of the kinase.
The protein PHAS-1 has been identified as an in vitro substrate of ATR
(Example 4). PHAS- I is a heat and acid-stable protein that phosphorylated at
several
sites in vivo in response to insulin and growth factors. PHAS-1 binds to the
mRNA
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cap binding factor, EIF-4E, and prevents translation of capped mRNAs.
Phosphorylation of PHAS-1 at a specific serine residue results in dissociation
of
PHAS-l form EIF-4E and thus releasing the inhibition of translation of capped
mRNAs. This mechanism allows for a rapid synthesis of protein in response to a
particular stimulus. PHAS-1 may be phosphorylated by several protein kinases
in
vivo including a protein kinase that is sensitive to rapamycin. Since the
rapamycin-
sensitive protein kinase, FRAP, is related to ATR, it would be reasonable to
assume
that there might be an overlap in substrate specificity between FRAP and ATR
and
that PHAS-1 is a substrate for both of these protein kinases in vitro. To test
this
hypothesis, ATR that was immunoprecipitated from a mouse testes cell extract
or His-
tagged ATR purified from baculovirus-infected SF9 cells (Example 4) was
incubated
with 10 ttg PHAS-1 (Stratagene) in kinase buffer (25 mM Hepes pH 7.4, 25 mM
KC 1, 10 mM MgC 12i 1 mM DTT, 0.1 % NP-40), 10 M ATP and 10 Ci32P=yATP
for 20 minutes at 37 C. Since phosphorylated PHAS-1 was known to bind to
phosphocellulose paper, the reaction was spotted onto phosphocellulose spin
columns
and centrifuged at 2500 x g, washed twice with 0.5 ml of 75 mM phosphoric acid
and
once with 0.5 ml absolute ethanol. The phosphocellulose disks were then
transferred
to scintillation vials and the counts per minutes incorporated into the PHAS-1
proteins
were recorded. ATR readily phosphorylated PHAS-1 whereas negative controls
showed little or no PHAS-1 phosphorylation. To map which residue is
phosphorylated, the following peptides representing PHAS-1 sequences
containing
serine and threonine residues were synthesized.
Peptide PH-1
MSGGSSCQTPSRAIPATRR (SEQ ID NO: 36)
Peptide PH-2
GDYSTTPGGTLFSTTPGGTRR (SEQ ID NO: 37)
Peptide PH-3
ECRNSPVTKTRR (SEQ ID NO: 38)
Peptide PH-4
GVTSPSSDEPRR (SEQ ID NO: 39)
Peptide PH-5
MEASQSHLRR (SEQ ID NO: 40)
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Peptide PH-6
RRNSPEDKRAGG (SEQ ID NO: 41)
Peptide PH-7
GEESQFEMDIRR (SEQ ID NO: 42)
These peptides are tested in the same kinase reaction to determine which
peptide(s)
is (are) phosphorylated by ATR. The peptide(s) are then used as substrate for
ATR
or MCCS 1 in assays such as described in Example 11 to identify modulators.
The same kinase reaction was also used to determine if proteins such
as histone H1 (Upstate Biotechnology, Inc., Waltham, NY) and myelin basic
protein
(Gibco BRL, Gaithersburg, MD) which are known to be substrates of other
protein
kinases are substrates of MCCSI and ATR. No phosphorylation of histone HI or
myelin basic protein was observed under the conditions of the assay. Moreover,
a
peptide from p53 known to be a substrate of DNA-PK was also not phosphorylated
in the assay.
B. Identification of Interacting Proteins
Interacting proteins may be identified by the following assays.
A first assay contemplated by the invention is a two-hybrid screen.
The two-hybrid system was developed in yeast [Chien et al., Proc. Natl. Acad.
Sci.
USA, 88: 9578-9582 (1991)] and is based on functional in vivo reconstitution
of a
transcription factor which activates a reporter gene. Specifically, a
polynucleotide
encoding a protein that interacts with MCCSI is isolated by: transforming or
transfecting appropriate host cells with a DNA construct comprising a reporter
gene
under the control of a promoter regulated by a transcription factor having a
DNA
binding domain and an activating domain; expressing in the host cells a first
hybrid
DNA sequence encoding a first fusion of part or all of MCCS 1 and either the
DNA
binding domain or the activating domain of the transcription factor;
expressing in the
host cells a library of second hybrid DNA sequences encoding second fusions of
part
or all of putative MCCS 1 binding proteins and the DNA binding domain or
activating
domain of the transcription factor which is not incorporated in the first
fusion;
detecting binding of an MCCS 1 interacting protein to MCCS 1 in a particular
host cell
by detecting the production of reporter gene product in the host cell; and
isolating
second hybrid DNA sequences encoding the interacting protein from the
particular
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host cell. Presently preferred for use in the assay are a lexA promoter to
drive
expression of the repoiter gene, the lacZ reporter gene, a transcription
factor
comprising the IexA DNA binding domain and the GAIA transactivation domain,
and
yeast host cells.
Other assays for identifying proteins that interact with MCCSI may
involve immobilizing MCCS1 or a test protein, detectably labelling the
nonimmobilized binding partner, incubating the binding partners together and
determining the amount of label bound. Bound label indicates that the test
protein
interacts with MCCS1.
Another type of assay for identifying MCCS 1 interacting proteins
involves immobilizing MCCS1 or a fragment thereof on a solid support coated
(or
impregnated with) a fluorescent agent, labelling a test protein with a
compound
capable of exciting the fluorescent agent, contacting the immobilized MCCS 1
with the
labelled test protein, detecting light emission by the fluorescent agent, and
identifying
interacting proteins as test proteins which result in the emission of light by
the
florescent agent. Alternatively, the putative interacting protein may be
immobilized
and MCCS I may be labelled in the assay.
Example 11
Modulators of MCCS I include MCCS 1 variants and other molecules.
The modulators may affect MCCS 1 kinase activity, its localization in the
cell, and/or
its interaction with members of the cell cycle checkpoint pathway. Presently
preferred regions of MCCS 1 which are targets for mutation or the development
of
selective modulators include the following four regions: the MCCS 1 a amino
telminal
effector domain (amino acids 1 to 1081 of SEQ ID NO: 31), the MCCS 1O amino
terminal effector domain (amino acids I to 1150 of SEQ ID NO: 33), the MCCSIa
rad3+ domain (amino acids 1082 to 2082 of SEQ ID NO: 31), the MCCS10 rad3+
domain (amino acids 1151 to 2151 of SEQ ID NO: 33), the MCCSI a PIK domain
(amino acids 2083 to 2410 of SEQ ID NO: 31), and the MCCS 10 PIK domain (amino
acids 2152 to 2480 of SEQ ID NO: 33).
MCCS 1 variants having mutations in the kinase domain may be useful
as a radiosensitizing agents. Mutations specifically contemplated by the
invention are,
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replacement of the MCCS1a aspartic acid at amino acid 2241, the asparagine at
2246,
and the aspartic acid at 2260 of SEQ ID NO: 31 with alanine or methionine, and
the
corresponding mutations in MCCS1O. Analogous mutations in the rad3+ gene
resulted in yeast hypersensitive to radiation. In addition, mutations in the
kinase
domain of ATM are found in patients with AT, a disease that causes radiation
sensitivity.
Furthermore, combinatorial libraries, peptide and peptide mimetics,
defined chemical entities, oligonucleotides, and natural product libraries may
be
screened for activity as modulators in assays such as those described below.
For example, an assay for identifying modulators of MCCS 1 kinase
activity involves incubating an MCCS1 kinase preparation in kinase buffer with
gamma 32P-ATP and an exogenous kinase substrate, both in the presence and
absence
of a test compound, and measuring the moles of phosphate transferred to the
substrate. For example, 2 l of the 50 mM imidazole elution pool is added to
kinase
buffer. (See Example 6.) The reactions are incubated at 37 C for 20 min and
samples are analyzed by SDS-PAGE prior to autoradiography or Western analysis.
An increase in the moles of phosphate transferred to the substrate in presence
of the
test compound compared to the moles of phosphate transferred to the substrate
in the
absence of the test compound indicates that the test compound is an activator
of said
MCCS l kinase. Conversely, a decrease in the moles of phosphate transferred to
the
substrate in presence of the test compound compared to the moles of phosphate
transferred to the substrate in the absence of the test compound indicates
that the
modulator is an inhibitor of said MCCSI kinase.
Moreover, assays for identifying compounds that modulate interaction
of MCCS 1 with other proteins may involve: transforming or transfecting
appropriate
host cells with a DNA construct comprising a reporter gene under the control
of a
promoter regulated by a transcription factor having a DNA-binding domain and
an
activating domain; expressing in the host cells a first hybrid DNA sequence
encoding
a first fusion of part or all of MCCS 1 and the DNA binding domain or the
activating
domain of the transcription factor; expressing in the host cells a second
hybrid DNA
sequence encoding part or all of a protein that interacts with MCCS I and the
DNA
binding domain or activating domain of the transcription factor which is not
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incorporated in the first fusion; evaluating the effect of a test compound on
the
interaction between MCCS 1 and the interacting protein by detecting binding of
the
interacting protein to MCCS1 in a particular host cell by measuring the
production
of reporter gene product in the host cell in the presence or absence of the
test
compound; and identifying modulating compounds as those test compounds
altering
production of the reported gene product in comparison to production of the
reporter
gene product in the absence of the modulating compound. Presently preferred
for use
in the assay are a lexA promoter to drive expression of the reporter gene, the
lacZ
reporter gene, a transcription factor comprising the lexA DNA binding domain
and
the GAL4 transactivation domain, and yeast host cells.
Another type of assay for identifying compounds that modulate the
interaction between MCCS 1 and an interacting protein involves immobilizing
MCCS I
or a natural MCCSI interacting protein, detectably labelling the
nonimmobilized
binding partner, incubating the binding partners together and determining the
effect
of a test compound on the amount of label bound wherein a reduction in the
label
bound in the present of the test compound compared to the amount of label
bound in
the absence of the test compound indicates that the test agent is an inhibitor
of
MCCSI interaction with protein. Conversely, an increase in the bound in the
presence of the test compound compared to the amount label bound in the
absence of
the compound indicates that the putative modulator is an activator of MCCS 1
interaction with the protein.
Yet another method contemplated by the invention for identifying
compounds that modulate the binding between MCCS 1 and an interacting protein
involves immobilizing MCCS 1 or a fragment thereof on a solid support coated
(or
impregnated with) a fluorescent agent, labelling the interacting protein with
a
compound capable of exciting the fluorescent agent, contacting the immobilized
MCCS 1 with the labelled interacting protein in the presence and absence of a
test
compound, detecting light emission by the fluorescent agent, and identifying
modulating compounds as those test compounds that affect the emission of light
by
the florescent agent in comparison to the emission of light by the fluorescent
agent
in the absence of the test compound. Alternatively, the MCCS 1 interacting
protein
may be immobilized and MCCS I may be labelled in the assay.
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Example 12
Cell based complementation assays for identifying modulators of
MCCS1 or ATM are described below.
In one type of assay, host cells (for example, esrl -1 yeast cells) are
transformed with MCCS1-encoding DNA as is described in Example 4. The esrl-l
yeast strain is normally sensitive to treatment with ultraviolet (UV) light,
but esrl-l
yeast cells expressing MCCS 1 or ATR are no longer sensitive to treatment with
W
light. The transformed yeast cells are exposed to test compounds and the
effect of
the test compounds on UV sensitivity of the transformed host cell is
determined. Test
compounds that are inhibitors of MCCS1 or ATR activity restore UV sensitivity
to
the MCCS 1 transformed esrl-l cells. Alternatively, esrl-l tell double mutant
yeast
cells are used as host cells instead of esrl-l yeast cells. The TELI gene is
homologous to ATM and the TEL1 mutation is described in Morrow, et al., Cell,
82:831-840 (1995). The invention also specifically contemplates that the esrl-
l or
esrl-1 tell double mutant yeast host cells may be transformed with ATM-
encoding
DNA (SEQ ID NO: 34).
In an alternative embodiment, the assays include clastogenic agents or
events instead of treatment with UV light (e. g. , IR, hydroxyurea, or DNA
damaging
agents). Appropriate host cells for use in such embodiments would be those
that are
sensitive to the alternative clastogenic agents or events.
Another type of complementation assay involves the use of mammalian
host cells such as cell lines derived from cells of AT patients. As described
above
for yeast cells, the mammalian cells are transfected with DNA encoding MCCS 1,
ATR, or ATM and then exposed to test compounds. Test compounds that are
inhibitors of MCCS 1, ATR, or ATM activity will restore the phenotype of the
untransformed host cell (e.g., sensitivity to IR).
The above assays can be used to identify compounds that inhibit
activity of MCCS 1, ATR, and ATM or compounds that inhibit activity of only
one
of the enzymes.
In an alternative type of assay, the yeast or mammalian host cells are
transformed with DNA encoding chimeric polypeptides including various
combinations of MCCS1 and ATM domains. MCCSI and ATM show structural
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similarities, and chimeric polypeptides which comprise portions of MCCS 1 and
ATM
are useful in elucidating active sites and binding domains of both MCCS 1 and
ATM.
Polynucleotides encoding the chimeras can be prepared by standard molecular
biology
techniques known to the skilled worker and as exemplified herein. The chimeric
polypeptides are expressed in host cells and modulators of the chimeras can be
identified by the assays disclosed herein.
Example 13
MCCS 1 and ATM are both involved in meiosis I checkpoints. Since
MCCSI is demonstrated herein to have kinase activity, assays were performed to
determine if ATM possessed kinase activity. To determine the kinase activity
of
ATM, ATM was immunoprecipitated from MRC-5 fibroblasts (ATCC #171-CCL)
with polyclonal antisera, 6076. MRC-5 cells are human lung embryonal diploid
fibroblasts. MRC-5 cells were obtained from the ATCC at passage 19 and
maintained in Minimal Essential Medium supplemented with 10 % fetal bovine
serum,
100 units/ml penicillin, 100 mg/mi streptomycin, and 100 mM MEM non-essential
amino acids. Media and media supplements were obtained through Gibco Life
Technologies. Cell lines were maintained in a water-saturated 37 C incubator
with
5% C.
MRC-5 cell extracts were prepared by lysis of a 10cm plate of log-
pliase cells in 0.5 ml of Lysis Buffer I(50 mM NaPO4i pH 7.2; 0.5 % TritonX-
100;
2 mM EDTA; 2 mM EGTA; 25 mM NaF; 25 mM 2-glycerophosphate; 1 mM
phenylmethylsulfonyl fluoride [PMSF]; 1 g/ml leupeptin 1 g/ml pepstatin A; 2
mM
DTT) on ice. Cells were scraped from plates using a rubber spatula then
sonicated
in a cup horn sonicator (Sonifier 250, Branson Ultrasonics Corp., Danbury, CT)
at
100% output for 90 seconds. Lysates were then clarified in a 4 C microfuge for
2
minutes. Preclearing was done by adding 10 g purified rabbit IgG (Zymed) and
30
l Protein A Agarose slurry (Pierce) followed by incubation at 4 C for 60
minutes
while rocking. To the precleared lysates, 10 g of affinity purified 6076
antisera (or
10 g 6076 pre-blocked with 0.04 mg P45 peptide for 30 min.) was added and
incubated on ice for 60 minutes. Immunoprecipitates were collected by addition
of
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30 l Protein A agarose slurry and incubated with rocking at 4 C for 30
minutes
followed by four washes in Lysis Buffer I.
Kinase reactions were carried out by washing the immunoprecipitations
once with kinase buffer (25 M Hepes pH 7.7; 50 mM KCI; 10 mM MgCI2; 0. 1 %
NP-40; 2% glycerol; I mM DTT), followed by incubation in 20 tiI of Kinase
Buffer
containing 10 M ATP + 10 Ci -y 32P-ATP [50 Ci/mmol] for 20 minutes at 37 C.
Reactions were stopped by the addition of 20 12X SDS sample buffer and boiled
for
5 minutes prior to separation on 6% SDS polyacrylamide gels. The gels were
dried
and exposed to x-ray film (Kodak, XAR-5) at -80 C overnight.
10 cm plates of log-phase MRC-5 cells were washed once with PBS
then incubated in Dulbeco's Modified Eagle Medium (minus methionine)
containing
2 % dialyzed fetal bovine serum for 30 minutes. Cells were labeled by adding
200
Ci35S-methionine (1000 Ci/mmol TRAN35S-LABEL, ICN Radiochemicals) for 2
hours. Labeled cells were then washed once with PBS and frozen at -80 C prior
to
immunoprecipitation.
The incubation of the immunoprecipitated complexes in kinase buffer
produced a phosphorylated product with a molecular weight of approximately
350,000
that co-migrated with ATM in polyacrylamide gels.
Similar results were obtained for ATR immune complexes
immunoprecipitated with anti-AgDH-2 (MCCS1) polyclonal antisera of Example 5.
ATR and ATM thus appear to be able to self-phosphorylate or associate with a
protein kinase.
To determine the role of ATR and ATM in meiosis, immunostaining
techniques on surface spreads of mouse spermatocytes were utilized to localize
ATR
and ATM to meiotic chromosomes. Antibodies recognizing ATR and ATM were
utilized with mouse antibodies against Corl. Corl is a component of
axial/lateral
elements of synapsing chromosomes [Dobson et al., J. Cell Sci., 107:2749-2760
(1994)]. Corl chromosomal staining appears when the axial elements begin to
form
between the sister chromatids of each homolog in leptonema of meiotic
prophase,
prior to the initiation of synapsis. As homologous bivalents synapse, the
axial
elements from the two homologs align and a central element forms between them,
completing the structure called the synaptonemal complex (SC).
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When short stretches of Corl begin to appear prior to any evidence of
synapsis, neither ATR nor ATM is detectable. As homologs start synapsis, both
proteins were seen at pairing forks; however, the location and behavior of the
two
proteins differed markedly. In nonmal zygotene nuclei, the stage during which
homologs synapse, ATR was present in small amounts and transiently at discrete
foci
along the asynapsed (unpaired) axes. As homologs synapse, ATR disappeared from
these locations. However, at regions delayed in synapsis, often seen near the
proximal ends of autosomal bivalents, there was an accumulation of ATR foci
along
the unsynapsed axes. ATR was detected at similar locations on the two axial
elements. In nuclei where an entire autosome fails to find its homologous
pairing
partner, ATR foci were detected along the entire lengths of these asynapsed
axis. In
males, where the X chromosome has no homolog, ATR foci were localized along
the
unpaired axis.
ATM was also visualized as foci and was first detected during
zygonema as homologs synapse, but ATM localization was different than ATR.
ATM was first observed along synapsed axes when homologous autosomal axial
elements come into contact. However, during mid-pachynema, after autosomal
synapsis has been completed, ATM foci appeared on the X chromosome axis. ATM
localization persisted on fully synapsed bivalents into pachynema, a substage
that lasts
3 days in mouse oocytes and 6 days in mouse spermatocytes. During pachynema,
the
number of foci drops gradually, stabilizing briefly in mid-pachynema before
eventually disappearing mid-to late pachynema. Thus, ATR and ATM protein
kinases
play important and complementary roles at distinct stages in meiosis I.
The involvement of ATR appears to be transient during early meiotic
prophase while the role of ATM appears to be more prolonged. However, both ATR
and ATM coordinate the various events of meiotic prophase by performing
similar
checkpoint functions.
The foregoing illustrative examples relate to presently preferred
embodiments of the invention and numerous modifications and variations thereof
are
expected to occur to those skilled in the art. Thus only such limitations as
appear in
the appended claims should be placed upon the scope of the present invention.
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SEQUENCE LISTING
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(i) APPLICANT: ICOS Corporation
(ii) TITLE OF INVENTION: Cell Cycle Checkpoint PIK-Related Kinase
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-52-
CTTGTGAAGA GAATGTTTTA CACTCTTGTT AGTGAAGTTT ATTCTTTAAA AGTCAATCGT 60
CAAGGATT'1'A GCAAATGAAT TAGCACTTCG GATATACTTG TTTATTTAAT ATCTTTTTTG 120
TTTATTTCAA AGAATTCAGT AATTGGATCA TAACGAGACT TCTGCGGATT GCAGCAACTC 180
CCTCCTGTCA TTTGTTACAC AAGAAFIFITCT GTGAAGTCAT CTGTTCATTA TTATTTCTTT 240
TTAAAAGCAA GAGTCCTGCT ATTTTTGGGG TACTCACAAA AGAATTATTA CAACTTTTTG 300
AAGACTTGGT TTACCTCCAT AGAAGAAATG TG ATG GGT CAT GCT GTG GAA TGG 353
Met Gly His Ala Val Glu Trp
1 5
CCA GTG GTC ATG AGC CGA TTT TTA AGT CAA TTA GAT GAA CAC ATG GGA 401
Pro Val Val Met Ser Arg Phe Leu Ser Gln Leu Asp Glu His Met Gly
15 20
TAT TTA CAA TCA GCT CCT TTG CAG TTG ATG AGT ATG CAA AAA TTA GAA 449
Tyr Leu Gln Ser Ala Pro Leu Gln Leu Met Ser Met Gln Lys Leu Glu
25 30 35
TTT ATT GAA GTC ACT TTA TTA ACG GTT CTT ACT CGT ATT ATT GCA ATT 497
Phe Ile Glu Val Thr Leu Leu Thr Val Leu Thr Arg Ile Ile Ala Ile
40 45 50 55
GTG TTT TTT AGA AGG CAA GAA CTC TTA CTT TGG CAG ATA GGT TGT GTT 545
Val Phe Phe Arg Arg Gln Glu Leu Leu Leu Trp Gln Ile Gly Cys Val
60 65 70
CTG CTA GAG TAT GGT AGT CCA AAA ATT AAA TCC CTA GCA ATT AGC TTT 593
Leu Leu Glu Tyr Gly Ser Pro Lys Ile Lys Ser Leu Ala Ile Ser Phe
75 80 85
TTA ACA GAA CTT TTT CAG CTT GGA GGA CTA CCA GCA CAA CCA GCT AGC 641
Leu Thr Glu Leu Phe Gin Leu Gly Gly Leu Pro Ala Gin Pro Ala Ser
90 95 100
ACT TTT TTC AGC TCA TTT TTG GAA TTA TTA AAA CAC CTT GTA GAA ATG 689
Thr Phe Phe Ser Ser Phe Leu Glu Leu Leu Lys His Leu Val Glu Met
105 110 115
GAT ACT GAC CAA TTG AAA CTC TAT GAA GAG CCA TTA TCA AAG CTG ATA 737
Asp Thr Asp Gln Leu Lys Leu Tyr Glu Glu Pro Leu Ser Lys Leu Ile
120 125 130 135
AAG ACA CTA TTT CCC TTT GAA GCA GAA GCT TAT AGA AAT ATT GAA CCT 785
Lys Thr Leu Phe Pro Phe Glu Ala Glu Ala Tyr Arg Asn Ile Glu Pro
140 145 150
GTC TAT TTA AAT ATG CTG CTG GAA AAA CTC TGT GTC ATG TTT GAA GAC 833
Val Tyr Leu Asn Met Leu Leu Glu Lys Leu Cys Val Met Phe Glu Asp
155 160 165
GGT GTG CTC ATG CGG CTT AAG TCT GAT TTG CTA AAA GCA GCT TTG TGC 881
Gly Val Leu Met Arg Leu Lys Ser Asp Leu Leu Lys Ala Ala Leu Cys
170 175 180
CAT TTA CTG CAG TAT TTC CTT AAA TTT GTG CCA GCT GGG TAT GAA TCT 929
His Leu Leu Gln Tyr Phe Leu Lys Phe Val Pro Ala Gly Tyr Glu Ser
185 190 195
GCT TTA CAA GTC AGG AAG GTC TAT GTG AGA AAT ATT TGT AAA GCT CTT 977
Ala Leu Gin Val Arg Lys Val Tyr Val Arg Asn Ile Cys Lys Ala Leu
200 205 210 215
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TTG GAT GTG CTT GGA ATT GAG GTA GAT GCA GAG TAC TTG TTG GGC CCA 1025
Leu Asp Val Leu Gly Ile Glu Val Asp Ala Glu Tyr Leu Leu Gly Pro
220 225 230
CTT TAT GCA GCT TTG AAA ATG GAA AGT ATG GAA ATC ATT GAG GAG ATT 1073
Leu Tyr Ala Ala Leu Lys Met Glu Ser Met Glu Ile Ile Glu Glu Ile
235 240 245
CAA TGC CAA ACT CAA CAG GAA AAC CTC AGC AGT AAT AGT GAT GGA ATA 1121
Gln Cys Gln Thr Gln Gln Glu Asn Leu Ser Ser Asn Ser Asp Gly Ile
250 255 260
TCA CCC AAA AGG CGT CGT CTC AGC TCG TCT CTA AAC CCT TCT AAA AGA 1169
Ser Pro Lys Arg Arg Arg Leu Ser Ser Ser Leu Asn Pro Ser Lys Arg
265 270 275
GCA CCA AAA CAG ACT GAG GAA ATT AAA CAT GTG GAC ATG AAC CAA AAG 1217
Ala Pro Lys Gln Thr Glu Glu Ile Lys His Val Asp Met Asn Gln Lys
280 285 290 295
AGC ATA TTA TGG AGT GCA CTG AAA CAG AAA GCT GAA TCC CTT CAG ATT 1265
Ser Ile Leu Trp Ser Ala Leu Lys Gln Lys Ala Glu Ser Leu Gln Ile
300 305 310
TCC CTT GAA TAC AGT GGC CTA AAG AAT CCT GTT ATT GAG ATG TTA GAA 1313
Ser Leu Glu Tyr Ser Gly Leu Lys Asn Pro Val Ile Glu Met Leu Glu
315 320 325
GGA ATT GCT GTT GTC TTA CAA CTG ACT GCT CTG TGT ACT GTT CAT TGT 1361
Gly Ile Ala Val Val Leu Gln Leu Thr Ala Leu Cys Thr Val His Cys
330 335 340
TCT CAT CAA AAC ATG AAC TGC CGT ACT TTC AAG GAC TGT CAA CAT AAA 1409
Ser His Gln Asn Met Asn Cys Arg Thr Phe Lys Asp Cys Gln His Lys
345 350 355
TCC AAG AAG AAA CCT TCT GTA GTG ATA ACT TGG ATG TCA TTG GAT TTT 1457
Ser Lys Lys Lys Pro Ser Val Val Ile Thr Trp Met Ser Leu Asp Phe
360 365 370 375
TAC ACA ACA GTG CTT AAG AGC TGT AGA AGG TTG TTA GAA TCT GTT CAG 1505
Tyr Thr Thr Val Leu Lys Ser Cys Arg Arg Leu Leu Glu Ser Val Gln
380 385 390
AAA CGG ACT GGA GGC AAC ATT GAT AAG GTG GTG AAA ATT TAT GAT GCT 1553
Lys Arg Thr Gly Gly Asn Ile Asp Lys Val Val Lys Ile Tyr Asp Ala
395 400 405
TTG ATT TAT ATG CAA GTA AAC AGT TCA TTT GAA GAT CAT ATC CTG GAA 1601
Leu Ile Tyr Met Gln Val Asn Ser Ser Phe Glu Asp His Ile Leu Glu
410 415 420
GAT TTA TGT GGA ATG CTC TCA CTT CCA TGG ATT TAT TCC CAT TCT GAT 1649
Asp Leu Cys Gly Met Leu Ser Leu Pro Trp Ile Tyr Ser His Ser Asp
425 430 435
GAT GGC TGT TTA AAG TTG ACC ACA TTT GCC GCT AAT CTT CTA ACA TTA 1697
Asp Gly Cys Leu Lys Leu Thr Thr Phe Ala Ala Asn Leu Leu Thr Leu
440 445 450 455
AGC TGT AGG ATT TCA GAT AGC TAT TCA CCA CAG GCA CAA TCA CGA TGT 1745
Ser Cys Arg Ile Ser Asp Ser Tyr Ser Pro Gln Ala Gln Ser Arg Cys
460 465 470
GTG TTT CTT CTG ACT CTG TTT CCA AGA AGA ATA TTC CTT GAG TGG AGA 1793
Val Phe Leu Leu Thr Leu Phe Pro Arg Arg Ile Phe Leu Glu Trp Arg
475 480 485
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ACA GCA GTT TAC AAC TGG GCC CTG CAG AGC TCC CAT GAA GTA ATC CGG 1841
Thr Ala Val Tyr Asn Trp Ala Leu Gln Ser Ser His Glu Val Ile Arg
490 495 500
GCT AGT TGT GTT AGT GGA TTT TTT ATC TTA TTG CAG CAG CAG AAT TCT 1889
Ala Ser Cys Val Ser Gly Phe Phe Ile Leu Leu Gln Gln Gln Asn Ser
505 510 515
TGT AAC AGA GTT CCC AAG ATT CTT ATA GAT AAA GTC AAA GAT GAT TCT 1937
Cys Asn Arg Val Pro Lys Ile Leu Ile Asp Lys Val Lys Asp Asp Ser
520 525 530 535
GAC ATT GTC AAG AAA GAA TTT GCT TCT ATA CTT GGT CAA CTT GTC TGT 1985
Asp Ile Val Lys Lys Glu Phe Ala Ser Ile Leu Gly Gln Leu Val Cys
540 545 550
ACT CTT CAC GGC ATG TTT TAT CTG ACA AGT TCT TTA ACA GAA CCT TTC 2033
Thr Leu His Gly Met Phe Tyr Leu Thr Ser Ser Leu Thr Glu Pro Phe
555 560 565
TCT GAA CAC GGA CAT GTG GAC CTC TTC TGT AGG AAC TTG AAA GCC ACT 2081
Ser Glu His Gly His Val Asp Leu Phe Cys Arg Asn Leu Lys Ala Thr
570 575 580
TCT CAA CAT GAA TGT TCA TCT TCT CAA CTA AAA GCT TCT GTC TGC AAG 2129
Ser Gln His Glu Cys Ser Ser Ser Gln Leu Lys Ala Ser Val Cys Lys
585 590 595
CCA TTC CTT TTC CTA CTG AAA AAA AAA ATA CCT AGT CCA GTA AAA CTT 2177
Pro Phe Leu Phe Leu Leu Lys Lys Lys Ile Pro Ser Pro Val Lys Leu
600 605 610 615
GCT TTC ATA GAT AAT CTA CAT CAT CTT TGT AAG CAT CTT GAT TTT AGA 2225
Ala Phe Ile Asp Asn Leu His His Leu Cys Lys His Leu Asp Phe Arg
620 625 630
GAA GAT GAA ACA GAT GTA AAA GCA GTT CTT GGA ACT TTA TTA AAT TTA 2273
Glu Asp Glu Thr Asp Val Lys Ala Val Leu Gly Thr Leu Leu Asn Leu
635 640 645
ATG GAA GAT CCA GAC AAA GAT GTT AGA GTG GCT TTT AGT GGA AAT ATC 2321
Met Glu Asp Pro Asp Lys Asp Val Arg Val Ala Phe Ser Gly Asn Ile
650 655 660
AAG CAC ATA TTG GAA TCC TTG GAC TCT GAA GAT GGA TTT ATA AAG GAG 2369
Lys His Ile Leu Glu Ser Leu Asp Ser Glu Asp Gly Phe Ile Lys Glu
665 670 675
CTT TTT GTC TTA AGA ATG AAG GAA GCA TAT ACA CAT GCC C.AA ATA TCA 2417
Leu Phe Val Leu Arg Met Lys Glu Ala Tyr Thr His Ala Gln Ile Ser
680 685 690 695
AGA AAT AAT GAG CTG AAG GAT ACC TTG ATT CTT ACA ACA GGG GAT ATT 2465
Arg Asn Asn Glu Leu Lys Asp Thr Leu Ile Leu Thr Thr Gly Asp Ile
700 705 710
GGA AGG GCC GCA AAA GGA GAT TTG GTA CCA TTT GCA CTC TTA CAC TTA 2513
Gly Arg Ala Ala Lys Gly Asp Leu Val Pro Phe Ala Leu Leu His Leu
715 720 725
TTG CAT TGT TTG TTA TCC AAG TCA GCA TCT GTC TCT GGA GCA GCA TAC 2561
Leu His Cys Leu Leu Ser Lys Ser Ala Ser Val Ser Gly Ala Ala Tyr
730 735 740
ACA GAA ATT AGA GCT CTG GTT GCA GCT AAA AGT GTT AAA CTG CAA AGT 2609
Thr Glu Ile Arg Ala Leu Val Ala Ala Lys Ser Val Lys Leu Gln Ser
745 750 755
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TTT TTC AGC CAG TAT AAG AAA CCC ATC TGT CAG TTT TTG GTA GAA TCC 2657
Phe Phe Ser Gln Tyr Lys Lys Pro Ile Cys Gin Phe Leu Val Glu Ser
760 765 770 775
CTT CAC TCT AGT CAG ATG ACA GCA CTT CCG AAT ACT CCA TGC CAG AAT 2705
Leu His Ser Ser Gin Met Thr Ala Leu Pro Asn Thr Pro Cys Gln Asn
780 785 790
GCT GAC GTG CGA AAA CAA GAT GTG GCT CAC CAG AGA GAA ATG GCT TTA 2753
Ala Asp Val Arg Lys Gln Asp Val Ala His Gln Arg Glu Met Ala Leu
795 800 805
AAT ACG TTG TCT GAA ATT GCC AAC GTT TTC GAC TTT CCT GAT CTT AAT 2801
Asn Thr Leu Ser Glu Ile Ala Asn Val Phe Asp Phe Pro Asp Leu Asn
810 815 820
CGT TTT CTT ACT AGG ACA TTA CAA GTT CTA CTA CCT GAT CTT GCT GCC 2849
Arg Phe Leu Thr Arg Thr Leu Gln Val Leu Leu Pro Asp Leu Ala Ala
825 830 835
AAA GCA AGC CCT GCA GCT TCT GCT CTC ATT CGA ACT TTA GGA AAA CAA 2897
Lys Ala Ser Pro Ala Ala Ser Ala Leu Ile Arg Thr Leu Gly Lys Gln
840 845 850 855
TTA AAT GTC AAT CGT AGA GAG ATT TTA ATA AAC AAC TTC AAA TAT ATT 2945
Leu Asn Val Asn Arg Arg Glu Ile Leu Ile Asn Asn Phe Lys Tyr IZe
860 865 870
TTT TCT CAT TTG GTC TGT TCT TGT TCC AAA GAT GAA TTA GAA CGT GCC 2993
Phe Ser His Leu Val Cys Ser Cys Ser Lys Asp Glu Leu Glu Arg Ala
875 880 885
CTT CAT TAT CTG AAG AAT GAA ACA GAA ATT GAA CTG GGG AGC CTG TTG 3041
Leu His Tyr Leu Lys Asn Glu Thr Glu Ile Glu Leu Gly Ser Leu Leu
890 895 900
AGA CAA GAT TTC CAA GGA TTG CAT AAT GAA TTA TTG CTG CGT ATT GGA 3089
Arg Gin Asp Phe Gln Gly Leu His Asn Glu Leu Leu Leu Arg Ile Gly
905 910 915
GAA CAC TAT CAA CAG GTT TTT AAT GGT TTG TCA ATA CTT GCC TCA TTT 3137
Glu His Tyr Gln Gln Val Phe Asn Gly Leu Ser Ile Leu Ala Ser Phe
920 925 930 935
GCA TCC AGT GAT GAT CCA TAT CAG GGC CCG AGA GAT ATC ATA TCA CCT 3185
Ala Ser Ser Asp Asp Pro Tyr Gln Gly Pro Arg Asp Ile Ile Ser Pro
940 945 950
GAA CTG ATG GCT GAT TAT TTA CAA CCC AAA TTG TTG GGC ATT TTG GCT 3233
Glu Leu Met Ala Asp Tyr Leu Gln Pro Lys Leu Leu Gly Ile Leu Ala
955 960 965
TTT TTT AAC ATG CAG TTA CTG AGC TCT AGT GTT GGC ATT GAA GAT AAG 3281
Phe Phe Asn Met Gln Leu Leu Ser Ser Ser Val Gly Ile Glu Asp Lys
970 975 980
AAA ATG GCC TTG AAC AGT TTG ATG TCT TTG ATG AAG TTA ATG GGA CCC 3329
Lys Met Ala Leu Asn Ser Leu Met Ser Leu Met Lys Leu Met Gly Pro
985 990 995
AAA CAT GTC AGT TCT GTG AGG GTG AAG ATG ATG ACC ACA CTG AGA ACT 3377
Lys His Val Ser Ser Val Arg Val Lys Met Met Thr Thr Leu Arg Thr
1000 1005 1010 1015
GGC CTT CGA TTC AAG GAT GAT TTT CCT GAA TTG TGT TGC AGA GCT TGG 3425
Gly Leu Arg Phe Lys Asp Asp Phe Pro Glu Leu Cys Cys Arg Ala Trp
1020 1025 1030
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GAC TGC TTT GTT CGC TGC CTG GAT CAT GCT TGT CTG GGC TCC CTT CTC 3473
Asp Cys Phe Val Arg Cys Leu Asp His Ala Cys Leu Gly Ser Leu Leu
1035 1040 1045
AGT CAT GTA ATA GTA GCT TTG TTA CCT CTT ATA CAC ATC CAG CCT AAA 3521
Ser His Val Ile Val Ala Leu Leu Pro Leu Ile His Ile Gln Pro Lys
1050 1055 1060
GAA ACT GCA GCT ATC TTC CAC TAC CTC ATA ATT GAA AAC AGG GAT GCT 3569
Glu Thr Ala Ala Ile Phe His Tyr Leu Ile Ile Glu Asn Arg Asp Ala
1065 1070 1075
GTG CAA GAT TT"T CTT CAT GAA ATA TAT TTT TTA CCT GAT CAT CCA GAA 3617
Val Gln Asp Phe Leu His Glu Ile Tyr Phe Leu Pro Asp His Pro Glu
1080 1085 1090 1095
TTA AAA AAG ATA AAA GCC GTT CTC CAG GAA TAC AGA AAG GAG ACC TCT 3665
Leu Lys Lys Ile Lys Ala Val Leu Gln Glu Tyr Arg Lys Giu Thr Ser
1100 1105 1110
GAG AGC ACT GAT CTT CAG ACA ACT CTT CAG CTC TCT ATG AAG GCC ATT 3713
Glu Ser Thr Asp Leu Gln Thr Thr Leu Gln Leu Ser Met Lys Ala Ile
1115 1120 1125
CAA CAT GAA AAT GTC GAT GTT CGT ATT CAT GCT CTT ACA AGC TTG AAG 3761
Gln His Glu Asn Val Asp Val Arg Ile His Ala Leu Thr Ser Leu Lys
1130 1135 1140
GAA ACC TTG TAT AAA AAT CAG GAA AAA CTG ATA AAG TAT GCA ACA GAC 3809
Glu Thr Leu Tyr Lys Asn Gln Glu Lys Leu Ile Lys Tyr Ala Thr Asp
1145 1150 1155
AGT GAA ACA GTA GAA CCT ATT ATC TCA CAG TTG GTG ACA GTG CTT TTG 3857
Ser Glu Thr Val Glu Pro Ile Ile Ser Gln Leu Val Thr Val Leu Leu
1160 1165 1170 1175
AAA GGT TGC CAA GAT GCA AAC TCT CAA GCT CGG TTG CTC TGT GGG GAA 3905
Lys Gly Cys Gln Asp Ala Asn Ser Gln Ala Arg Leu Leu Cys Gly Glu
1180 1185 1190
TGT TTA GGG GAA TTG GGG GCG ATA GAT CCA GGT CGA TTA GAT TTC TCA 3953
Cys Leu Gly Glu Leu Gly Ala Ile Asp Pro Gly Arg Leu Asp Phe Ser
1195 1200 1205
ACA ACT GAA ACT CAA GGA AAA GAT TTT ACA TTT GTG ACT GGA GTA GAA 4001
Thr Thr Glu Thr Gln Gly Lys Asp Phe Thr Phe Val Thr Gly Val Glu
1210 1215 1220
GAT TCA AGC TTT GCC TAT GGA TTA TTG ATG GAG CTA ACA AGA GCT TAC 4049
Asp Ser Ser Phe Ala Tyr Gly Leu Leu Met Glu Leu Thr Arg Ala Tyr
1225 1230 1235
CTT GCG TAT GCT GAT AAT AGC CGA GCT CCA GAT TCA GCT GCC TAT GCC 4097
Leu Ala Tyr Ala Asp Asn Ser Arg Ala Pro Asp Ser Ala Ala Tyr Ala
1240 1245 1250 1255
ATT CAG GAG TTG CTT TCT ATT TAT GAC TGT AGA GAG ATG GAG ACC AAC 4145
Ile Gln Glu Leu Leu Ser Ile Tyr Asp Cys Arg Glu Met Glu Thr Asn
1260 1265 1270
GGC CCA GGT CAC CAA TTG TGG AGG AGA TTT CCT GAG CAT GTT CGG GAA 4193
Gly Pro Gly His Gln Leu Trp Arg Arg Phe Pro Glu His Val Arg Glu
1275 1280 1285
ATA CTA GAA CCT CAT CTA AAT ACC AGA TAC AAG AGT TCT CAG AAG TCA 4241
Ile Leu Glu Pro His Leu Asn Thr Arg Tyr Lys Ser Ser Gln Lys Ser
1290 1295 1300
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ACC GAT TGG TCT GGA GTA AAG AAG CCA ATT TAC TTA AGT AAA TTG GGT 4289
Thr Asp Trp Ser Gly Val Lys Lys Pro Ile Tyr Leu Ser Lys Leu Gly
1305 1310 1315
AGT AAC TTT GCA GAA TGG TCA GCA TCT TGG GCA GGT TAT CTT ATT ACA 4337
Ser Asn Phe Ala Glu Trp Ser Ala Ser Trp Ala Gly Tyr Leu Ile Thr
1320 1325 1330 1335
AAG GTT CGA CAT GAT CTT GCC AGT AAA ATT TTC ACC TGC TGT AGC ATT 4385
Lys Val Arg His Asp Leu Ala Ser Lys Ile Phe Thr Cys Cys Ser Ile
1340 1345 1350
ATG ATG AAG CAT GAT TTC AAA GTG ACC ATC TAT CTT CTT CCA CAT ATT 4433
Met Met Lys His Asp Phe Lys Val Thr Ile Tyr Leu Leu Pro His Ile
1355 1360 1365
CTG GTG TAT GTC TTA CTG GGT TGT AAT CAA GAA GAT CAG CAG GAG GTT 4481
Leu Val Tyr Val Leu Leu Gly Cys Asn Gln Glu Asp Gln Gln Glu Val
1370 1375 1380
TAT GCA GAA ATT ATG GCA GTT CTA AAG CAT GAC GAT CAG CAT ACC ATA 4529
Tyr Ala Glu Ile Met Ala Val Leu Lys His Asp Asp Gln His Thr Ile
1385 1390 1395
AAT ACC CAA GAC ATT GCA TCT GAT CTG TGT CAA CTC AGT ACA CAG ACT 4577
Asn Thr Gln Asp Ile Ala Ser Asp Leu Cys Gln Leu Ser Thr Gln Thr
1400 1405 1410 1415
GTG TTC TCC ATG CTT GAC CAT CTC ACA CAG TGG GCA AGG CAC AAA TTT 4625
Val Phe Ser Met Leu Asp His Leu Thr Gln Trp Ala Arg His Lys Phe
1420 1425 1430
CAG GCA CTG AAA GCT GAG AAA TGT CCA CAC AGC AAA TCA AAC AGA AAT 4673
Gln Ala Leu Lys Ala Glu Lys Cys Pro His Ser Lys Ser Asn Arg Asn
1435 1440 1445
AAG GTA GAC TCA ATG GTA TCT ACT GTG GAT TAT GAA GAC TAT CAG AGT 4721
Lys Val Asp Ser Met Val Ser Thr Val Asp Tyr Glu Asp Tyr Gln Ser
1450 1455 1460
GTA ACC CGT TTT CTA GAC CTC ATA CCC CAG GAT ACT CTG GCA GTA GCT 4769
Val Thr Arg Phe Leu Asp Leu Ile Pro Gln Asp Thr Leu Ala Val Ala
1465 1470 1475
TCC TTT CGC TCC AAA GCA TAC ACA CGA GCT GTA ATG CAC TTT GAA TCA 4817
Ser Phe Arg Ser Lys Ala Tyr Thr Arg Ala Val Met His Phe Glu Ser
1480 1485 1490 1495
TTT ATT ACA GAA AAG AAG CAA AAT ATT CAG GAA CAT CTT GGA TTT TTA 4865
Phe Ile Thr Glu Lys Lys Gln Asn Ile Gln Glu His Leu Gly Phe Leu
1500 1505 1510
CAG AAA TTG TAT GCT GCT ATG CAT GAA CCT GAT GGA GTG TCC GGA GTC 4913
Gln Lys Leu Tyr Ala Ala Met His Glu Pro Asp Gly Val Ser Gly Val
1515 1520 1525
AGT GCA ATT AGA AAG GCA GAA CCA TCT CTA AAA GAA CAG ATC CTT GAA 4961
Ser Ala Ile Arg Lys Ala Glu Pro Ser Leu Lys Glu Gln Ile Leu Glu
1530 1535 1540
CAT GAA AGC CTT GGC TTG CTG AGG GAT GCC ACT GCT TGT TAT GAC AGG 5009
His Glu Ser Leu Gly Leu Leu Arg Asp Ala Thr Ala Cys Tyr Asp Arg
1545 1550 1555
GCT ATT CAG CTA GAA CCA GAC CAG ATC ATT CAT TAC CAT GGT GTA GTA 5057
Ala Ile Gln Leu Glu Pro Asp Gln Ile Ile His Tyr His Gly Val Val
1560 1565 1570 1575
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AAG TCC ATG TTA GGT CTT GGT CAG CTG TCT ACT GTT ATC ACT CAG GTG 5105
Lys Ser Met Leu Gly Leu Gly Gln Leu Ser Thr Val Ile Thr Gln Val
1580 1585 1590
AAT GGA GTG CAT GCT AAC AGG TCC GAG TGG ACA GAT GAA TTA AAC ACG 5153
Asn Gly Val His Ala Asn Arg Ser Glu Trp Thr Asp Glu Leu Asn Thr
1595 1600 1605
TAC AGA GTG GAA GCA GCT TGG AAA TTG TCA CAG TGG GAT TTG GTG GAA 5201
Tyr Arg Val Glu Ala Ala Trp Lys Leu Ser Gln Trp Asp Leu Val Glu
1610 1615 1620
AAC TAT TTG GCA GCA GAT GGA AAA TCT ACA ACA TGG AGT GTC AGA CTG 5249
Asn Tyr Leu Ala Ala Asp Gly Lys Ser Thr Thr Trp Ser Val Arg Leu
1625 1630 1635
GGA CAG CTA TTA TTA TCA GCC AAA AAA AGA GAT ATC ACA GCT TTT TAT 5297
Gly Gln Leu Leu Leu Ser Ala Lys Lys Arg Asp Ile Thr Ala Phe Tyr
1640 1645 1650 1655
GAC TCA CTG AAA CTA GTG AGA GCA GAA CAA ATT GTA CCT CTT TCA GCT 5345
Asp Ser Leu Lys Leu Val Arg Ala Glu Gln Ile Val Pro Leu Ser Ala
1660 1665 1670
GCA AGC TTT GAA AGA GGC TCC TAC CAA CGA GGA TAT GAA TAT ATT GTG 5393
Ala Ser Phe Glu Arg Gly Ser Tyr Gln Arg Gly Tyr Glu Tyr Ile Val
1675 1680 1685
AGA TTG CAC ATG TTA TGT GAG TTG GAG CAT AGC ATC AAA CCA CTT TTC 5441
Arg Leu His Met Leu Cys Glu Leu Glu His Ser Ile Lys Pro Leu Phe
1690 1695 1700
CAG CAT TCT CCA GGT GAC AGT TCT CAA GAA GAT TCT CTA AAC TGG GTA 5489
Gln His Ser Pro Gly Asp Ser Ser Gln Glu Asp Ser Leu Asn Trp Val
1705 1710 1715
GCT CGA CTA GAA ATG ACC CAG AAT TCC TAC AGA GCC AAG GAG CCT ATC 5537
Ala Arg Leu Glu Met Thr Gln Asn Ser Tyr Arg Ala Lys Glu Pro Ile
1720 1725 1730 1735
CTG GCT CTC CGG AGG GCT TTA CTA AGC CTC AAC AAA AGA CCA GAT TAC 5585
Leu Ala Leu Arg Arg Ala Leu Leu Ser Leu Asn Lys Arg Pro Asp Tyr
1740 1745 1750
AAT GAA ATG GTT GGA GAA TGC TGG CTG CAG AGT GCC AGG GTA GCT AGA 5633
Asn Glu Met Val Gly Glu Cys Trp Leu Gln Ser Ala Arg Val Ala Arg
1755 1760 1765
AAG GCT GGT CAC CAC CAG ACA GCC TAC AAT GCT CTC CTT AAT GCA GGG 5681
Lys Ala Gly His His Gln Thr Ala Tyr Asn Ala Leu Leu Asn Ala Gly
1770 1775 1780
GAA TCA CGA CTC GCT GAA CTG TAC GTG GAA AGG GCA AAG TGG CTC TGG 5729
Glu Ser Arg Leu Ala Glu Leu Tyr Val Glu Arg Ala Lys Trp Leu Trp
1785 1790 1795
TCC AAG GGT GAT GTT CAC CAG GCA CTA ATT GTT CTT CAA AAA GGT GTT 5777
Ser Lys Gly Asp Val His Gln Ala Leu Ile Val Leu Gln Lys Gly Val
1800 1805 1810 1815
GAA TTA TGT TTT CCT GAA AAT GAA ACC CC-A CCT GAG GGT AAG AAC ATG 5825
Glu Leu Cys Phe Pro Glu Asn Glu Thr Pro Pro Glu Gly Lys Asn Met
1820 1825 1830
TTA ATC CAT GGT CGA GCT ATG CTA CTA GTG GGC CGA TTT ATG GAA GAA 5873
Leu Ile His Gly Arg Ala Met Leu Leu Val Gly Arg Phe Met Glu Glu
1835 1840 1845
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ACA GCT AAC TTT GAA AGC AAT GCA ATT ATG AAA AAA TAT AAG GAT GTG 5921
Thr Ala Asn Phe Glu Ser Asn Ala Ile Met Lys Lys Tyr Lys Asp Val
1850 1855 1860
ACC GCG TGC CTG CCA GAA TGG GAG GAT GGG CAT TTT TAC CTT GCC AAG 5969
Thr Ala Cys Leu Pro Glu Trp Glu Asp Gly His Phe Tyr Leu Ala Lys
1865 1870 1875
TAC TAT GAC AAA TTG ATG CCC ATG GTC ACA GAC AAC AAA ATG GAA AAG 6017
Tyr Tyr Asp Lys Leu Met Pro Met Val Thr Asp Asn Lys Met Glu Lys
1880 1885 1890 1895
CAA GGT GAT CTC ATC CGG TAT ATA GTT CTT CAT TTT GGC AGA TCT CTA 6065
Gln Gly Asp Leu Ile Arg Tyr Ile Val Leu His Phe Gly Arg Ser Leu
1900 1905 1910
CAA TAT GGA AAT CAG TTC ATA TAT CAG TCA ATG CCA CGA ATG TTA ACT 6113
Gln Tyr Gly Asn Gln Phe Ile Tyr Gln Ser Met Pro Arg Met Leu Thr
1915 1920 1925
CTA TGG CTT GAT TAT GGT ACA AAG GCA TAT GAA TGG GAA AAA GCT GGC 6161
Leu Trp Leu Asp Tyr Gly Thr Lys Ala Tyr Glu Trp Glu Lys Ala Gly
1930 1935 1940
CGC TCC GAT CGT GTA CAA ATG AGG AAT GAT TTG GGT AAA ATA AAC AAG 6209
Arg Ser Asp Arg Val Gln Met Arg Asn Asp Leu Gly Lys Ile Asn Lys
1945 1950 1955
GTT ATC ACA GAG CAT ACA AAC TAT TTA GCT CCA TAT CAA TTT TTG ACT 6257
Val Ile Thr Glu His Thr Asn Tyr Leu Ala Pro Tyr Gln Phe Leu Thr
1960 1965 1970 1975
GCT TTT TCA CAA TTG ATC TCT CGA ATT TGT CAT TCT CAC GAT GAA GTT 6305
Ala Phe Ser Gln Leu Ile Ser Arg Ile Cys His Ser His Asp Glu Val
1980 1985 1990
TTT GTT GTG CTT GAT GGA AAT AAT AGC CAA GTA TTT CTA GCC TAT CCT 6353
Phe Val Val Leu Asp Gly Asn Asn Ser Gln Val Phe Leu Ala Tyr Pro
1995 2000 2005
CAA CAA GCA ATG TGG ATG ATG ACA GCT GTG TCA AAG TCA TCT TAT CCC 6401
Gln Gln Ala Met Trp Met Met Thr Ala Val Ser Lys Ser Ser Tyr Pro
2010 2015 2020
ATG CGT GTG AAC AGA TGC AAG GAA ATC CTC AAT AAA GCT ATT CAT ATG 6449
Met Arg Val Asn Arg Cys Lys Glu Ile Leu Asn Lys Ala Ile His Met
2025 2030 2035
AAA AAA TCC TTA GAG AAG TTT GTT GGA GAT GCA ACT CGC CTA ACA GAT 6497
Lys Lys Ser Leu Glu Lys Phe Val Gly Asp Ala Thr Arg Leu Thr Asp
2040 2045 2050 2055
AAG CTT CTA GAA TTG TGC AAT AAA CCG GTG GAA ATT CTT GCT TCT CTT 6545
Lys Leu Leu Glu Leu Cys Asn Lys Pro Val Glu Ile Leu Ala Ser Leu
2060 2065 2070
CAG AAA CCA AAG AAG ATT TCT TTA AAA GGC TCA GAT GGA AAG TTC TAC 6593
Gln Lys Pro Lys Lys Ile Ser Leu Lys Gly Ser Asp Gly Lys Phe Tyr
2075 2080 2085
ATC ATG ATG TGT AAG CCA AAA GAT GAC CTG AGA AAG GAT TGT AGA CTA 6641
Ile Met Met Cys Lys Pro Lys Asp Asp Leu Arg Lys Asp Cys Arg Leu
2090 2095 2100
ATG GAA TTC AAT TCC TTG ATT AAT AAG TGC TTA AGA AAA GAT GCA GAG 6689
Met Glu Phe Asn Ser Leu Ile Asn Lys Cys Leu Arg Lys Asp Ala Glu
2105 2110 2115
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TCT CGT AGA AGA GAA CTT CAT ATT CGA ACA TAT GCA GTT ATT CCA CTA 6737
Ser Arg Arg Arg Glu Leu His Ile Arg Thr Tyr Ala Val Ile Pro Leu
2120 2125 2130 2135
AAT GAT GAA TGT GGG ATT ATT GAA TGG GTG AAC AAC ACT GCT GGT TTG 6785
Asn Asp Glu Cys Gly Ile Ile Glu Trp Val Asn Asn Thr Ala Gly Leu
2140 2145 2150
AGA CCT ATT CTG ACC AAA CTA TAT AAA GAA AAG GGA GTG TAT ATG ACA 6833
Arg Pro Ile Leu Thr Lys Leu Tyr Lys Glu Lys Gly Val Tyr Met Thr
2155 2160 2165
GGA AAA GAA CTT CGC CAG TGT ATG CTA CCA AAG TCA GCA GCT TTA TCT 6881
Gly Lys Glu Leu Arg Gln Cys Met Leu Pro Lys Ser Ala Ala Leu Ser
2170 2175 2180
GAA AAA CTC AAA GTA TTC CGA GAA TTT CTC CTG CCC AGG CAT CCT CCT 6929
Glu Lys Leu Lys Val Phe Arg Glu Phe Leu Leu Pro Arg His Pro Pro
2185 2190 2195
ATT TTT CAT GAG TGG TTT CTG AGA ACA TTC CCT GAT CCT ACA TCA TGG 6977
Ile Phe His Glu Trp Phe Leu Arg Thr Phe Pro Asp Pro Thr Ser Trp
2200 2205 2210 2215
TAC AGT AGT AGA TCA GCT TAC TGC CGT TCC ACT GCA GTA ATG TCA ATG 7025
Tyr Ser Ser Arg Ser Ala Tyr Cys Arg Ser Thr Ala Val Met Ser Met
2220 2225 2230
GTT GGT TAT ATT CTG GGG CTT GGA GAC CGT CAT GGT GAA AAT ATT CTC 7073
Val Gly Tyr Ile Leu Gly Leu Gly Asp Arg His Gly Glu Asn Ile Leu
2235 2240 2245
TTT GAT TCT TTG ACT GGT GAA TGC GTA CAT GTA GAT TTC AAT TGT CTT 7121
Phe Asp Ser Leu Thr Gly Glu Cys Val His Val Asp Phe Asn Cys Leu
2250 2255 2260
TTC AAT AAG GGA GAA ACC TTT GAA GTT CCA GAA ATT GTG CCA TTT CGC 7169
Phe Asn Lys Gly Glu Thr Phe Glu Val Pro Glu Ile Val Pro Phe Arg
2265 2270 2275
CTG ACT CAT AAT ATG GTT AAT GGA ATG GGT CCT ATG GGA ACA GAG GGT 7217
Leu Thr His Asn Met Val Asn Gly Met Gly Pro Met Gly Thr Glu Gly
2280 2285 2290 2295
CTT TTT CGA AGA GCA TGT GAA GTT ACA ATG AGG CTG ATG CGT GAT CAG 7265
Leu Phe Arg Arg Ala Cys Glu Val Thr Met Arg Leu Met Arg Asp Gln
2300 2305 2310
CGA GAG CCT TTA ATG AGT GTC TTA AAG ACT TTT CTA CAT GAT CCT CTT 7313
Arg Glu Pro Leu Met Ser Val Leu Lys Thr Phe Leu His Asp Pro Leu
2315 2320 2325
GTG GAA TGG AGT AAA CCA GTG AAA GGG CAT TCC AAA GCG CCA CTG AAT 7361
Val Glu Trp Ser Lys Pro Val Lys Gly His Ser Lys Ala Pro Leu Asn
2330 2335 2340
GAA ACT GGA GAA GTT GTC AAT GAA AAG GCC AAG ACC CAT GTT CTT GAC 7409
Glu Thr Gly Glu Val Val Asn Glu Lys Ala Lys Thr His Val Leu Asp
2345 2350 2355
ATT GAG CAG CGA CTA CAA GGT GTA ATC AAG ACT CGA AAT AGA GTG ACA 7457
Ile Glu Gln Arg Leu Gln Gly Val Ile Lys Thr Arg Asn Arg Val Thr
2360 2365 2370 2375
GGA CTG CCG TTA TCT ATT GAA GGA CAT GTG CAT TAC CTT ATA CAA GAA 7505
Gly Leu Pro Leu Ser Ile Glu Gly His Val His Tyr Leu Ile Gln Glu
2380 2385 2390
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GCT ACT GAT GAA AAC TTA CTA TGC CAG ATG TAT CTT GGT TGG ACT CCA 7553
Ala Thr Asp Glu Asn Leu Leu Cys Gln Met Tyr Leu Gly Trp Thr Pro
2395 2400 2405
TAT ATG TGAAATGAAA TTATGTAAAA GAATATGTTA ATAATCTAAA AGTAAAAAAA 7609
Tyr Met
AAAAAAAAAA AA 7621
(2) INFORMATION FOR SEQ ID NO:2:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2409 amino acids
(B) TYPE: amino acid
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: protein
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:
Met Gly His Ala Val Glu Trp Pro Val Val Met Ser Arg Phe Leu Ser
1 5 10 15
Gln Leu Asp Glu His Met Gly Tyr Leu Gin Ser Ala Pro Leu Gln Leu
20 25 30
Met Ser Met Gln Lys Leu Glu Phe Ile Glu Val Thr Leu Leu Thr Val
35 40 45
Leu Thr Arg Ile Ile Ala Ile Val Phe Phe Arg Arg Gln Glu Leu Leu
50 55 60
Leu Trp Gln Ile Gly Cys Val Leu Leu Glu Tyr Gly Ser Pro Lys Ile
65 70 75 80
Lys Ser Leu Ala Ile Ser Phe Leu Thr Glu Leu Phe Gln Leu Gly Gly
85 90 95
Leu Pro Ala Gln Pro Ala Ser Thr Phe Phe Ser Ser Phe Leu Glu Leu
100 105 110
Leu Lys His Leu Val Glu Met Asp Thr Asp Gln Leu Lys Leu Tyr Glu
115 120 125
Glu Pro Leu Ser Lys Leu Ile Lys Thr Leu Phe Pro Phe Glu Ala Glu
130 135 140
Ala Tyr Arg Asn Ile Glu Pro Val Tyr Leu Asn Met Leu Leu Glu Lys
145 150 155 160
Leu Cys Val Met Phe Glu Asp Gly Val Leu Met Arg Leu Lys Ser Asp
165 170 175
Leu Leu Lys Ala Ala Leu Cys His Leu Leu Gln Tyr Phe Leu Lys Phe
180 185 190
Val Pro Ala Gly Tyr Glu Ser Ala Leu Gln Val Arg Lys Val Tyr Val
195 200 205
Arg Asn Ile Cys Lys Ala Leu Leu Asp Val Leu Gly Ile Glu Val Asp
210 215 220
Ala Glu Tyr Leu Leu Gly Pro Leu Tyr Ala Ala Leu Lys Met Glu Ser
225 230 235 240
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Met Glu Ile Ile Glu Glu Ile Gln Cys Gln Thr Gln Gln Glu Asn Leu
245 250 255
Ser Ser Asn Ser Asp Gly Ile Ser Pro Lys Arg Arg Arg Leu Ser Ser
260 265 270
Ser Leu Asn Pro Ser Lys Arg Ala Pro Lys Gln Thr Glu Glu Ile Lys
275 280 285
His Val Asp Met Asn Gln Lys Ser Ile Leu Trp Ser Ala Leu Lys Gln
290 295 300
Lys Ala Glu Ser Leu Gln Ile Ser Leu Glu Tyr Ser Gly Leu Lys Asn
305 310 315 320
Pro Val Ile Glu Met Leu Glu Gly Ile Ala Val Val Leu Gln Leu Thr
325 330 335
Ala Leu Cys Thr Val His Cys Ser His Gln Asn Met Asn Cys Arg Thr
340 345 350
Phe Lys Asp Cys Gln His Lys Ser Lys Lys Lys Pro Ser Val Val Ile
355 360 365
Thr Trp Met Ser Leu Asp Phe Tyr Thr Thr Val Leu Lys Ser Cys Arg
370 375 380
Arg Leu Leu Glu Ser Val Gln Lys Arg Thr Gly Gly Asn Ile Asp Lys
385 390 395 400
Val Val Lys Ile Tyr Asp Ala Leu Ile Tyr Met Gln Val Asn Ser Ser
405 410 415
Phe Glu Asp His Ile Leu Glu Asp Leu Cys Gly Met Leu Ser Leu Pro
420 425 430
Trp Ile Tyr Ser His Ser Asp Asp Gly Cys Leu Lys Leu Thr Thr Phe
435 440 445
Ala Ala Asn Leu Leu Thr Leu Ser Cys Arg Ile Ser Asp Ser Tyr Ser
450 455 460
Pro Gln Ala Gln Ser Arg Cys Val Phe Leu Leu Thr Leu Phe Pro Arg
465 470 475 480
Arg Ile Phe Leu Glu Trp Arg Thr Ala Val Tyr Asn Trp Ala Leu Gln
485 490 495
Ser Ser His Glu Val Ile Arg Ala Ser Cys Val Ser Gly Phe Phe Ile
500 505 510
Leu Leu Gln Gln Gln Asn Ser Cys Asn Arg Val Pro Lys Ile Leu Ile
515 520 525
Asp Lys Val Lys Asp Asp Ser Asp Ile Val Lys Lys Glu Phe Ala Ser
530 535 540
Ile Leu Gly Gln Leu Val Cys Thr Leu His Gly Met Phe Tyr Leu Thr
545 550 555 560
Ser Ser Leu Thr Glu Pro Phe Ser Glu His Gly His Val Asp Leu Phe
565 570 575
Cys Arg Asn Leu Lys Ala Thr Ser Gln His Glu Cys Ser Ser Ser Gln
580 585 590
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Leu Lys Ala Ser Val Cys Lys Pro Phe Leu Phe Leu Leu Lys Lys Lys
595 600 605
Ile Pro Ser Pro Val Lys Leu Ala Phe Ile Asp Asn Leu His His Leu
610 615 620
Cys Lys His Leu Asp Phe Arg Glu Asp Glu Thr Asp Val Lys Ala Val
625 630 635 640
Leu Gly Thr Leu Leu Asn Leu Met Glu Asp Pro Asp Lys Asp Val Arg
645 650 655
Val Ala Phe Ser Gly Asn Ile Lys His Ile Leu Glu Ser Leu Asp Ser
660 665 670
Glu Asp Gly Phe Ile Lys Glu Leu Phe Val Leu Arg Met Lys Glu Ala
675 680 685
Tyr Thr His Ala Gln Ile Ser Arg Asn Asn Glu Leu Lys Asp Thr Leu
690 695 700
Ile Leu Thr Thr Gly Asp Ile Gly Arg Ala Ala Lys Gly Asp Leu Val
705 710 715 720
Pro Phe Ala Leu Leu His Leu Leu His Cys Leu Leu Ser Lys Ser Ala
725 730 735
Ser Val Ser Gly Ala Ala Tyr Thr Glu Ile Arg Ala Leu Val Ala Ala
740 745 750
Lys Ser Val Lys Leu Gln Ser Phe Phe Ser Gln Tyr Lys Lys Pro Ile
755 760 765
Cys Gln Phe Leu Val Glu Ser Leu His Ser Ser Gln Met Thr Ala Leu
770 775 780
Pro Asn Thr Pro Cys Gln Asn Ala Asp Val Arg Lys Gln Asp Val Ala
785 790 795 800
His Gln Arg Glu Met Ala Leu Asn Thr Leu Ser Glu Ile Ala Asn Val
805 810 815
Phe Asp Phe Pro Asp Leu Asn Arg Phe Leu Thr Arg Thr Leu Gln Val
820 825 830
Leu Leu Pro Asp Leu Ala Ala Lys Ala Ser Pro Ala Ala Ser Ala Leu
835 840 845
Ile Arg Thr Leu Gly Lys Gln Leu Asn Val Asn Arg Arg Glu Ile Leu
850 855 860
Ile Asn Asn Phe Lys Tyr Ile Phe Ser His Leu Vai Cys Ser Cys Ser
865 870 875 880
Lys Asp Glu Leu Glu Arg Ala Leu His Tyr Leu Lys Asn Glu Thr Glu
885 890 895
Ile Glu Leu Gly Ser Leu Leu Arg Gln Asp Phe Gln Gly Leu His Asn
900 905 910
Glu Leu Leu Leu Arg Ile Gly Glu His Tyr Gln Gln Val Phe Asn Gly
915 920 925
Leu Ser Ile Leu Ala Ser Phe Ala Ser Ser Asp Asp Pro Tyr Gin Gly
930 935 940
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Pro Arg Asp Ile Ile Ser Pro Glu Leu Met Ala Asp Tyr Leu Gln Pro
945 950 955 960
Lys Leu Leu Gly Ile Leu Ala Phe Phe Asn Met Gln Leu Leu Ser Ser
965 970 975
Ser Val Gly Ile Glu Asp Lys Lys Met Ala Leu Asn Ser Leu Met Ser
980 985 990
Leu Met Lys Leu Met Gly Pro Lys His Val Ser Ser Val Arg Val Lys
995 1000 1005
Met Met Thr Thr Leu Arg Thr Gly Leu Arg Phe Lys Asp Asp Phe Pro
1010 1015 1020
Glu Leu Cys Cys Arg Ala Trp Asp Cys Phe Val Arg Cys Leu Asp His
1025 1030 1035 1040
Ala Cys Leu Gly Ser Leu Leu Ser His Val Ile Val Ala Leu Leu Pro
1045 1050 1055
Leu Ile His Ile Gln Pro Lys Glu Thr Ala Ala Ile Phe His Tyr Leu
1060 1065 1070
Ile Ile Glu Asn Arg Asp Ala Val Gln Asp Phe Leu His Glu Ile Tyr
1075 1080 1085
Phe Leu Pro Asp His Pro Glu Leu Lys Lys Ile Lys Ala Val Leu Gln
1090 1095 1100
Glu Tyr Arg Lys Glu Thr Ser Glu Ser Thr Asp Leu Gln Thr Thr Leu
1105 1110 1115 1120
Gln Leu Ser Met Lys Ala Ile Gln His Glu Asn Val Asp Val Arg Ile
1125 1130 1135
His Ala Leu Thr Ser Leu Lys Glu Thr Leu Tyr Lys Asn Gln Glu Lys
1140 1145 1150
Leu Ile Lys Tyr Ala Thr Asp Ser Glu Thr Val Glu Pro Ile Ile Ser
1155 1160 1165
Gln Leu Val Thr Val Leu Leu Lys Gly Cys Gln Asp Ala Asn Ser Gln
1170 1175 1180
Ala Arg Leu Leu Cys Gly Glu Cys Leu Gly Glu Leu Gly Ala Ile Asp
1185 1190 1195 1200
Pro Gly Arg Leu Asp Phe Ser Thr Thr Glu Thr Gln Gly Lys Asp Phe
1205 1210 1215
Thr Phe Val Thr Gly Val Glu Asp Ser Ser Phe Ala Tyr Gly Leu Leu
1220 1225 1230
Met Glu Leu Thr Arg Ala Tyr Leu Ala Tyr Ala Asp Asn Ser Arg Ala
1235 1240 1245
Pro Asp Ser Ala Ala Tyr Ala Ile Gln Glu Leu Leu Ser Ile Tyr Asp
1250 1255 1260
Cys Arg Glu Met Glu Thr Asn Gly Pro Gly His Gln Leu Trp Arg Arg
1265 1270 1275 1280
Phe Pro Glu His Val Arg Glu Ile Leu Glu Pro His Leu Asn Thr Arg
1285 1290 1295
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Tyr Lys Ser Ser Gln Lys Ser Thr Asp Trp Ser Gly Val Lys Lys Pro
1300 1305 1310
Ile Tyr Leu Ser Lys Leu Gly Ser Asn Phe Ala Glu Trp Ser Ala Ser
1315 1320 1325
Trp Ala Gly Tyr Leu Ile Thr Lys Val Arg His Asp Leu Ala Ser Lys
1330 1335 1340
Ile Phe Thr Cys Cys Ser Ile Met Met Lys His Asp Phe Lys Val Thr
1345 1350 1355 1360
Ile Tyr Leu Leu Pro His Ile Leu Val Tyr Val Leu Leu Gly Cys Asn
1365 1370 1375
Gln Glu Asp Gln Gln Glu Val Tyr Ala Glu Ile Met Ala Val Leu Lys
1380 1385 1390
His Asp Asp Gin His Thr Ile Asn Thr Gln Asp Ile Ala Ser Asp Leu
1395 1400 1405
Cys Gln Leu Ser Thr Gln Thr Val Phe Ser Met Leu Asp His Leu Thr
1410 1415 1420
Gln Trp Ala Arg His Lys Phe Gln Ala Leu Lys Ala Glu Lys Cys Pro
1425 1430 1435 1440
His Ser Lys Ser Asn Arg Asn Lys Val Asp Ser Met Val Ser Thr Val
1445 1450 1455
Asp Tyr Glu Asp Tyr Gln Ser Val Thr Arg Phe Leu Asp Leu Ile Pro
1460 1465 1470
Gln Asp Thr Leu Ala Val Ala Ser Phe Arg Ser Lys Ala Tyr Thr Arg
1475 1480 1485
i ~~ ~ Al~ u Met yi Y~~~~~pV~ OC).~f%A$~~e~'Oa~~l{~fA ^~e ~
hEMB# o"iDMu-eI~~A~oAS aa a 2 v_ .~ uzv &~''uR
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Gln Val Phe Leu Ala Tyr Pro Gln Gln Ala Met Trp Met Met Thr Ala
2005 2010 2015
Val Ser Lys Ser Ser Tyr Pro Met Arg Val Asn Arg Cys Lys Glu Ile
2020 2025 2030
Leu Asn Lys Ala Ile His Met Lys Lys Ser Leu Glu Lys Phe Val Gly
2035 2040 2045
Asp Ala Thr Arg Leu Thr Asp Lys Leu Leu Glu Leu Cys Asn Lys Pro
2050 2055 2060
Val Glu Ile Leu Ala Ser Leu Gln Lys Pro Lys Lys Ile Ser Leu Lys
2065 2070 2075 2080
Gly Ser Asp Gly Lys Phe Tyr Ile Met Met Cys Lys Pro Lys Asp Asp
2085 2090 2095
Leu Arg Lys Asp Cys Arg Leu Met Glu Phe Asn Ser Leu Ile Asn Lys
2100 2105 2110
Cys Leu Arg Lys Asp Ala Glu Ser Arg Arg Arg Glu Leu His Ile Arg
2115 2120 2125
Thr Tyr Ala Val Ile Pro Leu Asn Asp Glu Cys Gly Ile Ile Glu Trp
2130 2135 2140
Val Asn Asn Thr Ala Gly Leu Arg Pro Ile Leu Thr Lys Leu Tyr Lys
2145 2150 2155 2160
Glu Lys Gly Val Tyr Met Thr Gly Lys Glu Leu Arg Gin Cys Met Leu
2165 2170 2175
Pro Lys Ser Ala Ala Leu Ser Glu Lys Leu Lys Val Phe Arg Glu Phe
2180 2185 2190
Leu Leu Pro Arg His Pro Pro Ile Phe His Glu Trp Phe Leu Arg Thr
2195 2200 2205
Phe Pro Asp Pro Thr Ser Trp Tyr Ser Ser Arg Ser Ala Tyr Cys Arg
2210 2215 2220
Ser Thr Ala Val Met Ser Met Val Gly Tyr Ile Leu Gly Leu Gly Asp
2225 2230 2235 2240
Arg His Gly Glu Asn Ile Leu Phe Asp Ser Leu Thr Gly Glu Cys Val
2245 2250 2255
His Val Asp Phe Asn Cys Leu Phe Asn Lys Gly Glu Thr Phe Glu Val
2260 2265 2270
Pro Glu Ile Val Pro Phe Arg Leu Thr His Asn Met Val Asn Gly Met
2275 2280 2285
Gly Pro Met Gly Thr Glu Gly Leu Phe Arg Arg Ala Cys Glu Val Thr
2290 2295 2300
Met Arg Leu Met Arg Asp Gln Arg Glu Pro Leu Met Ser Val Leu Lys
2305 2310 2315 2320
Thr Phe Leu His Asp Pro Leu Val Glu Trp Ser Lys Pro Val Lys Gly
2325 2330 2335
His Ser Lys Ala Pro Leu Asn Glu Thr Gly Glu Val Val Asn Glu Lys
2340 2345 2350
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Ala Lys Thr His Val Leu Asp Ile Glu Gln Arg Leu Gln Gly Val Ile
2355 2360 2365
Lys Thr Arg Asn Arg Val Thr Gly Leu Pro Leu Ser Ile Glu Gly His
2370 2375 2380
Val His Tyr Leu Ile Gln Glu Ala Thr Asp Glu Asn Leu Leu Cys Gln
2385 2390 2395 2400
Met Tyr Leu Gly Trp Thr Pro Tyr Met
2405
(2) INFORMATION FOR SEQ ID NO:3:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2835 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: cDNA
( vi i ) IMMEDIATE SOURCE :
(B) CLONE: 517
(ix) FEATURE:
(A) NAME/KEY: CDS
(B) LOCATION: 1..2610
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:
GTG GAA GCA GCT TGG AAA TTG TCA CAG TGG GAT TTG GTG GAA AAC TAT 48
Val Glu Ala Ala Trp Lys Leu Ser Gln Trp Asp Leu Val Glu Asn Tyr
1 5 10 15
TTG GCA GCA GAT GGA AAA TCT ACA ACA TGG AGT GTC AGA CTG GGA CAG 96
Leu Ala Ala Asp Gly Lys Ser Thr Thr Trp Ser Val Arg Leu Gly Gln
20 25 30
CTA TTA TTA TCA GCC AAA AAA AGA GAT ATC ACA GCT TTT TAT GAC TCA 144
Leu Leu Leu Ser Ala Lys Lys Arg Asp Ile Thr Ala Phe Tyr Asp Ser
35 40 45
CTG AAA CTA GTG AGA GCA GAA CAA ATT GTA CCT CTT TCA GCT GCA AGC 192
Leu Lys Leu Val Arg Ala Glu Gln Ile Val Pro Leu Ser Ala Ala Ser
50 55 60
TTT GAA AGA GGC TCC TAC CAA CGA GGA TAT GAA TAT ATT GTG AGA TTG 240
Phe Glu Arg Gly Ser Tyr Gln Arg Gly Tyr Glu Tyr Ile Val Arg Leu
65 70 75 80
CAC ATG TTA TGT GAG TTG GAG CAT AGC ATC AAA CCA CTT TTC CAG CAT 288
His Met Leu Cys Glu Leu Glu His Ser Ile Lys Pro Leu Phe Gln His
85 90 95
TCT CCA GGT GAC AGT TCT CAA GAA GAT TCT CTA AAC TGG GTA GCT CGA 336
Ser Pro Gly Asp Ser Ser Gln Glu Asp Ser Leu Asn Trp Val Ala Arg
100 105 110
CTA GAA ATG ACC CAG AAT TCC TAC AGA GCC AAG GAG CCT ATC CTG GCT 384
Leu Glu Met Thr Gln Asn Ser Tyr Arg Ala Lys Glu Pro Ile Leu Ala
115 120 125
.
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CTC CGG AGG GCT TTA CTA AGC CTC AAC AAA AGA CCA GAT TAC AAT GAA 432
Leu Arg Arg Ala Leu Leu Ser Leu Asn Lys Arg Pro Asp Tyr Asn Glu
130 135 140
ATG GTT GGA GAA TGC TGG CTG CAG AGT GCC AGG GTA GCT AGA AAG GCT 480
Met Val Gly Glu Cys Trp Leu Gln Ser Ala Arg Val Ala Arg Lys Ala
145 150 155 160
GGT CAC CAC CAG ACA GCC TAC AAT GCT CTC CTT AAT GCA GGG GAA TCA 528
Gly His His Gln Thr Ala Tyr Asn Ala Leu Leu Asn Ala Gly Glu Ser
165 170 175
CGA CTC GCT GAA CTG TAC GTG GAA AGG GCA AAG TGG CTC TGG TCC AAG 576
Arg Leu Ala Glu Leu Tyr Val Glu Arg Ala Lys Trp Leu Trp Ser Lys
180 185 190
GGT GAT GTT CAC CAG GCA CTA ATT GTT CTT CAA AAA GGT GTT GAA TTA 624
Gly Asp Val His Gln Ala Leu Ile Val Leu Gln Lys Gly Val Glu Leu
195 200 205
TGT TTT CCT GAA AAT GAA ACC CCA CCT GAG GGT AAG AAC ATG TTA ATC 672
Cys Phe Pro Glu Asn Glu Thr Pro Pro Glu Gly Lys Asn Met Leu Ile
210 215 220
CAT GGT CGA GCT ATG CTA CTA GTG GGC CGA TTT ATG GAA GAA ACA GCT 720
His Gly Arg Ala Met Leu Leu Val Gly Arg Phe Met Glu Glu Thr Ala
225 230 235 240
AAC TTT GAA AGC AAT GCA ATT ATG AAA AAA TAT AAG GAT GTG ACC GCG 768
Asn Phe Glu Ser Asn Ala Ile Met Lys Lys Tyr Lys Asp Val Thr Ala
245 250 255
TGC CTG CCA GAA TGG GAG GAT GGG CAT T'I'T TAC CTT GCC AAG TAC TAT 816
Cys Leu Pro Glu Trp Glu Asp Gly His Phe Tyr Leu Ala Lys Tyr Tyr
260 265 270
GAC AAA TTG ATG CCC ATG GTC ACA GAC AAC AAA ATG GAA AAG CAA GGT 864
Asp Lys Leu Met Pro Met Val Thr Asp Asn Lys Met Glu Lys Gln Gly
275 280 285
GAT CTC ATC CGG TAT ATA GTT CTT CAT TTT GGC AGA TCT CTA CAA TAT 912
Asp Leu Ile Arg Tyr Ile Val Leu His Phe Gly Arg Ser Leu Gln Tyr
290 295 300
GGA AAT CAG TTC ATA TAT CAG TCA ATG CCA CGA ATG TTA ACT CTA TGG 960
Gly Asn Gln Phe Ile Tyr Gln Ser Met Pro Arg Met Leu Thr Leu Trp
305 310 315 320
CTT GAT TAT GGT ACA AAG TCA TAT GAA TGG GAA AAA GCT GGC CGC TCC 1008
Leu Asp Tyr Gly Thr Lys Ser Tyr Glu Trp Glu Lys Ala Gly Arg Ser
325 330 335
GAT CGT GTA CAA ATG AGG AAT GAT TTG GGT AAA ATA AAC AAG GTT ATC 1056
Asp Arg Val Gln Met Arg Asn Asp Leu Gly Lys Ile Asn Lys Val Ile
340 345 350
ACA GAG CAT ACA AAC TAT TTA GCT CCA TAT CAA TTT TI'G ACT GCT TTT 1104
Thr Glu His Thr Asn Tyr Leu Ala Pro Tyr Gln Phe Leu Thr Ala Phe
355 360 365
TCA CAA TTG ATC TCT CGA ATT TGT CAT TCT CAC GAT GAA GTT TTT GTT 1152
Ser Gln Leu Ile Ser Arg Ile Cys His Ser His Asp Glu Val Phe Val
370 375 380
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GTC TTG ATG GAA ATA ATA GCC AAA GTA TTT CTA GCC TAT CCT CAA CAA 1200
Val Leu Met Glu Ile Ile Ala Lys Val Phe Leu Ala Tyr Pro Gln Gln
385 390 395 400
GCA ATG TGG ATG ATG ACA GCT GTG TCA AAG TCA TCT TAT CCC ATG CGT 1248
Ala Met Trp Met Met Thr Ala Val Ser Lys Ser Ser Tyr Pro Met Arg
405 410 415
GTG AAC AGA TGC AAG GAA ATC CTC AAT AAA GCT ATT CAT ATG AAA AAA 1296
Val Asn Arg Cys Lys Glu Ile Leu Asn Lys Ala Ile His Met Lys Lys
420 425 430
TCC TTA GAG AAG TTT GTT GGA GAT GCA ACT CGC CTA ACA GAT AAG CTT 1344
Ser Leu Glu Lys Phe Val Gly Asp Ala Thr Arg Leu Thr Asp Lys Leu
435 440 445
CTA GAA TTG TGC AAT AAA CCG GTT GAT GGA AGT AGT TCC ACA TTA AGC 1392
Leu Glu Leu Cys Asn Lys Pro Val Asp Gly Ser Ser Ser Thr Leu Ser
450 455 460
ATG AGC ACT CAT TTT AAA ATG CTT AAA AAG CTG GTA GAA GAA GCA ACA 1440
Met Ser Thr His Phe Lys Met Leu Lys Lys Leu Val Glu Glu Ala Thr
465 470 475 480
TTT AGT GAA ATC CTC ATT CCT CTA CAA TCA GTC ATG ATA CCT ACA CTT 1488
Phe Ser Glu Ile Leu Ile Pro Leu Gln Ser Val Met Ile Pro Thr Leu
485 490 495
CCA TCA ATT CTG GGT ACC CAT GCT AAC CAT GCT AGC CAT GAA CCA TTT 1536
Pro Ser Ile Leu Gly Thr His Ala Asn His Ala Ser His Glu Pro Phe
500 505 510
CCT GGA CAT TGG GCC TAT ATT GCA GGG TTT GAT GAT ATG GTG GAA A'I'I' 1584
Pro Gly His Trp Ala Tyr Ile Ala Gly Phe Asp Asp Met Val Glu Ile
515 520 525
CTT GCT TCT CTT CAG AAA CCA AAG AAG ATT TCT TTA AAA GGC TCA GAT 1632
Leu Ala Ser Leu Gln Lys Pro Lys Lys Ile Ser Leu Lys Gly Ser Asp
530 535 540
GGA AAG TTC TAC ATC ATG ATG TGT AAG CCA AAA GAT GAC CTG AGA AAG 1680
Gly Lys Phe Tyr Ile Met Met Cys Lys Pro Lys Asp Asp Leu Arg Lys
545 550 555 560
GAT TGT AGA CTA ATG GAA TTC AAT TCC TTG ATT AAT AAG TGC TTA AGA 1728
Asp Cys Arg Leu Met Glu Phe Asn Ser Leu Ile Asn Lys Cys Leu Arg
565 570 575
AAA GAT GCA GAG TCT CGT AGA AGA GAA CTT CAT ATT CGA ACA TAT GCA 1776
Lys Asp Ala Glu Ser Arg Arg Arg Glu Leu His Ile Arg Thr Tyr Ala
580 585 590
GTT ATT CCA CTA AAT GAT GAA TGT GGG ATT ATT GAA TGG GTG AAC AAC 1824
Val Ile Pro Leu Asn Asp Glu Cys Gly Ile Ile Glu Trp Val Asn Asn
595 600 605
ACT GCT GGT TTG AGA CCT ATT CTG ACC AAA CTA TAT AAA GAA AAG GGA 1872
Thr Ala Gly Leu Arg Pro Ile Leu Thr Lys Leu Tyr Lys Glu Lys Gly
610 615 620
GTG TAT ATG ACA GGA AAA GAA CTT CGC CAG TGT ATG CTA CCA AAG TCA 1920
Val Tyr Met Thr Gly Lys Glu Leu Arg Gln Cys Met Leu Pro Lys Ser
625 630 635 640
GCA GCT TTA TCT GAA AAA CTC AAA GTA TTC CGA GAA TTT CTC CTG CCC 1968
Ala Ala Leu Ser Glu Lys Leu Lys Val Phe Arg Glu Phe Leu Leu Pro
645 650 655
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AGG CAT CCT CCT ATT TTT CAT GAG TGG TTT CTG AGA ACA TTC CCT GAT 2016
Arg His Pro Pro Ile Phe His Glu Trp Phe Leu Arg Thr Phe Pro Asp
660 665 670
CCT ACA TCA TGG TAC AGT AGT AGA TCA GCT TAC TGC CGT TCC ACT GCA 2064
Pro Thr Ser Trp Tyr Ser Ser Arg Ser Ala Tyr Cys Arg Ser Thr Ala
675 680 685
GTA ATG TCA ATG GTT GGT TAT ATT CTG GGG CTT GGA GAC CGT CAT GGT 2112
Val Met Ser Met Val Gly Tyr Ile Leu Gly Leu Gly Asp Arg His Gly
690 695 700
GAA AAT ATT CTC TIT GAT TCT TTG ACT GGT GAA TGC GTA CAT GTA GAT 2160
Glu Asn Ile Leu Phe Asp Ser Leu Thr Gly Glu Cys Val His Val Asp
705 710 715 720
TTC AAT TGT CTT TTC AAT AAG GGA GAA ACC TTT GAA GTT CCA GAA ATT 2208
Phe Asn Cys Leu Phe Asn Lys Gly Glu Thr Phe Glu Val Pro Glu Ile
725 730 735
GTG CCA TTT CGC CTG ACT CAT AAT ATG GTT AAT GGA ATG GGT CCT ATG 2256
Val Pro Phe Arg Leu Thr His Asn Met Val Asn Gly Met Gly Pro Met
740 745 750
GGA ACA GAG GGT CTT TTT CGA AGA GCA TGT GAA GTT ACA ATG AGG CTG 2304
Gly Thr Glu Gly Leu Phe Arg Arg Ala Cys Glu Val Thr Met Arg Leu
755 760 765
ATG CGT GAT CAG CGA GAG CCT TTA ATG AGT GTC TTA AAG ACT TTT CTA 2352
Met Arg Asp Gln Arg Glu Pro Leu Met Ser Val Leu Lys Thr Phe Leu
770 775 780
CAT GAT CCT CTT GTG GAA TGG AGT AAA CCA GTG AAA GGG CAT TCC AAA 2400
His Asp Pro Leu Val Glu Trp Ser Lys Pro Val Lys Gly His Ser Lys
785 790 795 900
GCG CCA CTG AAT GAA ACT GGA GAA GTT GTC AAT GAA AAG GCC AAG ACC 2448
Ala Pro Leu Asn Glu Thr Gly Glu Val Val Asn Glu Lys Ala Lys Thr
805 810 815
CAT GTT CTT GAC ATT GAG CAG CGA CTA CAA GGT GTA ATC AAG ACT CGA 2496
His Val Leu Asp Ile Glu Gln Arg Leu Gln Gly Val Ile Lys Thr Arg
820 825 830
AAT AGA GTG ACA GGA CTG CCG TTA TCT ATT GAA GGA CAT GTG CAT TAC 2544
Asn Arg Val Thr Gly Leu Pro Leu Ser Ile Glu Gly His Val His Tyr
835 840 845
CTT ATA CAA GAA GCT ACT GAT GAA AAC TTA CTA TGC CAG ATG TAT CTT 2592
Leu Ile Gln Glu Ala Thr Asp Glu Asn Leu Leu Cys Gln Met Tyr Leu
850 855 860
GGT TGG ACT CCA TAT ATG TGAAATGAAA TTATGTAP.AA GAATATGTTA 2640
Gly Trp Thr Pro Tyr Met
865 870
ATAATCTAAA AGTAATGCAT TTGGTATGAA TCTGTGGTTG TATCTGTTCA ATTCTAAAGT 2700
ACAACATAAA TTTACGTTCT CAGCAACTGT TATTTCTCTC TGATCATTAA TTATATGTAA 2760
AATAATATAC ATTCAGTTAT TAAGAAATAA ACTGCTTTCT TAATAAAAAFI AAAAAAAAAA 2820
AAAAAAAAAA AAAAA 2835
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(2) INFORMATION FOR SEQ ID NO:4:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 870 amino acids
(B) TYPE: amino acid
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: protein
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:
Val Glu Ala Ala Trp Lys Leu Ser Gln Trp Asp Leu Val Glu Asn Tyr
1 5 10 15
Leu Ala Ala Asp Gly Lys Ser Thr Thr Trp Ser Val Arg Leu Gly Gln
20 25 30
Leu Leu Leu Ser Ala Lys Lys Arg Asp Ile Thr Ala Phe Tyr Asp Ser
35 40 45
Leu Lys Leu Val Arg Ala Glu Gln Ile Val Pro Leu Ser Ala Ala Ser
50 55 60
Phe Glu Arg Gly Ser Tyr Gln Arg Gly Tyr Glu Tyr Ile Val Arg Leu
65 70 75 80
His Met Leu Cys Glu Leu Glu His Ser Ile Lys Pro Leu Phe Gln His
85 90 95
Ser Pro Gly Asp Ser Ser Gln Glu Asp Ser Leu Asn Trp Val Ala Arg
100 105 110
Leu Glu Met Thr Gln Asn Ser Tyr Arg Ala Lys Glu Pro Ile Leu Ala
115 120 125
Leu Arg Arg Ala Leu Leu Ser Leu Asn Lys Arg Pro Asp Tyr Asn Glu
130 135 140
Met Val Gly Glu Cys Trp Leu Gln Ser Ala Arg Val Ala Arg Lys Ala
145 150 155 160
Gly His His Gln Thr Ala Tyr Asn Ala Leu Leu Asn Ala Gly Glu Ser
165 170 175
Arg Leu Ala Glu Leu Tyr Val Glu Arg Ala Lys Trp Leu Trp Ser Lys
180 185 190
Gly Asp Val His Gin Ala Leu Ile Val Leu Gin Lys Gly Vai Glu Leu
195 200 205
Cys Phe Pro Glu Asn Glu Thr Pro Pro Glu Gly Lys Asn Met Leu Ile
210 215 220
His Gly Arg Ala Met Leu Leu Val Gly Arg Phe Met Glu Glu Thr Ala
225 230 235 240
Asn Phe Glu Ser Asn Ala Ile Met Lys Lys Tyr Lys Asp Val Thr Ala
245 250 255
Cys Leu Pro Glu Trp Glu Asp Gly His Phe Tyr Leu Ala Lys Tyr Tyr
260 265 270
Asp Lys Leu Met Pro Met Val Thr Asp Asn Lys Met Glu Lys Gln Gly
275 280 285
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Asp Leu Ile Arg Tyr Ile Val Leu His Phe Gly Arg Ser Leu Gln Tyr
290 295 300
Gly Asn Gln Phe Ile Tyr Gln Ser Met Pro Arg Met Leu Thr Leu Trp
305 310 315 320
Leu Asp Tyr Gly Thr Lys Ser Tyr Glu Trp Glu Lys Ala Gly Arg Ser
325 330 335
Asp Arg Val Gln Met Arg Asn Asp Leu Gly Lys Ile Asn Lys Val Ile
340 345 350
Thr Glu His Thr Asn Tyr Leu Ala Pro Tyr Gln Phe Leu Thr Ala Phe
355 360 365
Ser Gln Leu Ile Ser Arg Ile Cys His Ser His Asp Glu Val Phe Val
370 375 380
Val Leu Met Glu Ile Ile Ala Lys Val Phe Leu Ala Tyr Pro Gln Gln
385 390 395 400
Ala Met Trp Met Met Thr Ala Val Ser Lys Ser Ser Tyr Pro Met Arg
405 410 415
Val Asn Arg Cys Lys Glu Ile Leu Asn Lys Ala Ile His Met Lys Lys
420 425 430
Ser Leu Glu Lys Phe Val Gly Asp Ala Thr Arg Leu Thr Asp Lys Leu
435 440 445
Leu Glu Leu Cys Asn Lys Pro Val Asp Gly Ser Ser Ser Thr Leu Ser
450 455 460
Met Ser Thr His Phe Lys Met Leu Lys Lys Leu Val Glu Glu Ala Thr
465 470 475 480
Phe Ser Glu Ile Leu Ile Pro Leu Gln Ser Val Met Ile Pro Thr Leu
485 490 495
Pro Ser Ile Leu Gly Thr His Ala Asn His Ala Ser His Glu Pro Phe
500 505 510
Pro Gly His Trp Ala Tyr Ile Ala Gly Phe Asp Asp Met Val Glu Ile
515 520 525
Leu Ala Ser Leu Gln Lys Pro Lys Lys Ile Ser Leu Lys Gly Ser Asp
530 535 540
Gly Lys Phe Tyr Ile Met Met Cys Lys Pro Lys Asp Asp Leu Arg Lys
545 550 555 560
Asp Cys Arg Leu Met Glu Phe Asn Ser Leu Ile Asn Lys Cys Leu Arg
565 570 575
Lys Asp Ala Glu Ser Arg Arg Arg Glu Leu His Ile Arg Thr Tyr Ala
580 585 590
Val Ile Pro Leu Asn Asp Glu Cys Gly Ile Ile Glu Trp Val Asn Asn
595 600 605
Thr Ala Gly Leu Arg Pro Ile Leu Tlir Lys Leu Tyr Lys Glu Lys Gly
610 615 620
Val Tyr Met Thr Gly Lys Glu Leu Arg Gln Cys Met Leu Pro Lys Ser
625 630 635 640
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Ala Ala Leu Ser Glu Lys Leu Lys Val Phe Arg Glu Phe Leu Leu Pro
645 650 655
Arg His Pro Pro Ile Phe His Glu Trp Phe Leu Arg Thr Phe Pro Asp
660 665 670
Pro Thr Ser Trp Tyr Ser Ser Arg Ser Ala Tyr Cys Arg Ser Thr Ala
675 680 685
Val Met Ser Met Val Gly Tyr Ile Leu Gly Leu Gly Asp Arg His Gly
690 695 700
Glu Asn Ile Leu Phe Asp Ser Leu Thr Gly Glu Cys Val His Val Asp
705 710 715 720
Phe Asn Cys Leu Phe Asn Lys Gly Glu Thr Phe Glu Val Pro Glu Ile
725 730 735
Val Pro Phe Arg Leu Thr His Asn Met Val Asn Gly Met Gly Pro Met
740 745 750
Gly Thr Glu Gly Leu Phe Arg Arg Ala Cys Glu Val Thr Met Arg Leu
755 760 765
Met Arg Asp Gln Arg Glu Pro Leu Met Ser Val Leu Lys Thr Phe Leu
770 775 780
His Asp Pro Leu Val Glu Trp Ser Lys Pro Val Lys Gly His Ser Lys
785 790 795 800
Ala Pro Leu Asn Glu Thr Gly Glu Val Val Asn Glu Lys Ala Lys Thr
805 810 815
His Val Leu Asp Ile Glu G1n Arg Leu Gln Gly Val Ile Lys Thr Arg
820 825 830
Asn Arg Val Thr Gly Leu Pro Leu Ser Ile Glu Gly His Val His Tyr
835 840 845
Leu Ile Gin Glu Ala Thr Asp Glu Asn Leu Leu Cys Gln Met Tyr Leu
850 855 860
Gly Trp Thr Pro Tyr Met
865 870
(2) INFORMATION FOR SEQ ID NO:5:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 33 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: DNA
(vii) IMMEDIATE SOURCE:
(B) CLONE: Primer oDHl5a
(ix) FEATURE:
(A) NAME/KEY: modified_base
(B) LOCATION: group(15, 18, 24, 30)
(D) OTHER INFORMATION: The nucleotides at these positions are
inosines.
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(xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:
GCAGACGGAT CCGGNWCNGA YGGNAAYHTN TAY 33
(2) INFORMATION FOR SEQ ID NO:6:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 27 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: DNA
(ix) FEATURE:
(A) NAME/KEY: modified_base
(B) LOCATION: group(15, 18, 24)
(D) OTHER INFORMATION: The nucleotides at these positions are
inosines.
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:
GCAGACGGAT CCGGNWCNGA YGGNAAY 27
(2) INFORMATION FOR SEQ ID NO:7:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 30 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: DNA
(vii) IMMEDIATE SOURCE:
(B) CLONE: Primer oDH16
(ix) FEATURE:
(A) NAME/KEY: modified_base
(B) LOCATION: 24
(D) OTHER INFORMATION: The nucleotides at these positions are
inosines.
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:
GCAGACGAAT TCRCARTYRA ARTCNACRTG 30
(2) INFORMATION FOR SEQ ID NO:8:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 41 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: DNA
(vii) IMMEDIATE SOURCE:
(B) CLONE: Primer oDH17a
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(ix) FEATURE:
(A) NAME/KEY: modified_base
(B) LOCATION: group(21, 24, 27, 30)
(D) OTHER INFORMATION: The nucleotides at these positions are
inosines.
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:
GCAGACGGAT CCAARTTYCC NCCNRTNYTN TAYSARTGGT T 41
(2) INFORMATION FOR SEQ ID NO:9:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 41 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: DNA
(vii) IMMEDIATE SOURCE:
(B) CLONE: Primer oDH17b
(ix) FEATURE:
(A) NAME/KEY: modifiedbase
(B) LOCATION: group(24, 27, 30, 33)
(D) OTHER INFORMATION: The nucleotides at these positions are
inosines.
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:
GCAGACGAAT CCAACCAYTS RTANARNAYN GGNGGRAAYT T 41
(2) INFORMATION FOR SEQ ID NO:10:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 32 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: DNA
(vii) IMMEDIATE SOURCE:
(B) CLONE: Primer oDH18a
(ix) FEATURE:
(A) NAME/KEY: modified_base
(B) LOCATION: group(15, 18, 21, 24, 30)
(D) OTHER INFORMATION: The nucleotides at these positions are
inosines.
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:
GCAGACGGAT CCYTNGGNYT NGGNGAYCGN CA 32
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(2) INFORMATION FOR SEQ ID NO:11:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 32 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: DNA
(vii) IMMEDIATE SOURCE:
(B) CLONE: Primer oDH18b
(ix) FEATURE:
(A) NAME/KEY: modifiedbase
(B) LOCATION: group(15, 18, 21)
(D) OTHER INFORMATION: The nucleotides at these positions are
inosines.
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:
GCAGACGGAT CCYTNGGNYT NGGNGAYAGR CA 32
(2) INFORMATION FOR SEQ ID NO:12:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 33 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: DNA
(vii) IMMEDIATE SOURCE:
(B) CLONE: Primer oDH23
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:
GACGCAGAAT TCACCAGTCA AAGAATCAAA GAG 33
(2) INFORMATION FOR SEQ ID NO:13:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: DNA
(vii) IMMEDIATE SOURCE:
(B) CLONE: Primer mo3
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:
CTACAGAGCC AAGGAG 16
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(2) INFORMATION FOR SEQ ID NO:14:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 22 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: DNA
(vii) IDMEDIATE SOURCE:
(B) CLONE: Primer mo6
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:
TCGAGCTATG CTACTAGTGG GC 22
(2) INFORMATION FOR SEQ ID NO:15:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 17 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: DNA
(vii) IMMEDIATE SOURCE:
(B) CLONE: Primer oHT9-1
(xi) SEQUENCE DESCRIPTION: SEQ ID N0:15:
CCAGTAAACT TGCTTTC 17
(2) INFORMATION FOR SEQ ID NO:16:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 20 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: DNA
(vii) IMMEDIATE SOURCE:
(B) CLONE: Primer oHT9-4
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:
TTTGCGGCCC TTCCAATATC 20
(2) INFORMATION FOR SEQ ID NO:17:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 7440 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: cDNA
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(vii) IMMEDIATE SOURCE:
(B) CLONE: MCCSlbeta
(ix) FEATURE:
(A) NAME/KEY: CDS
(B) LOCATION: 1__7437
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:
ATG GGT CAT GCT GTG GAA TGG CCA GTG GTC ATG AGC CGA TTT TTA AGT 48
Met Gly His Ala Val Glu Trp Pro Val Val Met Ser Arg Phe Leu Ser
1 5 10 15
CAA TTA GAT GAA CAC ATG GGA TAT TTA CAA TCA GCT CCT TTG CAG TTG 96
Gin Leu Asp Glu His Met Gly Tyr Leu Gln Ser Ala Pro Leu Gln Leu
20 25 30
ATG AGT ATG CAA AAA TTA GAA TTT ATT GAA GTC ACT TTA TTA ACG GTT 144
Met Ser Met Gln Lys Leu Glu Phe Ile Glu Val Thr Leu Leu Thr Val
35 40 45
CTT ACT CGT ATT ATT GCA ATT GTG TTT TTT AGA AGG CAA GAA CTC TTA 192
Leu Thr Arg Ile Ile Ala Ile Val Phe Phe Arg Arg Gln Glu Leu Leu
50 55 60
CTT TGG CAG ATA GGT TGT GTT CTG CTA GAG TAT GGT AGT CCA AAA ATT 240
Leu Trp Gln Ile Gly Cys Val Leu Leu Glu Tyr Gly Ser Pro Lys Ile
65 70 75 80
AAA TCC CTA GCA ATT AGC TTT TTA ACA GAA CTT TTT CAG CTT GGA GGA 288
Lys Ser Leu Ala Ile Ser Phe Leu Thr Glu Leu Phe Gln Leu Gly Gly
85 90 95
CTA CCA GCA CAA CCA GCT AGC ACT TTT TTC AGC TCA TTT TTG GAA TTA 336
Leu Pro Ala Gin Pro Ala Ser Thr Phe Phe Ser Ser Phe Leu Glu Leu
100 105 110
TTA AAA CAC CTT GTA GAA ATG GAT ACT GAC CAA TTG AAA CTC TAT GAA 384
Leu Lys His Leu Val Glu Met Asp Thr Asp Gln Leu Lys Leu Tyr Glu
115 120 125
GAG CCA TTA TCA AAG CTG ATA AAG ACA CTA TTT CCC TTT GAA GCA GAA 432
Glu Pro Leu Ser Lys Leu Ile Lys Thr Leu Phe Pro Phe Glu Ala Glu
130 135 140
GCT TAT AGA AAT ATT GAA CCT GTC TAT TTA AAT ATG CTG CTG GAA AAA 480
Ala Tyr Arg Asn Ile Glu Pro Val Tyr Leu Asn Met Leu Leu Glu Lys
145 150 155 160
CTC TGT GTC ATG TTT GAA GAC GGT GTG CTC ATG CGG CTT AAG TCT GAT 528
Leu Cys Val Met Phe Glu Asp Gly Val Leu Met Arg Leu Lys Ser Asp
165 170 175
TTG CTA AAA GCA GCT TTG TGC CAT TTA CTG CAG TAT TTC CTT AAA TTT 576
Leu Leu Lys Ala Ala Leu Cys His Leu Leu Gln Tyr Phe Leu Lys Phe
180 185 190
GTG CCA GCT GGG TAT GAA TCT GCT TTA CAA GTC AGG AAG GTC TAT GTG 624
Val Pro Ala Gly Tyr Glu Ser Ala Leu Gln Val Arg Lys Val Tyr Val
195 200 205
AGA AAT ATT TGT AAA GCT CTT TTG GAT GTG CTT GGA ATT GAG GTA GAT 672
Arg Asn Ile Cys Lys Ala Leu Leu Asp Val Leu Gly Ile Glu Val Asp
210 215 220
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GCA GAG TAC TTG TTG GGC CCA CTT TAT GCA GCT TTG AAA ATG GAA AGT 720
Ala Glu Tyr Leu Leu Gly Pro Leu Tyr Ala Ala Leu Lys Met Glu Ser
225 230 235 240
ATG GAA ATC ATT GAG GAG ATT CAA TGC CAA ACT CAA CAG GAA AAC CTC 768
Met Glu Ile Ile Glu Glu Ile Gln Cys Gln Thr Gln Gln Glu Asn Leu
245 250 255
AGC AGT AAT AGT GAT GGA ATA TCA CCC AAA AGG CGT CGT CTC AGC TCG 816
Ser Ser Asn Ser Asp Gly Ile Ser Pro Lys Arg Arg Arg Leu Ser Ser
260 265 270
TCT CTA AAC CCT TCT AAA AGA GCA CCA AAA CAG ACT GAG GAA ATT AAA 864
Ser Leu Asn Pro Ser Lys Arg Ala Pro Lys Gln Thr Glu Glu Ile Lys
275 280 285
CAT GTG GAC ATG AAC CAA AAG AGC ATA TTA TGG AGT GCA CTG AAA CAG 912
His Val Asp Met Asn Gln Lys Ser Ile Leu Trp Ser Ala Leu Lys Gln
290 295 300
AAA GCT GAA TCC CTT CAG ATT TCC CTT GAA TAC AGT GGC CTA AAG AAT 960
Lys Ala Glu Ser Leu Gln Ile Ser Leu Glu Tyr Ser Gly Leu Lys Asn
305 310 315 320
CCT GTT ATT GAG ATG TTA GAA GGA ATT GCT GTT GTC TTA CAA CTG ACT 1008
Pro Val Ile Glu Met Leu Glu Gly Ile Ala Val Val Leu Gln Leu Thr
325 330 335
GCT CTG TGT ACT GTT CAT TGT TCT CAT CAA AAC ATG AAC TGC CGT ACT 1056
Ala Leu Cys Thr Val His Cys Ser His Gln Asn Met Asn Cys Arg Thr
340 345 350
TTC AAG GAC TGT CAA CAT AAA TCC AAG AAG AAA CCT TCT GTA GTG ATA 1104
Phe Lys Asp Cys Gln His Lys Ser Lys Lys Lys Pro Ser Val Val Ile
355 360 365
ACT TGG ATG TCA TTG GAT TTT TAC ACA ACA GTG CTT AAG AGC TGT AGA 1152
Thr Trp Met Ser Leu Asp Phe Tyr Thr Thr Val Leu Lys Ser Cys Arg
370 375 380
AGG TTG TTA GAA TCT GTT CAG AAA CGG ACT GGA GGC AAC ATT GAT AAG 1200
Arg Leu Leu Glu Ser Val Gln Lys Arg Thr Gly Gly Asn Ile Asp Lys
385 390 395 400
GTG GTG AAA ATT TAT GAT GCT TTG ATT TAT ATG CAA GTA AAC AGT TCA 1248
Val Val Lys Ile Tyr Asp Ala Leu Ile Tyr Met Gin Val Asn Ser Ser
405 410 415
TTT GAA GAT CAT ATC CTG GAA GAT TTA TGT GGA ATG CTC TCA CTT CCA 1296
Phe Glu Asp His Ile Leu Glu Asp Leu Cys Gly Met Leu Ser Leu Pro
420 425 430
TGG ATT TAT TCC CAT TCT GAT GAT GGC TGT TTA AAG TTG ACC ACA TTT 1344
Trp Ile Tyr Ser His Ser Asp Asp Gly Cys Leu Lys Leu Thr Thr Phe
435 440 445
GCC GCT AAT CTT CTA ACA TTA AGC TGT AGG ATT TCA GAT AGC TAT TCA 1392
Ala Ala Asn Leu Leu Thr Leu Ser Cys Arg Ile Ser Asp Ser Tyr Ser
450 455 460
CCA CAG GCA CAA TCA CGA TGT GTG TTT CTT CTG ACT CTG TTT CCA AGA 1440
Pro Gln Ala Gln Ser Arg Cys Val Phe Leu Leu Thr Leu Phe Pro Arg
465 470 475 480
AGA ATA TTC CTT GAG TGG AGA ACA GCA GTT TAC AAC TGG GCC CTG CAG 1488
Arg Ile Phe Leu Glu Trp Arg Thr Ala Val Tyr Asn Trp Ala Leu Gln
485 490 495
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AGC TCC CAT GAA GTA ATC CGG GCT AGT TGT GTT AGT GGA TTT TTT ATC 1536
Ser Ser His Glu Val Ile Arg Ala Ser Cys Val Ser Gly Phe Phe Ile
500 505 510
TTA TTG CAG CAG CAG AAT TCT TGT AAC AGA GTT CCC AAG ATT CTT ATA 1584
Leu Leu Gln Gln Gln Asn Ser Cys Asn Arg Val Pro Lys Ile Leu Ile
515 520 525
GAT AAA GTC AAA GAT GAT TCT GAC ATT GTC AAG AAA GAA TTT GCT TCT 1632
Asp Lys Val Lys Asp Asp Ser Asp Ile Val Lys Lys Glu Phe Ala Ser
530 535 540
ATA CTT GGT CAA CTT GTC TGT ACT CTT CAC GGC ATG TTT TAT CTG ACA 1680
Ile Leu Gly Gln Leu Val Cys Thr Leu His Gly Met Phe Tyr Leu Thr
545 550 555 560
AGT TCT TTA ACA GAA CCT TTC TCT GAA CAC GGA CAT GTG GAC CTC TTC 1728
Ser Ser Leu Thr Glu Pro Phe Ser Glu His Gly His Val Asp Leu Phe
565 570 575
TGT AGG AAC TTG AAA GCC ACT TCT CAA CAT GAA TGT TCA TCT TCT CAA 1776
Cys Arg Asn Leu Lys Ala Thr Ser Gln His Glu Cys Ser Ser Ser Gln
580 585 590
CTA AAA GCT TCT GTC TGC AAG CCA TTC CTT TTC CTA CTG AAA AAA AAA 1824
Leu Lys Ala Ser Val Cys Lys Pro Phe Leu Phe Leu Leu Lys Lys Lys
595 600 605
ATA CCT AGT CCA GTA AAA CTT GCT TTC ATA GAT AAT CTA CAT CAT CTT 1872
Ile Pro Ser Pro Val Lys Leu Ala Phe Ile Asp Asn Leu His His Leu
610 615 620
TGT AAG CAT CTT GAT TTT AGA GAA GAT GAA ACA GAT GTA AAA GCA GTT 1920
Cys Lys His Leu Asp Phe Arg Glu Asp Glu Thr Asp Val Lys Ala Val
625 630 635 640
CTT GGA ACT TTA TTA AAT TTA ATG GAA GAT CCA GAC AAA GAT GTT AGA 1968
Leu Gly Thr Leu Leu Asn Leu Met Glu Asp Pro Asp Lys Asp Val Arg
645 650 655
GTG GCT TTT AGT GGA AAT ATC AAG CAC ATA TTG GAA TCC TTG GAC TCT 2016
Val Ala Phe Ser Gly Asn Ile Lys His Ile Leu Glu Ser Leu Asp Ser
660 665 670
GAA GAT GGA TTT ATA AAG GAG CTT TTT GTC TTA AGA ATG AAG GAA GCA 2064
Glu Asp Gly Phe Ile Lys Glu Leu Phe Val Leu Arg Met Lys Glu Ala
675 680 685
TAT ACA CAT GCC CAA ATA TCA AGA AAT AAT GAG CTG AAG GAT ACC TTG 2112
Tyr Thr His Ala Gin Ile Ser Arg Asn Asn Glu Leu Lys Asp Thr Leu
690 695 700
ATT CTT ACA ACA GGG GAT ATT GGA AGG GCC GCA AAA GGA GAT TTG GTA 2160
Ile Leu Thr Thr Gly Asp Ile Gly Arg Ala Ala Lys Gly Asp Leu Val
705 710 715 720
CCA TTT GCA CTC TTA CAC TTA TTG CAT TGT TTG TTA TCC AAG TCA GCA 2208
Pro Phe Ala Leu Leu His Leu Leu His Cys Leu Leu Ser Lys Ser Ala
725 730 735
TCT GTC TCT GGA GCA GCA TAC ACA GAA ATT AGA GCT CTG GTT GCA GCT 2256
Ser Val Ser Gly Ala Ala Tyr Thr Glu Ile Arg Ala Leu Val Ala Ala
740 745 750
AAA AGT GTT AAA CTG CAA AGT TTT TTC AGC CAG TAT AAG AAA CCC ATC 2304
Lys Ser Val Lys Leu Gln Ser Phe Phe Ser Gln Tyr Lys Lys Pro Ile
755 760 765
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TGT CAG TTT TTG GTA GAA TCC CTT CAC TCT AGT CAG ATG ACA GCA CTT 2352
Cys Gln Phe Leu Val Glu Ser Leu His Ser Ser Gln Met Thr Ala Leu
770 775 780
CCG AAT ACT CCA TGC CAG AAT GCT GAC GTG CGA AAA CAA GAT GTG GCT 2400
Pro Asn Thr Pro Cys Gln Asn Ala Asp Val Arg Lys Gln Asp Val Ala
785 790 795 800
CAC CAG AGA GAA ATG GCT TTA AAT ACG TTG TCT GAA ATT GCC AAC GTT 2448
His Gln Arg Glu Met Ala Leu Asn Thr Leu Ser Glu Ile Ala Asn Val
805 810 815
TTC GAC TTT CCT GAT CTT AAT CGT TTT CTT ACT AGG ACA TTA CAA GTT 2496
Phe Asp Phe Pro Asp Leu Asn Arg Phe Leu Thr Arg Thr Leu Gln Val
820 825 830
CTA CTA CCT GAT CTT GCT GCC AAA GCA AGC CCT GCA GCT TCT GCT CTC 2544
Leu Leu Pro Asp Leu Ala Ala Lys Ala Ser Pro Ala Ala Ser Ala Leu
835 840 845
ATT CGA ACT TTA GGA AAA CAA TTA AAT GTC AAT CGT AGA GAG ATT TTA 2592
Ile Arg Thr Leu Gly Lys Gln Leu Asn Val Asn Arg Arg Glu Ile Leu
850 855 860
ATA AAC AAC TTC AAA TAT ATT TTT TCT CAT TTG GTC TGT TCT TGT TCC 2640
Ile Asn Asn Phe Lys Tyr Ile Phe Ser His Leu Val Cys Ser Cys Ser
865 870 875 880
AAA GAT GAA TTA GAA CGT GCC CTT CAT TAT CTG AAG AAT GAA ACA GAA 2688
Lys Asp Glu Leu Glu Arg Ala Leu His Tyr Leu Lys Asn Glu Thr Glu
885 890 895
ATT GAA CTG GGG AGC CTG TTG AGA CAA GAT TTC CAA GGA TTG CAT AAT 2736
Ile Glu Leu Gly Ser Leu Leu Arg Gln Asp Phe Gln Gly Leu His Asn
900 905 910
GAA TTA TTG CTG CGT ATT GGA GAA CAC TAT CAA CAG GTT TT'T AAT GGT 2784
Glu Leu Leu Leu Arg Ile Gly Glu His Tyr Gln Gln Val Phe Asn Gly
915 920 925
TTG TCA ATA CTT GCC TCA TTT GCA TCC AGT GAT GAT CCA TAT CAG GGC 2832
Leu Ser Ile Leu Ala Ser Phe Ala Ser Ser Asp Asp Pro Tyr Gln Gly
930 935 940
CCG AGA GAT ATC ATA TCA CCT GAA CTG ATG GCT GAT TAT TTA CAA CCC 2880
Pro Arg Asp Ile Ile Ser Pro Glu Leu Met Ala Asp Tyr Leu Gln Pro
945 950 955 960
AAA TTG TTG GGC ATT TTG GCT TTT TTT AAC ATG CAG TTA CTG AGC TCT 2928
Lys Leu Leu Gly Ile Leu Ala Phe Phe Asn Met Gln Leu Leu Ser Ser
965 970 975
AGT GTT GGC ATT GAA GAT AAG AAA ATG GCC TTG AAC AGT TTG ATG TCT 2976
Ser Val Gly Ile Glu Asp Lys Lys Met Ala Leu Asn Ser Leu Met Ser
980 985 990
TTG ATG AAG TTA ATG GGA CCC AAA CAT GTC AGT TCT GTG AGG GTG AAG 3024
Leu Met Lys Leu Met Gly Pro Lys His Val Ser Ser Val Arg Val Lys
995 1000 1005
ATG ATG ACC ACA CTG AGA ACT GGC CTT CGA TTC AAG GAT GAT TTT CCT 3072
Met Met Thr Thr Leu Arg Thr Gly Leu Arg Phe Lys Asp Asp Phe Pro
1010 1015 1020
GAA TTG TGT TGC AGA GCT TGG GAC TGC TTT GTT CGC TGC CTG GAT CAT 3120
Glu Leu Cys Cys Arg Ala Trp Asp Cys Phe Val Arg Cys Leu Asp His
1025 1030 1035 1040
CA 02210650 1997-07-16
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GCT TGT CTG GGC TCC CTT CTC AGT CAT GTA ATA GTA GCT TTG TTA CCT 3168
Ala Cys Leu Gly Ser Leu Leu Ser His Val Ile Val Ala Leu Leu Pro
1045 1050 1055
CTT ATA CAC ATC CAG CCT AAA GAA ACT GCA GCT ATC TTC CAC TAC CTC 3216
Leu Ile His Ile Gln Pro Lys Glu Thr Ala Ala Ile Phe His Tyr Leu
1060 1065 1070
ATA ATT GAA AAC AGG GAT GCT GTG CAA GAT TTT CTT CAT GAA ATA TAT 3264
Ile Ile Glu Asn Arg Asp Ala Val Gln Asp Phe Leu His Glu Ile Tyr
1075 1080 1085
TTT TTA CCT GAT CAT CCA GAA TTA AAA AAG ATA AAA GCC GTT CTC CAG 3312
Phe Leu Pro Asp His Pro Glu Leu Lys Lys Ile Lys Ala Val Leu Gln
1090 1095 1100
GAA TAC AGA AAG GAG ACC TCT GAG AGC ACT GAT CTT CAG ACA ACT CTT 3360
Glu Tyr Arg Lys Glu Thr Ser Glu Ser Thr Asp Leu Gln Thr Thr Leu
1105 1110 1115 1120
CAG CTC TCT ATG AAG GCC ATT CAA CAT GAA AAT GTC GAT GTT CGT ATT 3408
Gln Leu Ser Met Lys Ala Ile Gln His Glu Asn Val Asp Val Arg Ile
1125 1130 1135
CAT GCT CTT ACA AGC TTG AAG GAA ACC TTG TAT AAA AAT CAG GAA AAA 3456
His Ala Leu Thr Ser Leu Lys Glu Thr Leu Tyr Lys Asn Gin Glu Lys
1140 1145 1150
CTG ATA AAG TAT GCA ACA GAC AGT GAA ACA GTA GAA CCT ATT ATC TCA 3504
Leu Ile Lys Tyr Ala Thr Asp Ser Glu Thr Val Glu Pro Ile Ile Ser
1155 1160 1165
CAG TTG GTG ACA GTG CTT TTG AAA GGT TGC CAA GAT GCA AAC TCT CAA 3552
Gln Leu Val Thr Val Leu Leu Lys Gly Cys Gln Asp Ala Asn Ser Gln
1170 1175 1180
GCT CGG TTG CTC TGT GGG GAA TGT TTA GGG GAA TTG GGG GCG ATA GAT 3600
Ala Arg Leu Leu Cys Gly Glu Cys Leu Gly Glu Leu Gly Ala Ile Asp
1185 1190 1195 1200
CCA GGT CGA TTA GAT TTC TCA ACA ACT GAA ACT CAA GGA AAA GAT TTT 3648
Pro Gly Arg Leu Asp Phe Ser Thr Thr Glu Thr Gln Gly Lys Asp Phe
1205 1210 1215
ACA TTT GTG ACT GGA GTA GAA GAT TCA AGC TTT GCC TAT GGA TTA TTG 3696
Thr Phe Val Thr Gly Val Glu Asp Ser Ser Phe Ala Tyr Gly Leu Leu
1220 1225 1230
ATG GAG CTA ACA AGA GCT TAC CTT GCG TAT GCT GAT AAT AGC CGA GCT 3744
Met Glu Leu Thr Arg Ala Tyr Leu Ala Tyr Ala Asp Asn Ser Arg Ala
1235 1240 1245
CCA GAT TCA GCT GCC TAT GCC ATT CAG GAG TTG CTT TCT ATT TAT GAC 3792
Pro Asp Ser Ala Ala Tyr Ala Ile Gln Glu Leu Leu Ser Ile Tyr Asp
1250 1255 1260
TGT AGA GAG ATG GAG ACC AAC GGC CCA GGT CAC CAA TTG TGG AGG AGA 3840
Cys Arg Glu Met Glu Thr Asn Gly Pro Gly His Gln Leu Trp Arg Arg
1265 1270 1275 1280
TTT CCT GAG CAT GTT CGG GAA ATA CTA GAA CCT CAT CTA AAT ACC AGA 3888
Phe Pro Glu His Val Arg Glu Ile Leu Glu Pro His Leu Asn Thr Arg
1285 1290 1295
TAC AAG AGT TCT CAG AAG TCA ACC GAT TGG TCT GGA GTA AAG AAG CCA 3936
Tyr Lys Ser Ser Gln Lys Ser Thr Asp Trp Ser Giy Val Lys Lys Pro
1300 1305 1310
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ATT TAC TTA AGT AAA TTG GGT AGT AAC TTT GCA GAA TGG TCA GCA TCT 3984
Ile Tyr Leu Ser Lys Leu Gly Ser Asn Phe Ala Glu Trp Ser Ala Ser
1315 1320 1325
TGG GCA GGT TAT CTT ATT ACA AAG GTT CGA CAT GAT CTT GCC AGT AAA 4032
Trp Ala Gly Tyr Leu Ile Thr Lys Val Arg His Asp Leu Ala Ser Lys
1330 1335 1340
ATT TTC ACC TGC TGT AGC ATT ATG ATG AAG CAT GAT TTC AAA GTG ACC 4080
Ile Phe Thr Cys Cys Ser Ile Met Met Lys His Asp Phe Lys Val Thr
1345 1350 1355 1360
ATC TAT CTT CTT CCA CAT ATT CTG GTG TAT GTC TTA CTG GGT TGT AAT 4128
Ile Tyr Leu Leu Pro His I1e Leu Val Tyr Val Leu Leu Gly Cys Asn
1365 1370 1375
CAA GAA GAT CAG CAG GAG GTT TAT GCA GAA ATT ATG GCA GTT CTA AAG 4176
Gln Glu Asp Gln Gln Glu Val Tyr Ala Glu Ile Met Ala Val Leu Lys
1380 1385 1390
CAT GAC GAT CAG CAT ACC ATA AAT ACC CAA GAC ATT GCA TCT GAT CTG 4224
His Asp Asp Gln His Thr Ile Asn Thr Gln Asp Ile Ala Ser Asp Leu
1395 1400 1405
TGT CAA CTC AGT ACA CAG ACT GTG TTC TCC ATG CTT GAC CAT CTC ACA 4272
Cys Gln Leu Ser Thr Gln Thr Val Phe Ser Met Leu Asp His Leu Thr
1410 1415 1420
CAG TGG GCA AGG CAC AAA TTT CAG GCA CTG AAA GCT GAG AAA TGT CCA 4320
Gln Trp Ala Arg His Lys Phe Gln Ala Leu Lys Ala Glu Lys Cys Pro
1425 1430 1435 1440
CAC AGC AAA TCA AAC AGA AAT AAG GTP. GAC TCA ATG GTA TCT ACT GTG 4368
His Ser Lys Ser Asn Arg Asn Lys Val Asp Ser Met Val Ser Thr Val
1445 1450 1455
GAT TAT GAA GAC TAT CAG AGT GTA ACC CGT TTT CTA GAC CTC ATA CCC 4416
Asp Tyr Glu Asp Tyr Gln Ser Val Thr Arg Phe Leu Asp Leu Ile Pro
1460 1465 1470
CAG GAT ACT CTG GCA GTA GCT TCC TTT CGC TCC AAA GCA TAC ACA CGA 4464
Gln Asp Thr Leu Ala Val Ala Ser Phe Arg Ser Lys Ala Tyr Thr Arg
1475 1480 1485
GCT GTA ATG CAC TTT GAA TCA TTT ATT ACA GAA AAG AAG CAA AAT ATT 4512
Ala Val Met His Phe Glu Ser Phe Ile Thr Glu Lys Lys Gln Asn Ile
1490 1495 1500
CAG GAA CAT CTT GGA TTT TTA CAG AAA TTG TAT GCT GCT ATG CAT GAA 4560
Gln Glu His Leu Gly Phe Leu Gln Lys Leu Tyr Ala Ala Met His Glu
1505 1510 1515 1520
CCT GAT GGA GTG TCC GGA GTC AGT GCA ATT AGA AAG GCA GAA CCA TCT 4608
Pro Asp Gly Val Ser Gly Val Ser Ala Ile Arg Lys Ala Glu Pro Ser
1525 1530 1535
CTA AAA GAA CAG ATC CTT GAA CAT GAA AGC CTT GGC TTG CTG AGG GAT 4656
Leu Lys Glu Gln Ile Leu Glu His Glu Ser Leu Gly Leu Leu Arg Asp
1540 1545 1550
GCC ACT GCT TGT TAT GAC AGG GCT ATT CAG CTA GAA CCA GAC CAG ATC 4704
Ala Thr Ala Cys Tyr Asp Arg Ala Ile Gln Leu Glu Pro Asp Gln Ile
1555 1560 1565
ATT CAT TAC CAT GGT GTA GTA AAG TCC ATG TTA GGT CTT GGT CAG CTG 4752
Ile His Tyr His Gly Val Val Lys Ser Met Leu Gly Leu Gly Gln Leu
1570 1575 1580
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TCT ACT GTT ATC ACT CAG GTG AAT GGA GTG CAT GCT AAC AGG TCC GAG 4800
Ser Thr Val Ile Thr Gln Val Asn Gly Val His Ala Asn Arg Ser Glu
1585 1590 1595 1600
TGG ACA GAT GAA TTA AAC ACG TAC AGA GTG GAA GCA GCT TGG AAA TTG 4848
Trp Thr Asp Glu Leu Asn Thr Tyr Arg Val Glu Ala Ala Trp Lys Leu
1605 1610 1615
TCA CAG TGG GAT TTG GTG GAA AAC TAT TTG GCA GCA GAT GGA AAA TCT 4896
Ser Gln Trp Asp Leu Val Glu Asn Tyr Leu Ala Ala Asp Gly Lys Ser
1620 1625 1630
ACA ACA TGG AGT GTC AGA CTG GGA CAG CTA TTA TTA TCA GCC AAA AAA 4944
Thr Thr Trp Ser Val Arg Leu Gly Gln Leu Leu Leu Ser Ala Lys Lys
1635 1640 1645
AGA GAT ATC ACA GCT TTT TAT GAC TCA CTG AAA CTA GTG AGA GCA GAA 4992
Arg Asp Ile Thr Ala Phe Tyr Asp Ser Leu Lys Leu Val Arg Ala Glu
1650 1655 1660
CAA ATT GTA CCT CTT TCA GCT GCA AGC TTT GAA AGA GGC TCC TAC CAA 5040
Gln Ile Val Pro Leu Ser Ala Ala Ser Phe Glu Arg Gly Ser Tyr Gln
1665 1670 1675 1680
CGA GGA TAT GAA TAT ATT GTG AGA TTG CAC ATG TTA TGT GAG TTG GAG 5088
Arg Gly Tyr Glu Tyr Ile Val Arg Leu His Met Leu Cys Glu Leu Glu
1685 1690 1695
CAT AGC ATC AAA CCA CTT TTC CAG CAT TCT CCA GGT GAC AGT TCT CAA 5136
His Ser Ile Lys Pro Leu Phe Gln His Ser Pro Gly Asp Ser Ser Gln
1700 1705 1710
GAA GAT TCT CTA AAC TGG GTA GCT CGA CTA GAA ATG ACC CAG AAT TCC 5184
Glu Asp Ser Leu Asn Trp Val Ala Arg Leu Glu Met Thr Gln Asn Ser
1715 1720 1725
TAC AGA GCC AAG GAG CCT ATC CTG GCT CTC CGG AGG GCT TTA CTA AGC 5232
Tyr Arg Ala Lys Glu Pro Ile Leu Ala Leu Arg Arg Ala Leu Leu Ser
1730 1735 1740
CTC AAC AAA AGA CCA GAT TAC AAT GAA ATG GTT GGA GAA TGC TGG CTG 5280
Leu Asn Lys Arg Pro Asp Tyr Asn Glu Met Val Gly Glu Cys Trp Leu
1745 1750 1755 1760
CAG AGT GCC AGG GTA GCT AGA AAG GCT GGT CAC CAC CAG ACA GCC TAC 5328
Gln Ser Ala Arg Val Ala Arg Lys Ala Gly His His Gln Thr Ala Tyr
1765 1770 1775
AAT GCT CTC CTT AAT GCA GGG GAA TCA CGA CTC GCT GAA CTG TAC GTG 5376
Asn Ala Leu Leu Asn Ala Gly Glu Ser Arg Leu Ala Glu Leu Tyr Val
1780 1785 1790
GAA AGG GCA AAG TGG CTC TGG TCC AAG GGT GAT GTT CAC CAG GCA CTA 5424
Glu Arg Ala Lys Trp Leu Trp Ser Lys Gly Asp Val His Gin Ala Leu
1795 1800 1805
ATT GTT CTT CAA AAA GGT GTT GAA TTA TGT TTT CCT GAA AAT GAA ACC 5472
Ile Val Leu Gln Lys Gly Val Glu Leu Cys Phe Pro Glu Asn Glu Thr
1810 1815 1820
CCA CCT GAG GGT AAG AAC ATG TTA ATC CAT GGT CGA GCT ATG CTA CTA 5520
Pro Pro Glu Gly Lys Asn Met Leu Ile His Gly Arg Ala Met Leu Leu
1825 1830 1835 1840
GTG GGC CGA TTT ATG GAA GAA ACA GCT AAC TTT GAA AGC AAT GCA ATT 5568
Val Gly Arg Phe Met Glu Glu Thr Ala Asn Phe Glu Ser Asn Ala Ile
1845 1850 1855
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ATG AAA AAA TAT AAG GAT GTG ACC GCG TGC CTG CCA GAA TGG GAG GAT 5616
Met Lys Lys Tyr Lys Asp Val Thr Ala Cys Leu Pro Glu Trp Glu Asp
1860 1865 1870
GGG CAT TTT TAC CTT GCC AAG TAC TAT GAC AAA TTG ATG CCC ATG GTC 5664
Gly His Phe Tyr Leu Ala Lys Tyr Tyr Asp Lys Leu Met Pro Met Val
1875 1880 1885
ACA GAC AAC AAA ATG GAA AAG CAA GGT GAT CTC ATC CGG TAT ATA GTT 5712
Thr Asp Asn Lys Met Glu Lys Gln Gly Asp Leu Ile Arg Tyr Ile Val
1890 1895 1900
CTT CAT TTT GGC AGA TCT CTA CAA TAT GGA AAT CAG TTC ATA TAT CAG 5760
Leu His Phe Gly Arg Ser Leu Gln Tyr Gly Asn Gln Phe Ile Tyr Gin
1905 1910 1915 1920
TCA ATG CCA CGA ATG TTA ACT CTA TGG CTT GAT TAT GGT ACA AAG GCA 5808
Ser Met Pro Arg Met Leu Thr Leu Trp Leu Asp Tyr Gly Thr Lys Ala
1925 1930 1935
TAT GAA TGG GAA AAA GCT GGC CGC TCC GAT CGT GTA CAA ATG AGG AAT 5856
Tyr Glu Trp Glu Lys Ala Gly Arg Ser Asp Arg Val Gln Met Arg Asn
1940 1945 1950
GAT TTG GGT AAA ATA AAC AAG GTT ATC ACA GAG CAT ACA AAC TAT TTA 5904
Asp Leu Gly Lys Ile Asn Lys Val Ile Thr Glu His Thr Asn Tyr Leu
1955 1960 1965
GCT CCA TAT CAA TTT TTG ACT GCT TTT TCA CAA TTG ATC TCT CGA ATT 5952
Ala Pro Tyr Gln Phe Leu Thr Ala Phe Ser Gln Leu Ile Ser Arg Ile
1970 1975 1980
TGT CAT TCT CAC GAT GAA GTT TTT GTT GTG CTT GAT GGA AAT AAT AGC 6000
Cys His Ser His Asp Glu Val Phe Val Val Leu Asp Gly Asn Asn Ser
1985 1990 1995 2000
CAA GTA TTT CTA GCC TAT CCT CAA CAA GCA ATG TGG ATG ATG ACA GCT 6048
Gln Val Phe Leu Ala Tyr Pro Gln Gln Ala Met Trp Met Met Thr Ala
2005 2010 2015
GTG TCA AAG TCA TCT TAT CCC ATG CGT GTG AAC AGA TGC AAG GAA ATC 6096
Val Ser Lys Ser Ser Tyr Pro Met Arg Val Asn Arg Cys Lys Glu Ile
2020 2025 2030
CTC AAT AAA GCT ATT CAT ATG AAA AAA TCC TTA GAG AAG TTT GTT GGA 6144
Leu Asn Lys Ala Ile His Met Lys Lys Ser Leu Glu Lys Phe Val Gly
2035 2040 2045
GAT GCA ACT CGC CTA ACA GAT AAG CTT CTA GAA TTG TGC AAT AAA CCG 6192
Asp Ala Thr Arg Leu Thr Asp Lys Leu Leu Glu Leu Cys Asn Lys Pro
2050 2055 2060
GTT GAT GGA AGT AGT TCC ACA TTA AGC ATG AGC ACT CAT TTT AAA ATG 6240
Val Asp Gly Ser Ser Ser Thr Leu Ser Met Ser Thr His Phe Lys Met
2065 2070 2075 2080
CTT AAA AAG CTG GTA GAA GAA GCA ACA TTT AGT GAA ATC CTC ATT CCT 6288
Leu Lys Lys Leu Val Glu Glu Ala Thr Phe Ser Glu Ile Leu Ile Pro
2085 2090 2095
CTA CAA TCA GTC ATG ATA CCT ACA CTT CCA TCA ATT CTG GGT ACC CAT 6336
Leu Gln Ser Val Met Ile Pro Thr Leu Pro Ser Ile Leu Gly Thr His
2100 2105 2110
GCT AAC CAT GCT AGC CAT GAA CCA TTT CCT GGA CAT TGG GCC TAT ATT 6384
Ala Asn His Ala Ser His Glu Pro Phe Pro Gly His Trp Ala Tyr Ile
2115 2120 2125
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GCA GGG TTT GAT GAT ATG GTG GAA ATT CTT GCT TCT CTT CAG AAA CCA 6432
Ala Gly Phe Asp Asp Met Val Glu Ile Leu Ala Ser Leu Gln Lys Pro
2130 2135 2140
AAG AAG ATT TCT TTA AAA GGC TCA GAT GGA AAG TTC TAC ATC ATG ATG 6480
Lys Lys Ile Ser Leu Lys Gly Ser Asp Gly Lys Phe Tyr Ile Met Met
2145 2150 2155 2160
TGT AAG CCA AAA GAT GAC CTG AGA AAG GAT TGT AGA CTA ATG GAA TTC 6528
Cys Lys Pro Lys Asp Asp Leu Arg Lys Asp Cys Arg Leu Met Glu Phe
2165 2170 2175
AAT TCC TTG ATT AAT AAG TGC TTA AGA AAA GAT GCA GAG TCT CGT AGA 6576
Asn Ser Leu Ile Asn Lys Cys Leu Arg Lys Asp Ala Glu Ser Arg Arg
2180 2185 2190
AGA GAA CTT CAT ATT CGA ACA TAT GCA GTT ATT CCA CTA AAT GAT GAA 6624
Arg Glu Leu His Ile Arg Thr Tyr Ala Val Ile Pro Leu Asn Asp Glu
2195 2200 2205
TGT GGG ATT ATT GAA TGG GTG AAC AAC ACT GCT GGT TTG AGA CCT ATT 6672
Cys Gly Ile Ile Glu Trp Val Asn Asn Thr Ala Gly Leu Arg Pro Ile
2210 2215 2220
CTG ACC AAA CTA TAT AAA GAA AAG GGA GTG TAT ATG ACA GGA AAA GAA 6720
Leu Thr Lys Leu 'Iyr Lys Glu Lys Gly Val Tyr Met Thr Gly Lys Glu
2225 2230 2235 2240
CTT CGC CAG TGT ATG CTA CCA AAG TCA GCA GCT TTA TCT GAA AAA CTC 6768
Leu Arg Gln Cys Met Leu Pro Lys Ser Ala Ala Leu Ser Glu Lys Leu
2245 2250 2255
AAA GTA TTC CGA GAA TTT CTC CTG CCC AGG CAT CCT CCT ATT TTT CAT 6816
Lys Val Phe Arg Glu Phe Leu Leu Pro Arg His Pro Pro Ile Phe His
2260 2265 2270
GAG TGG TTT CTG AGA ACA TTC CCT GAT CCT ACA TCA TGG TAC AGT AGT 6864
Glu Trp Phe Leu Arg Thr Phe Pro Asp Pro Thr Ser Trp Tyr Ser Ser
2275 2280 2285
AGA TCA GCT TAC TGC CGT TCC ACT GCA GTA ATG TCA ATG GTT GGT TAT 6912
Arg Ser Ala Tyr Cys Arg Ser Thr Ala Val Met Ser Met Val Gly Tyr
2290 2295 2300
ATT CTG GGG CTT GGA GAC CGT CAT GGT GAA AAT ATT CTC TTT GAT TCT 6960
Ile Leu Gly Leu Gly Asp Arg His Gly Glu Asn Ile Leu Phe Asp Ser
2305 2310 2315 2320
TTG ACT GGT GAA TGC GTA CAT GTA GAT TTC AAT TGT CTT TTC AAT AAG 7008
Leu Thr Gly Glu Cys Val His Val Asp Phe Asn Cys Leu Phe Asn Lys
2325 2330 2335
GGA GAA ACC TTT GAA GTT CCA GAA ATT GTG CCA TTT CGC CTG ACT CAT 7056
Gly Glu Thr Phe Glu Val Pro Glu Ile Val Pro Phe Arg Leu Thr His
2340 2345 2350
AAT ATG GTT AAT GGA ATG GGT CCT ATG GGA ACA GAG GGT CTT TTT CGA 7104
Asn Met Val Asn Gly Met Gly Pro Met Gly Thr Glu Gly Leu Phe Arg
2355 2360 2365
AGA GCA TGT GAA GTT ACA ATG AGG CTG ATG CGT GAT CAG CGA GAG CCT 7152
Arg Ala Cys Glu Val Thr Met Arg Leu Met Arg Asp Gln Arg Glu Pro
2370 2375 2380
TTA ATG AGT GTC TTA AAG ACT TTT CTA CAT GAT CCT CTT GTG GAA TGG 7200
Leu Met Ser Val Leu Lys Thr Phe Leu His Asp Pro Leu Val Glu Trp
2385 2390 2395 2400
CA 02210650 1997-07-16
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AGT AAA CCA GTG AAA GGG CAT TCC AAA GCG CCA CTG AAT GAA ACT GGA 7248
Ser Lys Pro Val Lys Gly His Ser Lys Ala Pro Leu Asn Glu Thr Gly
2405 2410 2415
GAA GTT GTC AAT GAA AAG GCC AAG ACC CAT GTT CTT GAC ATT GAG CAG 7296
Glu Val Val Asn Glu Lys Ala Lys Thr His Val Leu Asp Ile Glu Gln
2420 2425 2430
CGA CTA CAA GGT GTA ATC AAG ACT CGA AAT AGA GTG ACA GGA CTG CCG 7344
Arg Leu Gln Gly Val Ile Lys Thr Arg Asn Arg Val Thr Gly Leu Pro
2435 2440 2445
TTA TCT ATT GAA GGA CAT GTG CAT TAC CTT ATA CAA GAA GCT ACT GAT 7392
Leu Ser Ile Glu Gly His Val His Tyr Leu Ile Gln Glu Ala Thr Asp
2450 2455 2460
GAA AAC TTA CTA TGC CAG ATG TAT CTT GGT TGG ACT CCA TAT ATG 7437
Glu Asn Leu Leu Cys Gln Met Tyr Leu Gly Trp Thr Pro Tyr Met
2465 2470 2475
TGA 7440
(2) INFORMATION FOR SEQ ID NO:18:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2479 amino acids
(B) TYPE: amino acid
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: protein
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:
Met Gly His Ala Val Glu Trp Pro Val Val Met Ser Arg Phe Leu Ser
1 5 10 15
Gln Leu Asp Glu His Met Gly Tyr Leu Gln Ser Ala Pro Leu Gln Leu
20 25 30
Met Ser Met Gln Lys Leu Glu Phe I1e Glu Val Thr Leu Leu Thr Val
35 40 45
Leu Thr Arg Ile Ile Ala Ile Val Phe Phe Arg Arg Gln Glu Leu Leu
50 55 60
Leu Tzp Gln Ile Gly Cys Val Leu Leu Glu Tyr Gly Ser Pro Lys Ile
65 70 75 80
Lys Ser Leu Ala Ile Ser Phe Leu Thr Glu Leu Phe Gln Leu Gly Giy
85 90 95
Leu Pro Ala Gin Pro Ala Ser Thr Phe Phe Ser Ser Phe Leu Glu Leu
100 105 110
Leu Lys His Leu Val Glu Met Asp Thr Asp Gln Leu Lys Leu Tyr Glu
115 120 125
Glu Pro Leu Ser Lys Leu Ile Lys Thr Leu Phe Pro Phe Glu Ala Glu
130 135 140
Ala Tyr Arg Asn Ile Glu Pro Val Tyr Leu Asn Met Leu Leu Glu Lys
145 150 155 160
Leu Cys Val Met Phe Glu Asp Gly Val Leu Met Arg Leu Lys Ser Asp
165 170 175
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Leu Leu Lys Ala Ala Leu Cys His Leu Leu Gln Tyr Phe Leu Lys Phe
180 185 190
Val Pro Ala Gly Tyr Glu Ser Ala Leu Gln Val Arg Lys Val Tyr Val
195 200 205
Arg Asn Ile Cys Lys Ala Leu Leu Asp Val Leu Gly Ile Glu Val Asp
210 215 220
Ala Glu Tyr Leu Leu Gly Pro Leu Tyr Ala Ala Leu Lys Met Glu Ser
225 230 235 240
Met Glu Ile Ile Glu Glu Ile Gin Cys Gln Thr Gln Gln Glu Asn Leu
245 250 255
Ser Ser Asn Ser Asp Gly Ile Ser Pro Lys Arg Arg Arg Leu Ser Ser
260 265 270
Ser Leu Asn Pro Ser Lys Arg Ala Pro Lys Gln Thr Glu Glu Ile Lys
275 280 285
His Val Asp Met Asn Gln Lys Ser Ile Leu Trp Ser Ala Leu Lys Gln
290 295 300
Lys Ala Glu Ser Leu Gln Ile Ser Leu Glu Tyr Ser Gly Leu Lys Asn
305 310 315 320
Pro Val Ile Glu Met Leu Glu Gly Ile Ala Val Val Leu Gln Leu Thr
325 330 335
Ala Leu Cys Thr Val His Cys Ser His Gln Asn Met Asn Cys Arg Thr
340 345 350
Phe Lys Asp Cys Gln His Lys Ser Lys Lys Lys Pro Ser Val Val Ile
355 360 365
Thr Trp Met Ser Leu Asp Phe Tyr Thr Thr Val Leu Lys Ser Cys Arg
370 375 380
Arg Leu Leu Glu Ser Val Gln Lys Arg Thr Gly Gly Asn Ile Asp Lys
385 390 395 400
Val Val Lys Ile Tyr Asp Ala Leu Ile Tyr Met Gin Val Asn Ser Ser
405 410 415
Phe Glu Asp His Ile Leu Glu Asp Leu Cys Gly Met Leu Ser Leu Pro
420 425 430
Trp Ile Tyr Ser His Ser Asp Asp Gly Cys Leu Lys Leu Thr Thr Phe
435 440 445
Ala Ala Asn Leu Leu Thr Leu Ser Cys Arg Ile Ser Asp Ser Tyr Ser
450 455 460
Pro Gln Ala Gln Ser Arg Cys Val Phe Leu Leu Thr Leu Phe Pro Arg
465 470 475 480
Arg Ile Phe Leu Glu Trp Arg Thr Ala Val Tyr Asn Trp Ala Leu Gln
485 490 495
Ser Ser His Glu Val Ile Arg Ala Ser Cys Val Ser Gly Phe Phe Ile
500 505 510
Leu Leu Gln Gln Gln Asn Ser Cys Asn Arg Val Pro Lys Ile Leu Ile
515 520 525
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Asp Lys Val Lys Asp Asp Ser Asp Ile Val Lys Lys Glu Phe Ala Ser
530 535 540
Ile Leu Gly Gln Leu Val Cys Thr Leu His Gly Met Phe Tyr Leu Thr
545 550 555 560
Ser Ser Leu Thr Glu Pro Phe Ser Glu His Gly His Val Asp Leu Phe
565 570 575
Cys Arg Asn Leu Lys Ala Thr Ser Gln His Glu Cys Ser Ser Ser Gln
580 585 590
Leu Lys Ala Ser Val Cys Lys Pro Phe Leu Phe Leu Leu Lys Lys Lys
595 600 605
Ile Pro Ser Pro Val Lys Leu Ala Phe Ile Asp Asn Leu His His Leu
610 615 620
Cys Lys His Leu Asp Phe Arg Glu Asp Glu Thr Asp Val Lys Ala Val
625 630 635 640
Leu Gly Thr Leu Leu Asn Leu Met Glu Asp Pro Asp Lys Asp Val Arg
645 650 655
Val Ala Phe Ser Gly Asn Ile Lys His Ile Leu Glu Ser Leu Asp Ser
660 665 670
Glu Asp Gly Phe Ile Lys Glu Leu Phe Val Leu Arg Met Lys Glu Ala
675 680 685
Tyr Thr His Ala Gln Ile Ser Arg Asn Asn Glu Leu Lys Asp Thr Leu
690 695 700
Ile Leu Thr Thr Gly Asp Ile Gly Arg Ala Ala Lys Gly Asp Leu Val
705 710 715 720
Pro Phe Ala Leu Leu His Leu Leu His Cys Leu Leu Ser Lys Ser Ala
725 730 735
Ser Val Ser Gly Ala Ala Tyr Thr Glu Ile Arg Ala Leu Val Ala Ala
740 745 750
Lys Ser Val Lys Leu Gln Ser Phe Phe Ser Gln Tyr Lys Lys Pro Ile
755 760 765
Cys Gln Phe Leu Val Glu Ser Leu His Ser Ser Gln Met Thr Ala Leu
770 775 780
Pro Asn Thr Pro Cys Gln Asn Ala Asp Val Arg Lys Gln Asp Val Ala
785 790 795 800
His Gln Arg Glu Met Ala Leu Asn Thr Leu Ser Glu Ile Ala Asn Val
805 810 815
Phe Asp Phe Pro Asp Leu Asn Arg Phe Leu Thr Arg Thr Leu Gln Val
820 825 830
Leu Leu Pro Asp Leu Ala Ala Lys Ala Ser Pro Ala Ala Ser Ala Leu
835 840 845
Ile Arg Thr Leu Gly Lys Gln Leu Asn Val Asn Arg Arg Glu Ile Leu
850 855 860
Ile Asn Asn Phe Lys Tyr Ile Phe Ser His Leu Val Cys Ser Cys Ser
865 870 875 880
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Lys Asp Glu Leu Glu Arg Ala Leu His Tyr Leu Lys Asn Glu Thr Glu
885 890 895
Ile Glu Leu Gly Ser Leu Leu Arg Gln Asp Phe Gln Gly Leu His Asn
900 905 910
Glu Leu Leu Leu Arg Ile Gly Glu His Tyr Gln Gln Val Phe Asn Gly
915 920 925
Leu Ser Ile Leu Ala Ser Phe Ala Ser Ser Asp Asp Pro Tyr Gln Gly
930 935 940
Pro Arg Asp Ile Ile Ser Pro Glu Leu Met Ala Asp Tyr Leu Gln Pro
945 950 955 960
Lys Leu Leu Gly Ile Leu Ala Phe Phe Asn Met Gln Leu Leu Ser Ser
965 970 975
Ser Val Gly Ile Glu Asp Lys Lys Met Ala Leu Asn Ser Leu Met Ser
980 985 990
Leu Met Lys Leu Met Gly Pro Lys His Val Ser Ser Val Arg Val Lys
995 1000 1005
Met Met Thr Thr Leu Arg Thr Gly Leu Arg Phe Lys Asp Asp Phe Pro
1010 1015 1020
Glu Leu Cys Cys Arg Ala Trp Asp Cys Phe Val Arg Cys Leu Asp His
1025 1030 1035 1040
Ala Cys Leu Gly Ser Leu Leu Ser His Val Ile Val Ala Leu Leu Pro
1045 1050 1055
Leu Ile His Ile Gln Pro Lys Glu Thr Ala Ala Ile Phe His Tyr Leu
1060 1065 1070
Ile Ile Glu Asn Arg Asp Ala Val Gln Asp Phe Leu His Glu Ile Tyr
1075 1080 1085
Phe Leu Pro Asp His Pro Glu Leu Lys Lys Ile Lys Ala Val Leu Gln
1090 1095 1100
Glu Tyr Arg Lys Glu Thr Ser Glu Ser Thr Asp Leu Gln Thr Thr Leu
1105 1110 1115 1120
Gln Leu Ser Met Lys Ala Ile Gln His Glu Asn Val Asp Val Arg Ile
1125 1130 1135
His Ala Leu Thr Ser Leu Lys Glu Thr Leu Tyr Lys Asn Gln Glu Lys
1140 1145 1150
Leu Ile Lys Tyr Ala Thr Asp Ser Glu Thr Val Glu Pro Ile Ile Ser
1155 1160 1165
Gln Leu Val Thr Val Leu Leu Lys Gly Cys Gln Asp Ala Asn Ser Gln
1170 1175 1180
Ala Arg Leu Leu Cys Gly Glu Cys Leu Gly Glu Leu Gly Ala Ile Asp
1185 1190 1195 1200
Pro Gly Arg Leu Asp Phe Ser Thr Thr Glu Thr Gln Gly Lys Asp Phe
1205 1210 1215
Thr Phe Val Thr Giy Val Glu Asp Ser Ser Phe Ala Tyr Gly Leu Leu
1220 1225 1230
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Met Glu Leu Thr Arg Ala Tyr Leu Ala Tyr Ala Asp Asn Ser Arg Ala
1235 1240 1245
Pro Asp Ser Ala Ala Tyr Ala Ile Gln Glu Leu Leu Ser Ile Tyr Asp
1250 1255 1260
Cys Arg Glu Met Glu Thr Asn Gly Pro Gly His Gln Leu Trp Arg Arg
1265 1270 1275 1280
Phe Pro Glu His Val Arg Glu Ile Leu Glu Pro His Leu Asn Thr Arg
1285 1290 1295
Tyr Lys Ser Ser Gln Lys Ser Thr Asp Trp Ser Gly Val Lys Lys Pro
1300 1305 1310
Ile Tyr Leu Ser Lys Leu Gly Ser Asn Phe Ala Glu Trp Ser Ala Ser
1315 1320 1325
Trp Ala Gly Tyr Leu Ile Thr Lys Val Arg His Asp Leu Ala Ser Lys
1330 1335 1340
Ile Phe Thr Cys Cys Ser Ile Met Met Lys His Asp Phe Lys Val Thr
1345 1350 1355 1360
Ile Tyr Leu Leu Pro His Ile Leu Val Tyr Val Leu Leu Gly Cys Asn
1365 1370 1375
Gln Glu Asp Gln Gln Glu Val Tyr Ala Glu Ile Met Ala Val Leu Lys
1380 1385 1390
His Asp Asp Gln His Thr Ile Asn Thr Gin Asp Ile Ala Ser Asp Leu
1395 1400 1405
Cys Gin Leu Ser Thr Gln Thr Val Phe Ser Met Leu Asp His Leu Thr
1410 1415 1420
Gln Trp Ala Arg His Lys Phe Gln Ala Leu Lys Ala Glu Lys Cys Pro
1425 1430 1435 1440
His Ser Lys Ser Asn Arg Asn Lys Val Asp Ser Met Val Ser Thr Val
1445 1450 1455
Asp Tyr Glu Asp Tyr Gln Ser Val Thr Arg Phe Leu Asp Leu Ile Pro
1460 1465 1470
Gln Asp Thr Leu Ala Val Ala Ser Phe Arg Ser Lys Ala Tyr Thr Arg
1475 1480 1485
Ala Val Met His Phe Glu Ser Phe Ile Thr Glu Lys Lys Gln Asn Ile
1490 1495 1500
Gln Glu His Leu Gly Phe Leu Gln Lys Leu Tyr Ala Ala Met His Glu
1505 1510 1515 1520
Pro Asp Gly Val Ser Gly Val Ser Ala Ile Arg Lys Ala Glu Pro Ser
1525 1530 1535
Leu Lys Glu Gln Ile Leu Glu His Glu Ser Leu Gly Leu Leu Arg Asp
1540 1545 1550
Ala Thr Ala Cys 'Iyr Asp Arg Ala Ile Gln Leu Glu Pro Asp Gln Ile
1555 1560 1565
Ile His Tyr His Gly Val Val Lys Ser Met Leu Gly Leu Gly Gln Leu
1570 1575 1580
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Ser Thr Val Ile Thr Gln Val Asn Gly Val His Ala Asn Arg Ser Glu
1585 1590 1595 1600
Trp Thr Asp Glu Leu Asn Thr Tyr Arg Val Glu Ala Ala Trp Lys Leu
1605 1610 1615
Ser Gln Trp Asp Leu Val Glu Asn Tyr Leu Ala Ala Asp Gly Lys Ser
1620 1625 1630
Thr Thr Trp Ser Val Arg Leu Gly Gln Leu Leu Leu Ser Ala Lys Lys
1635 1640 1645
Arg Asp Ile Thr Ala Phe Tyr Asp Ser Leu Lys Leu Val Arg Ala Glu
1650 1655 1660
Gln Ile Val Pro Leu Ser Ala Ala Ser Phe Glu Arg Gly Ser Tyr Gln
1665 1670 1675 1680
Arg Gly Tyr Glu Tyr Ile Val Arg Leu His Met Leu Cys Glu Leu Glu
1685 1690 1695
His Ser Ile Lys Pro Leu Phe Gln His Ser Pro Gly Asp Ser Ser Gln
1700 1705 1710
Glu Asp Ser Leu Asn Trp Val Ala Arg Leu Glu Met Thr Gln Asn Ser
1715 1720 1725
Tyr Arg Ala Lys Glu Pro Ile Leu Ala Leu Arg Arg Ala Leu Leu Ser
1730 1735 1740
Leu Asn Lys Arg Pro Asp Tyr Asn Glu Met Val Gly Glu Cys Trp Leu
1745 1750 1755 1760
Gln Ser Ala Arg Val Ala Arg Lys Ala Gly His His Gln Thr Ala Tyr
1765 1770 1775
Asn Ala Leu Leu Asn Ala Gly Glu Ser Arg Leu Ala Glu Leu Tyr Val
1780 1785 1790
Glu Arg Ala Lys Trp Leu Trp Ser Lys Gly Asp Val His Gln Ala Leu
1795 1800 1805
Ile Val Leu Gln Lys Gly Val Glu Leu Cys Phe Pro Glu Asn Glu Thr
1810 1815 1820
Pro Pro Glu Gly Lys Asn Met Leu Ile His Gly Arg Ala Met Leu Leu
1825 1830 1835 1840
Val Gly Arg Phe Met Glu Glu Thr Ala Asn Phe Glu Ser Asn Ala Ile
1845 1850 1855
Met Lys Lys Tyr Lys Asp Val Thr Ala Cys Leu Pro Glu Trp Glu Asp
1860 1865 1870
Gly His Phe Tyr Leu Ala Lys Tyr Tyr Asp Lys Leu Met Pro Met Val
1875 1880 1885
Thr Asp Asn Lys Met Glu Lys Gln Gly Asp Leu Ile Arg Tyr Ile Val
1890 1895 1900
Leu His Phe Gly Arg Ser Leu Gln Tyr Gly Asn Gln Phe Ile Tyr Gln
1905 1910 1915 1920
Ser Met Pro Arg Met Leu Thr Leu Trp Leu Asp Tyr Gly Thr Lys Ala
1925 1930 1935
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Tyr Glu Trp Glu Lys Ala Gly Arg Ser Asp Arg Val Gln Met Arg Asn
1940 1945 1950
Asp Leu Gly Lys Ile Asn Lys Val Ile Thr Glu His Thr Asn Tyr Leu
1955 1960 1965
Ala Pro Tyr Gln Phe Leu Thr Ala Phe Ser Gln Leu Ile Ser Arg Ile
1970 1975 1980
Cys His Ser His Asp Glu Val Phe Val Val Leu Asp Gly Asn Asn Ser
1985 1990 1995 2000
Gln Val Phe Leu Ala Tyr Pro Gln Gln Ala Met Trp Met Met Thr Ala
2005 2010 2015
Val Ser Lys Ser Ser Tyr Pro Met Arg Val Asn Arg Cys Lys Glu Ile
2020 2025 2030
Leu Asn Lys Ala Ile His Met Lys Lys Ser Leu Glu Lys Phe Val Gly
2035 2040 2045
Asp Ala Thr Arg Leu Thr Asp Lys Leu Leu Glu Leu Cys Asn Lys Pro
2050 2055 2060
Val Asp Gly Ser Ser Ser Thr Leu Ser Met Ser Thr His Phe Lys Met
2065 2070 2075 2080
Leu Lys Lys Leu Val Glu Glu Ala Thr Phe Ser Glu Ile Leu Ile Pro
2085 2090 2095
Leu Gln Ser Val Met Ile Pro Thr Leu Pro Ser Ile Leu Gly Thr His
2100 2105 2110
Ala Asn His Ala Ser His Glu Pro Phe Pro Gly His Trp Ala Tyr Ile
2115 2120 2125
Ala Gly Phe Asp Asp Met Val Glu Ile Leu Ala Ser Leu Gln Lys Pro
2130 2135 2140
Lys Lys Ile Ser Leu Lys Gly Ser Asp Gly Lys Phe Tyr Ile Met Met
2145 2150 2155 2160
Cys Lys Pro Lys Asp Asp Leu Arg Lys Asp Cys Arg Leu Met Glu Phe
2165 2170 2175
Asn Ser Leu Ile Asn Lys Cys Leu Arg Lys Asp Ala Glu Ser Arg Arg
2180 2185 2190
Arg Glu Leu His Ile Arg Thr Tyr Ala Val Ile Pro Leu Asn Asp Glu
2195 2200 2205
Cys Gly Ile Ile Glu Trp Val Asn Asn Thr Ala Gly Leu Arg Pro Ile
2210 2215 2220
Leu Thr Lys Leu Tyr Lys Glu Lys Gly Val Tyr Met Thr Gly Lys Glu
2225 2230 2235 2240
Leu Arg Gln Cys Met Leu Pro Lys Ser Ala Ala Leu Ser Glu Lys Leu
2245 2250 2255
Lys Val Phe Arg Glu Phe Leu Leu Pro Arg His Pro Pro Ile Phe His
2260 2265 2270
Glu Trp Phe Leu Arg Thr Phe Pro Asp Pro Thr Ser Trp Tyr Ser Ser
2275 2280 2285
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Arg Ser Ala Tyr Cys Arg Ser Thr Ala Val Met Ser Met Val Gly Tyr
2290 2295 2300
Ile Leu Gly Leu Gly Asp Arg His Gly Glu Asn Ile Leu Phe Asp Ser
2305 2310 2315 2320
Leu Thr Gly Glu Cys Val His Val Asp Phe Asn Cys Leu Phe Asn Lys
2325 2330 2335
Gly Glu Thr Phe Glu Val Pro Glu Ile Val Pro Phe Arg Leu Thr His
2340 2345 2350
Asn Met Val Asn Gly Met Gly Pro Met Gly Thr Glu Gly Leu Phe Arg
2355 2360 2365
Arg Ala Cys Glu Val Thr Met Arg Leu Met Arg Asp Gln Arg Glu Pro
2370 2375 2380
Leu Met Ser Val Leu Lys Thr Phe Leu His Asp Pro Leu Val Glu Trp
2385 2390 2395 2400
Ser Lys Pro Val Lys Gly His Ser Lys Ala Pro Leu Asn Glu Thr Gly
2405 2410 2415
Glu Val Val Asn Glu Lys Ala Lys Thr His Val Leu Asp Ile Glu Gln
2420 2425 2430
Arg Leu Gln Gly Val Ile Lys Thr Arg Asn Arg Val Thr Gly Leu Pro
2435 2440 2445
Leu Ser Ile Glu Gly His Val His Tyr Leu Ile Gln Glu Ala Thr Asp
2450 2455 2460
Glu Asn Leu Leu Cys Gln Met Tyr Leu Gly Trp Thr Pro Tyr Met
2465 2470 2475
(2) INFORMATION FOR SEQ ID NO:19:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 23 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: DNA
(vii) IMMEDIATE SOURCE:
(B) CLONE: Primer oDH26
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:19:
TGGTTTCTGA GAACATTCCC TGA 23
(2) INFORMATION FOR SEQ ID NO:20:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 9 amino acids
(B) TYPE: amino acid
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(vii) IMMEDIATE SOURCE:
(B) CLONE: FLAG tag
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(xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:
Met Asp Tyr Lys Asp Asp Asp Asp Lys
1 5
(2) INFORMATION FOR SEQ ID NO:21:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 20 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: DNA
(vii) IMMEDIATE SOURCE:
(B) CLONE: Primer 279-3
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:
TGGATGATGA CAGCTGTGTC 20
(2) INFORMATION FOR SEQ ID NO:22:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 20 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: DNA
(vii) IMMEDIATE SOURCE:
(B) CLONE: Primer 279-6
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:
TGTAGTCGCT GCTCAATGTC 20
(2) INFORMATION FOR SEQ ID NO:23:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 7624 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: cDNA
(ix) FEATURE:
(A) NAME/KEY: CDS
(B) LOCATION: 333..7562
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:
CTTGTGAAGA GAATGTTTTA CACTCTTGTT AGTGAAGTTT ATTCTTTAAA AGTCAATCGT 60
CAAGGATTTA GCAAATGAAT TAGCACTTCG GATATACTTG TTTATT'TAAT ATCTTT TTTG 120
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TTTATTTCAA AGAATTCAGT AATTGGATCA TAACGAGACT TCTGCGGATT GCAGCAACTC 180
CCTCCTGTCA TPTGTTACAC AAGAAAATCT GTGAAGTCAT CTGTTCATTA TTATTTCTTT 240
TTAAAP.GCAA GAGTCCTGCT ATTTTTGGGG TACTCACAAA AGAATTATTA CAACTTTTTG 300
AAGACTTGGT TTACCTCCAT AGAAGAAATG TG ATG GGT CAT GCT GTG GAA TGG 353
Met Gly His Ala Val Glu Trp
1 5
CCA GTG GTC ATG AGC CGA TTT TTA AGT CAA TTA GAT GAA CAC ATG GGA 401
Pro Val Val Met Ser Arg Phe Leu Ser Gln Leu Asp Glu His Met Gly
15 20
TAT TTA CAA TCA GCT CCT TTG CAG TTG ATG AGT ATG CAA AAT TTA GAA 449
Tyr Leu Gln Ser Ala Pro Leu Gln Leu Met Ser Met Gln Asn Leu Glu
25 30 35
TTT ATT GAA GTC ACT TTA TTA ATG GTT CTT ACT CGT ATT ATT GCA ATT 497
Phe Ile Glu Val Thr Leu Leu Met Val Leu Thr Arg Ile Ile Ala Ile
40 45 50 55
GTG TTT TTT AGA AGG CAA GAA CTC TTA CTT TGG CAG ATA GGT TGT GTT 545
Val Phe Phe Arg Arg Gln Glu Leu Leu Leu Trp Gln Ile Gly Cys Val
60 65 70
CTG CTA GAG TAT GGT AGT CCA AAA ATT AAA TCC CTA GCA ATT AGC TTT 593
Leu Leu Glu Tyr Gly Ser Pro Lys Ile Lys Ser Leu Ala Ile Ser Phe
75 80 85
TTA ACA GAA CTT TTT CAG CTT GGA GGA CTA CCA GCA CAA CCA GCT AGC 641
Leu Thr Glu Leu Phe Gln Leu Gly Gly Leu Pro Ala Gln Pro Ala Ser
90 95 100
ACT TTT TTC AGC TCA TTT TTG GAA TTA TTA AAA CAC CTT GTA GAA ATG 689
Thr Phe Phe Ser Ser Phe Leu Glu Leu Leu Lys His Leu Val Glu Met
105 110 115
GAT ACT GAC CAA TTG AAA CTC TAT GAA GAG CCA TTA TCA AAG CTG ATA 737
Asp Thr Asp Gln Leu Lys Leu Tyr Glu Glu Pro Leu Ser Lys Leu Ile
120 125 130 135
AAG ACA CTA TTT CCC TTT GAA GCA GAA GCT TAT AGA AAT ATT GAA CCT 785
Lys Thr Leu Phe Pro Phe Glu Ala Glu Ala Tyr Arg Asn Ile Glu Pro
140 145 150
GTC TAT TTA AAT ATG CTG CTG GAA AAA CTC TGT GTC ATG TTT GAA GAC 833
Val Tyr Leu Asn Met Leu Leu Glu Lys Leu Cys Val Met Phe Glu Asp
155 160 165
GGT GTG CTC ATG CGG CTT AAG TCT GAT TTG CTA AAA GCA GCT TTG TGC 881
Gly Val Leu Met Arg Leu Lys Ser Asp Leu Leu Lys Ala Ala Leu Cys
170 175 180
CAT TTA CTG CAG TAT TTC CTT AAA TTT GTG CCA GCT GGG TAT GAA TCT 929
His Leu Leu Gin Tyr Phe Leu Lys Phe Val Pro Ala Gly Tyr Glu Ser
185 190 195
GCT TTA CAA GTC AGG AAG GTC TAT GTG AGA AAT ATT TGT AAA GCT CTT 977
Ala Leu Gln Val Arg Lys Val Tyr Val Arg Asn Ile Cys Lys Ala Leu
200 205 210 215
TTG GAT GTG CTT GGA ATT GAG GTA GAT GCA GAG TAC TTG TTG GGC CCA 1025
Leu Asp Val Leu Gly Ile Glu Val Asp Ala Glu Tyr Leu Leu Gly Pro
220 225 230
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CTT TAT GCA GCT TTG AAA ATG GAA AGT ATG GAA ATC ATT GAG GAG ATT 1073
Leu Tyr Ala Ala Leu Lys Met Glu Ser Met Glu Ile Ile Glu Glu Ile
235 240 245
CAA TGC CAA ACT CAA CAG GAA AAC CTC AGC AGT AAT AGT GAT GGA ATA 1121
Gln Cys Gln Thr Gln Gln Glu Asn Leu Ser Ser Asn Ser Asp Gly Ile
250 255 260
TCA CCC AAA AGG CGT CGT CTC AGC TCG TCT CTA AAC CCT TCT AAA AGA 1169
Ser Pro Lys Arg Arg Arg Leu Ser Ser Ser Leu Asn Pro Ser Lys Arg
265 270 275
GCA CCA AAA CAG ACT GAG GAA ATT AAA CAT GTG GAC ATG AAC CAA AAG 1217
Ala Pro Lys Gin Thr Glu Glu Ile Lys His Val Asp Met Asn Gln Lys
280 285 290 295
AGC ATA TTA TGG AGT GCA CTG AAA CAG AAA GCT GAA TCC CTT CAG ATT 1265
Ser Ile Leu Trp Ser Ala Leu Lys Gln Lys Ala Glu Ser Leu Gln Ile
300 305 310
TCC CTT GAA TAC AGT GGC CTA AAG AAT CCT GTT ATT GAG ATG TTA GAA 1313
Ser Leu Glu Tyr Ser Gly Leu Lys Asn Pro Val Ile Glu Met Leu Glu
315 320 325
GGA ATT GCT GTT GTC TTA CAA CTG ACT GCT CTG TGT ACT GTT CAT TGT 1361
Gly Ile Ala Val Val Leu Gln Leu Thr Ala Leu Cys Thr Val His Cys
330 335 340
TCT CAT CAA AAC ATG AAC TGC CGT ACT TTC AAG GAC TGT CAA CAT AAA 1409
Ser His Gln Asn Met Asn Cys Arg Thr Phe Lys Asp Cys Gln His Lys
345 350 355
TCC AAG AAG AAA CCT TCT GTA GTG ATA ACT TGG ATG TCA TTG GAT TTT 1457
Ser Lys Lys Lys Pro Ser Val Val Ile Thr Trp Met Ser Leu Asp Phe
360 365 370 375
TAC ACA AAA GTG CTT AAG AGC TGT AGA AGT TTG TTA GAA TCT GTT CAG 1505
Tyr Thr Lys Val Leu Lys Ser Cys Arg Ser Leu Leu Glu Ser Val Gln
380 385 390
AAA CTG GAC CTG GAG GCA ACC ATT GAT AAG GTG GTG AAA ATT TAT GAT 1553
Lys Leu Asp Leu Glu Ala Thr Ile Asp Lys Val Val Lys Ile Tyr Asp
395 400 405
GCT TTG ATT TAT ATG CAA GTA AAC AGT TCA TTT GAA GAT CAT ATC CTG 1601
Ala Leu Ile Tyr Met Gln Val Asn Ser Ser Phe Glu Asp His Ile Leu
410 415 420
GAA GAT TTA TGT GGA ATG CTC TCA CTT CCA TGG ATT TAT TCC CAT TCT 1649
Glu Asp Leu Cys Gly Met Leu Ser Leu Pro Trp Ile Tyr Ser His Ser
425 430 435
GAT GAT GGC TGT TTA AAG TTG ACC ACA TTT GCC GCT AAT CTT CTA ACA 1697
Asp Asp Gly Cys Leu Lys Leu Thr Thr Phe Ala Ala Asn Leu Leu Thr
440 445 450 455
TTA AGC TGT AGG ATT TCA GAT AGC TAT TCA CCA CAG GCA CAA TCA CGA 1745
Leu Ser Cys Arg Ile Ser Asp Ser Tyr Ser Pro Gln Ala Gln Ser Arg
460 465 470
TGT GTG TTT CTT CTG ACT CTG TTT CCA AGA AGA ATA TTC CTT GAG TGG 1793
Cys Val Phe Leu Leu Thr Leu Phe Pro Arg Arg Ile Phe Leu Glu Trp
475 480 485
AGA ACA GCA GTT TAC AAC TGG GCC CTG CAG AGC TCC CAT GAA GTA ATC 1841
Arg Thr Ala Val Tyr Asn Trp Ala Leu Gln Ser Ser His Glu Val Ile
490 495 500
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CGG GCT AGT TGT GTT AGT GGA TTT TTT ATC TTA TTG CAG CAG CAG AAT 1889
Arg Ala Ser Cys Val Ser Gly Phe Phe Ile Leu Leu Gln Gln Gln Asn
505 510 515
TCT TGT AAC AGA GTT CCC AAG ATT CTT ATA GAT AAA GTC AAA GAT GAT 1937
Ser Cys Asn Arg Val Pro Lys Ile Leu Ile Asp Lys Val Lys Asp Asp
520 525 530 535
TCT GAC ATT GTC AAG AAA GAA TTT GCT TCT ATA CTT GGT CAA CTT GTC 1985
Ser Asp Ile Val Lys Lys Glu Phe Ala Ser Ile Leu Gly Gln Leu Val
540 545 550
TGT ACT CTT CAC GGC ATG TTT TAT CTG ACA AGT TCT TTA ACA GAA CCT 2033
Cys Thr Leu His Gly Met Phe Tyr Leu Thr Ser Ser Leu Thr Glu Pro
555 560 565
TTC TCT GAA CAC GGA CAT GTG GAC CTC TTC TGT AGG AAC TTG AAA GCC 2081
Phe Ser Glu His Gly His Val Asp Leu Phe Cys Arg Asn Leu Lys Ala
570 575 580
ACT TCT CAA CAT GAA TGT TCA TCT TCT CAA CTA AAA GCT TCT GTC TGC 2129
Thr Ser Gln His Glu Cys Ser Ser Ser Gln Leu Lys Ala Ser Val Cys
585 590 595
AAG CCA TTC CTT TTC CTA CTG AAA AAA AAA ATA CCT AGT CCA GTA AAA 2177
Lys Pro Phe Leu Phe Leu Leu Lys Lys Lys Ile Pro Ser Pro Val Lys
600 605 610 615
CTT GCT TTC ATA GAT AAT CTA CAT CAT CTT TGT AAG CAT CTT GAT TTT 2225
Leu Ala Phe Ile Asp Asn Leu His His Leu Cys Lys His Leu Asp Phe
620 625 630
AGA GAA GAT GAA ACA GAT GTA AAA GCA GTT CTT GGA ACT TTA TTA AAT 2273
Arg Glu Asp Glu Thr Asp Val Lys Ala Val Leu Gly Thr Leu Leu Asn
635 640 645
TTA ATG GAA GAT CCA GAC AAA GAT GTT AGA GTG GCT TTT AGT GGA AAT 2321
Leu Met Glu Asp Pro Asp Lys Asp Val Arg Val Ala Phe Ser Gly Asn
650 655 660
ATC AAG CAC ATA TTG GAA TCC TTG GAC TCT GAA GAT GGA TTT ATA AAG 2369
Ile Lys His Ile Leu Glu Ser Leu Asp Ser Glu Asp Gly Phe Ile Lys
665 670 675
GAG CTT TTT GTC TTA AGA ATG AAG GAA GCA TAT ACA CAT GCC CAA ATA 2417
Glu Leu Phe Val Leu Arg Met Lys Glu Ala Tyr Thr His Ala Gln Ile
680 685 690 695
TCA AGA AAT AAT GAG CTG AAG GAT ACC TTG ATT CTT ACA ACA GGG GAT 2465
Ser Arg Asn Asn Glu Leu Lys Asp Thr Leu Ile Leu Thr Thr Gly Asp
700 705 710
ATT GGA AGG GCC GCA AAA GGA GAT TTG GTA CCA TTT GCA CTC TTA CAC 2513
Ile Gly Arg Ala Ala Lys Gly Asp Leu Val Pro Phe Ala Leu Leu His
715 720 725
TTA TTG CAT TGT TTG TTA TCC AAG TCA GCA TCT GTC TCT GGA GCA GCA 2561
Leu Leu His Cys Leu Leu Ser Lys Ser Ala Ser Val Ser Gly Ala Ala
730 735 740
TAC ACA GAA ATT AGA GCT CTG GTT GCA GCT AAA AGT GTT AAA CTG CAA 2609
Tyr Thr Glu Ile Arg Ala Leu Val Ala Ala Lys Ser Val Lys Leu Gln
745 750 755
AGT TTT TTC AGC CAG TAT AAG AAA CCC ATC TGT CAG TTT TTG GTA GAA 2657
Ser Phe Phe Ser Gln Tyr Lys Lys Pro Ile Cys Gln Phe Leu Val Glu
760 765 770 775
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TCC CTT CAC TCT AGT CAG ATG ACA GCA CTT CCG AAT ACT CCA TGC CAG 2705
Ser Leu His Ser Ser Gln Met Thr Ala Leu Pro Asn Thr Pro Cys Gln
780 785 790
AAT GCT GAC GTG CGA AAA CAA GAT GTG GCT CAC CAG AGA GAA ATG GCT 2753
Asn Ala Asp Val Arg Lys Gln Asp Val Ala His Gln Arg Glu Met Ala
795 800 805
TTA AAT ACG TTG TCT GAA ATT GCC AAC GTT TTC GAC TTT CCT GAT CTT 2801
Leu Asn Thr Leu Ser Glu Ile Ala Asn Val Phe Asp Phe Pro Asp Leu
810 815 820
AAT CGT TTT CTT ACT AGG ACA TTA CAA GTT CTA CTA CCT GAT CTT GCT 2849
Asn Arg Phe Leu Thr Arg Thr Leu G1n Val Leu Leu Pro Asp Leu Ala
825 830 835
GCC AAA GCA AGC CCT GCA GCT TCT GCT CTC ATT CGA ACT TTA GGA AAA 2897
Ala Lys Ala Ser Pro Ala Ala Ser Ala Leu Ile Arg Thr Leu Gly Lys
840 845 850 855
CAA TTA AAT GTC AAT CGT AGA GAG ATT TTA ATA AAC AAC TTC AAA TAT 2945
Gln Leu Asn Val Asn Arg Arg Glu Ile Leu Ile Asn Asn Phe Lys Tyr
860 865 870
ATT TTT TCT CAT TTG GTC TGT TCT TGT TCC AAA GAT GAA TTA GAA CGT 2993
Ile Phe Ser His Leu Val Cys Ser Cys Ser Lys Asp Glu Leu Glu Arg
875 880 885
GCC CTT CAT TAT CTG AAG AAT GAA ACA GAA ATT GAA CTG GGG AGC CTG 3041
Ala Leu His Tyr Leu Lys Asn Glu Thr Glu Ile Glu Leu Gly Ser Leu
890 895 900
TTG AGA CAA GAT TTC CAA GGA TTG CAT AAT GAA TTA TTG CTG CGT ATT 3089
Leu Arg Gln Asp Phe Gln Gly Leu His Asn Glu Leu Leu Leu Arg Ile
905 910 915
GGA GAA CAC TAT CAA CAG GTT TTT AAT GGT TTG TCA ATA CTT GCC TCA 3137
Gly Glu His Tyr Gln Gln Val Phe Asn Gly Leu Ser Ile Leu Ala Ser
920 925 930 935
TTT GCA TCC AGT GAT GAT CCA TAT CAG GGC CCG AGA GAT ATC ATA TCA 3185
Phe Ala Ser Ser Asp Asp Pro Tyr Gln Gly Pro Arg Asp Ile Ile Ser
940 945 950
CCT GAA CTG ATG GCT GAT TAT TTA CAA CCC AAA TTG TTG GGC ATT TTG 3233
Pro Glu Leu Met Ala Asp Tyr Leu Gln Pro Lys Leu Leu Gly Ile Leu
955 960 965
GCT TTT TTT AAC ATG CAG TTA CTG AGC TCT AGT GTT GGC ATT GAA GAT 3281
Ala Phe Phe Asn Met Gln Leu Leu Ser Ser Ser Val Gly Ile Glu Asp
970 975 980
AAG AAA ATG GCC TTG AAC AGT TTG ATG TCT TTG ATG AAG TTA ATG GGA 3329
Lys Lys Met Ala Leu Asn Ser Leu Met Ser Leu Met Lys Leu Met Gly
985 990 995
CCC AAA CAT GTC AGT TCT GTG AGG GTG AAG ATG ATG ACC ACA CTG AGA 3377
Pro Lys His Val Ser Ser Val Arg Val Lys Met Met Thr Thr Leu Arg
1000 1005 1010 1015
ACT GGC CTT CGA TTC AAG GAT GAT TTT CCT GAA TTG TGT TGC AGA GCT 3425
Thr Gly Leu Arg Phe Lys Asp Asp Phe Pro Glu Leu Cys Cys Arg Ala
1020 1025 1030
TGG GAC TGC TTT GTT CGC TGC CTG GAT CAT GCT TGT CTG GGC TCC CTT 3473
Trp Asp Cys Phe Vai Arg Cys Leu Asp His Ala Cys Leu Gly Ser Leu
1035 1040 1045
CA 02210650 1997-07-16
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CTC AGT CAT GTA ATA GTA GCT TTG TTA CCT CTT ATA CAC ATC CAG CCT 3521
Leu Ser His Val Ile Val Ala Leu Leu Pro Leu Ile His Ile Gln Pro
1050 1055 1060
AAA GAA ACT GCA GCT ATC TTC CAC TAC CTC ATA ATT GAA AAC AGG GAT 3569
Lys Glu Thr Ala Ala Ile Phe His Tyr Leu Ile Ile Glu Asn Arg Asp
1065 1070 1075
GCT GTG CAA GAT TTT CTT CAT GAA ATA TAT TTT TTA CCT GAT CAT CCA 3617
Ala Val Gln Asp Phe Leu His Glu Ile Tyr Phe Leu Pro Asp His Pro
1080 1085 1090 1095
GAA TTA AAA AAG ATA AAA GCC GTT CTC CAG GAA TAC AGA AAG GAG ACC 3665
Glu Leu Lys Lys Ile Lys Ala Val Leu Gln Glu Tyr Arg Lys Glu Thr
1100 1105 1110
TCT GAG AGC ACT GAT CTT CAG ACA ACT CTT CAG CTC TCT ATG AAG GCC 3713
Ser Glu Ser Thr Asp Leu Gln Thr Thr Leu Gln Leu Ser Met Lys Ala
1115 1120 1125
ATT CAA CAT GAA AAT GTC GAT GTT CGT ATT CAT GCT CTT ACA AGC TTG 3761
Ile Gin His Glu Asn Val Asp Val Arg Ile His Ala Leu Thr Ser Leu
1130 1135 1140
AAG GAA ACC TTG TAT AAA AAT CAG GAA AAA CTG ATA AAG TAT GCA ACA 3809
Lys Glu Thr Leu Tyr Lys Asn Gln Glu Lys Leu Ile Lys Tyr Ala Thr
1145 1150 1155
GAC AGT GAA ACA GTA GAA CCT ATT ATC TCA CAG TTG GTG ACA GTG CTT 3857
Asp Ser Glu Thr Val Glu Pro Ile Ile Ser Gln Leu Val Thr Val Leu
1160 1165 1170 1175
TTG AAA GGT TGC CAA GAT GCA AAC TCT CAA GCT CGG TTG CTC TGT GGG 3905
Leu Lys Gly Cys Gln Asp Ala Asn Ser Gln Ala Arg Leu Leu Cys Gly
1180 1185 1190
GAA TGT TTA GGG GAA TTG GGG GCG ATA GAT CCA GGT CGA TTA GAT TTC 3953
Glu Cys Leu Gly Glu Leu Gly Ala Ile Asp Pro Gly Arg Leu Asp Phe
1195 1200 1205
TCA ACA ACT GAA ACT CAA GGA AAA GAT TTT ACA TTT GTG ACT GGA GTA 4001
Ser Thr Thr Glu Thr Gln Gly Lys Asp Phe Thr Phe Val Thr Gly Val
1210 1215 1220
GAA GAT TCA AGC TTT GCC TAT GGA TTA TTG ATG GAG CTA ACA AGA GCT 4049
Glu Asp Ser Ser Phe Ala Tyr Gly Leu Leu Met Glu Leu Thr Arg Ala
1225 1230 1235
TAC CTT GCG TAT GCT GAT AAT AGC CGA GCT CAA GAT TCA GCT GCC TAT 4097
Tyr Leu Ala Tyr Ala Asp Asn Ser Arg Ala Gln Asp Ser Ala Ala Tyr
1240 1245 1250 1255
GCC ATT CAG GAG TTG CTT TCT ATT TAT GAC TGT AGA GAG ATG GAG ACC 4145
Ala Ile Gln Glu Leu Leu Ser Ile Tyr Asp Cys Arg Glu Met Glu Thr
1260 1265 1270
AAC GGC CCA GGT CAC CAA TTG TGG AGG AGA TTT CCT GAG CAT GTT CGG 4193
Asn Gly Pro Gly His Gln Leu Trp Arg Arg Phe Pro Glu His Val Arg
1275 1280 1285
GAA ATA CTA GAA CCT CAT CTA AAT ACC AGA TAC AAG AGT TCT CAG AAG 4241
Glu Ile Leu Glu Pro His Leu Asn Thr Arg Tyr Lys Ser Ser Gln Lys
1290 1295 1300
TCA ACC GAT TGG TCT GGA GTA AAG AAG CCA ATT TAC TTA AGT AAA TTG 4289
Ser Thr Asp Trp Ser Gly Val Lys Lys Pro Ile Tyr Leu Ser Lys Leu
1305 1310 1315
CA 02210650 1997-07-16
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GGT AGT AAC TTT GCA GAA TGG TCA GCA TCT TGG GCA GGT TAT CTT ATT 4337
Gly Ser Asn Phe Ala Glu Trp Ser Ala Ser Trp Ala Gly Tyr Leu Ile
1320 1325 1330 1335
ACA AAG GTT CGA CAT GAT CTT GCC AGT AAA ATT TTC ACC TGC TGT AGC 4385
Thr Lys Val Arg His Asp Leu Ala Ser Lys Ile Phe Thr Cys Cys Ser
1340 1345 1350
ATT ATG ATG AAG CAT GAT TTC AAA GTG ACC ATC TAT CTT CTT CCA CAT 4433
Ile Met Met Lys His Asp Phe Lys Val Thr Ile Tyr Leu Leu Pro His
1355 1360 1365
ATT CTG GTG TAT GTC TTA CTG GGT TGT AAT CAA GAA GAT CAG CAG GAG 4481
Ile Leu Val Tyr Val Leu Leu Gly Cys Asn Gln Glu Asp Gln Gln Glu
1370 1375 1380
GTT TAT GCA GAA ATT ATG GCA GTT CTA AAG CAT GAC GAT CAG CAT ACC 4529
Val Tyr Ala Glu Ile Met Ala Val Leu Lys His Asp Asp Gln His Thr
1385 1390 1395
ATA AAT ACC CAA GAC ATT GCA TCT GAT CTG TGT CAA CTC AGT ACA CAG 4577
Ile Asn Thr Gln Asp Ile Ala Ser Asp Leu Cys Gln Leu Ser Thr Gln
1400 1405 1410 1415
ACT GTG TTC TCC ATG CTT GAC CAT CTC ACA CAG TGG GCA AGG CAC AAA 4625
Thr Val Phe Ser Met Leu Asp His Leu Thr Gln Trp Ala Arg His Lys
1420 1425 1430
TTT CAG GCA CTG AAA GCT GAG AAA TGT CCA CAC AGC AAA TCA AAC AGA 4673
Phe Gln Ala Leu Lys Ala Glu Lys Cys Pro His Ser Lys Ser Asn Arg
1435 1440 1445
AAT AAG GTA GAC TCA ATG GTA TCT ACT GTG GAT TAT GAA GAC TAT CAG 4721
Asn Lys Val Asp Ser Met Val Ser Thr Val Asp Tyr Glu Asp Tyr Gln
1450 1455 1460
AGT GTA ACC CGT TTT CTA GAC CTC ATA CCC CAG GAT ACT CTG GCA GTA 4769
Ser Val Thr Arg Phe Leu Asp Leu Ile Pro Gln Asp Thr Leu Ala Val
1465 1470 1475
GCT TCC TTT CGC TCC AAA GCA TAC ACA CGA GCT GTA ATG CAC TTT GAA 4817
Ala Ser Phe Arg Ser Lys Ala Tyr Thr Arg Ala Val Met His Phe Glu
1480 1485 1490 1495
TCA TTT ATT ACA GAA AAG AAG CAA AAT ATT CAG GAA CAT CTT GGA TTT 4865
Ser Phe Ile Thr Glu Lys Lys Gln Asn Ile Gln Glu His Leu Gly Phe
1500 1505 1510
TTA CAG AAA TTG TAT GCT GCT ATG CAT GAA CCT GAT GGA GTG GCC GGA 4913
Leu Gln Lys Leu Tyr Ala Ala Met His Glu Pro Asp Gly Val Ala Gly
1515 1520 1525
GTC AGT GCA ATT AGA AAG GCA GAA CCA TCT CTA AAA GAA CAG ATC CTT 4961
Val Ser Ala Ile Arg Lys Ala Glu Pro Ser Leu Lys Glu Gln Ile Leu
1530 1535 1540
GAA CAT GAA AGC CTT GGC TTG CTG AGG GAT GCC ACT GCT TGT TAT GAC 5009
Glu His Glu Ser Leu Gly Leu Leu Arg Asp Ala Thr Ala Cys Tyr Asp
1545 1550 1555
AGG GCT ATT CAG CTA GAA CCA GAC CAG ATC ATT CAT TAC CAT GGT GTA 5057
Arg Ala Ile Gln Leu Glu Pro Asp Gln Ile Ile His Tyr His Gly Val
1560 1565 1570 1575
GTA AAG TCC ATG TTA GGT CTT GGT CAG CTG TCT ACT GTT ATC ACT CAG 5105
Val Lys Ser Met Leu Gly Leu Gly Gln Leu Ser Thr Val Ile Thr Gln
1580 1585 1590
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GTG AAT GGA GTG CAT GCT AAC AGG TCC GAG TGG ACA GAT GAA TTA AAC 5153
Val Asn Gly Val His Ala Asn Arg Ser Glu Trp Thr Asp Glu Leu Asn
1595 1600 1605
ACG TAC AGA GTG GAA GCA GCT TGG AAA TTG TCA CAG TGG GAT TTG GTG 5201
Thr Tyr Arg Val Glu Ala Ala Trp Lys Leu Ser Gln Trp Asp Leu Val
1610 1615 1620
GAA AAC TAT TTG GCA GCA GAT GGA AAA TCT ACA ACA TGG AGT GTC AGA 5249
Glu Asn Tyr Leu Ala Ala Asp Gly Lys Ser Thr Thr Trp Ser Val Arg
1625 1630 1635
CTG GGA CAG CTA TTA TTA TCA GCC AAA AAA AGA GAT ATC ACA GCT TTT 5297
Leu Gly Gln Leu Leu Leu Ser Ala Lys Lys Arg Asp Ile Thr Ala Phe
1640 1645 1650 1655
TAT GAC TCA CTG AAA CTA GTG AGA GCA GAA CAA ATT GTA CCT CTT TCA 5345
Tyr Asp Ser Leu Lys Leu Val Arg Ala Glu Gln Ile Val Pro Leu Ser
1660 1665 1670
GCT GCA AGC TTT GAA AGA GGC TCC TAC CAA CGA GGA TAT GAA TAT ATT 5393
Ala Ala Ser Phe Glu Arg Gly Ser Tyr Gln Arg Gly Tyr Glu Tyr Ile
1675 1680 1685
GTG AGA TTG CAC ATG TTA TGT GAG TTG GAG CAT AGC ATC AAA CCA CTT 5441
Val Arg Leu His Met Leu Cys Glu Leu Giu His Ser Ile Lys Pro Leu
1690 1695 1700
TTC CAG CAT TCT CCA GGT GAC AGT TCT CAA GAA GAT TCT CTA AAC TGG 5489
Phe Gln His Ser Pro Gly Asp Ser Ser Gln Glu Asp Ser Leu Asn Trp
1705 1710 1715
GTA GCT CGA CTA GAA ATG ACC CAG AAT TCC TAC AGA GCC AAG GAG CCT 5537
Val Ala Arg Leu Glu Met Thr Gln Asn Ser Tyr Arg Ala Lys Glu Pro
1720 1725 1730 1735
ATC CTG GCT CTC CGG AGG GCT TTA CTA AGC CTC AAC AAA AGA CCA GAT 5585
Ile Leu Ala Leu Arg Arg Ala Leu Leu Ser Leu Asn Lys Arg Pro Asp
1740 1745 1750
TAC AAT GAA ATG GTT GGA GAA TGC TGG CTG CAG AGT GCC AGG GTA GCT 5633
Tyr Asn Glu Met Val Gly Glu Cys Trp Leu Gln Ser Ala Arg Val Ala
1755 1760 1765
AGA AAG GCT GGT CAC CAC CAG ACA GCC TAC AAT GCT CTC CTT AAT GCA 5681
Arg Lys Ala Gly His His Gln Thr Ala Tyr Asn Ala Leu Leu Asn Ala
1770 1775 1780
GGG GAA TCA CGA CTC GCT GAA CTG TAC GTG GAA AGG GCA AAG TGG CTC 5729
Gly Glu Ser Arg Leu Ala Glu Leu Tyr Val Glu Arg Ala Lys Trp Leu
1785 1790 1795
TGG TCC AAG GGT GAT GTT CAC CAG GCA CTA ATT GTT CTT CAA AAA GGT 5777
Trp Ser Lys Gly Asp Val His Gln Ala Leu Ile Val Leu Gln Lys Gly
1800 1805 1810 1815
GTT GAA TTA TGT TTT CCT GAA AAT GAA ACC CCA CCT GAG GGT AAG AAC 5825
Val Glu Leu Cys Phe Pro Glu Asn Glu Thr Pro Pro Glu Gly Lys Asn
1820 1825 1830
ATG TTA ATC CAT GGT CGA GCT ATG CTA CTA GTG GGC CGA TTT ATG GAA 5873
Met Leu Ile His Gly Arg Ala Met Leu Leu Val Gly Arg Phe Met Glu
1835 1840 1845
GAA ACA GCT AAC TTT GAA AGC AAT GCA ATT ATG AAA AAA TAT AAG GAT 5921
Glu Thr Ala Asn Phe Glu Ser Asn Ala Ile Met Lys Lys Tyr Lys Asp
1850 1855 1860
CA 02210650 1997-07-16
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GTG ACC GCG TGC CTG CCA GAA TGG GAG GAT GGG CAT TTT TAC CTT GCC 5969
Val Thr Ala Cys Leu Pro Glu Trp Glu Asp Gly His Phe Tyr Leu Ala
1865 1870 1875
AAG TAC TAT GAC AAA TTG ATG CCC ATG GTC ACA GAC AAC AAA ATG GAA 6017
Lys Tyr Tyr Asp Lys Leu Met Pro Met Val Thr Asp Asn Lys Met Glu
1880 1885 1890 1895
AAG CAA GGT GAT CTC ATC CGG TAT ATA GTT CTT CAT TTT GGC AGA TCT 6065
Lys Gln Gly Asp Leu Ile Arg Tyr Ile Val Leu His Phe Gly Arg Ser
1900 1905 1910
CTA CAA TAT GGA AAT CAG TTC ATA TAT CAG TCA ATG CCA CGA ATG TTA 6113
Leu Gln Tyr Gly Asn Gln Phe Ile Tyr Gln Ser Met Pro Arg Met Leu
1915 1920 1925
ACT CTA TGG CTT GAT TAT GGT ACA AAG GCA TAT GAA TGG GAA AAA GCT 6161
Thr Leu Trp Leu Asp Tyr Gly Thr Lys Ala Tyr Glu Trp Glu Lys Ala
1930 1935 1940
GGC CGC TCC GAT CGT GTA CAA ATG AGG AAT GAT TTG GGT AAA ATA AAC 6209
Gly Arg Ser Asp Arg Val Gln Met Arg Asn Asp Leu Gly Lys Ile Asn
1945 1950 1955
AAG GTT ATC ACA GAG CAT ACA AAC TAT TTA GCT CCA TAT CAA TTT 'ITG 6257
Lys Val Ile Thr Glu His Thr Asn Tyr Leu Ala Pro Tyr Gln Phe Leu
1960 1965 1970 1975
ACT GCT TTT TCA CAA TTG ATC TCT CGA ATT TGT CAT TCT CAC GAT GAA 6305
Thr Ala Phe Ser Gln Leu Ile Ser Arg Ile Cys His Ser His Asp Glu
1980 1985 1990
GTT TTT GTT GTG CTT GAT GGA AAT AAT AGC CAA GTA TTT CTA GCC TAT 6353
Val Phe Val Val Leu Asp Gly Asn Asn Ser Gln Val Phe Leu Ala Tyr
1995 2000 2005
CCT CAA CAA GCA ATG TGG ATG ATG ACA GCT GTG TCA AAG TCA TCT TAT 6401
Pro Gln Gln Ala Met Trp Met Met Thr Ala Val Ser Lys Ser Ser Tyr
2010 2015 2020
CCC ATG CGT GTG AAC AGA TGC AAG GAA ATC CTC AAT AAA GCT ATT CAT 6449
Pro Met Arg Val Asn Arg Cys Lys Glu Ile Leu Asn Lys Ala Ile His
2025 2030 2035
ATG AAA AAA TCC TTA GAG AAG TTT GTT GGA GAT GCA ACT CGC CTA ACA 6497
Met Lys Lys Ser Leu Glu Lys Phe Val Gly Asp Ala Thr Arg Leu Thr
2040 2045 2050 2055
GAT AAG CTT CTA GAA TTG TGC AAT AAA CCG GTG GAA ATT CTT GCT TCT 6545
Asp Lys Leu Leu Glu Leu Cys Asn Lys Pro Val Glu Ile Leu Ala Ser
2060 2065 2070
CTT CAG AAA CCA AAG AAG ATT TCT TTA AAA GGC TCA GAT GGA AAG TTC 6593
Leu Gln Lys Pro Lys Lys Ile Ser Leu Lys Gly Ser Asp Gly Lys Phe
2075 2080 2085
TAC ATC ATG ATG TGT AAG CCA AAA GAT GAC CTG AGA AAG GAT TGT AGA 6641
Tyr Ile Met Met Cys Lys Pro Lys Asp Asp Leu Arg Lys Asp Cys Arg
2090 2095 2100
CTA ATG GAA TTC AAT TCC TTG ATT AAT AAG TGC TTA AGA AAA GAT GCA 6689
Leu Met Glu Phe Asn Ser Leu Ile Asn Lys Cys Leu Arg Lys Asp Ala
2105 2110 2115
GAG TCT CGT AGA AGA GAA CTT CAT ATT CGA ACA TAT GCA GTT ATT CCA 6737
Glu Ser Arg Arg Arg Glu Leu His Ile Arg Thr Tyr Ala Val Ile Pro
2120 2125 2130 2135
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CTA AAT GAT GAA TGT GGG ATT ATT GAA TGG GTG AAC AAC ACT GCT GGT 6785
Leu Asn Asp Glu Cys Gly Ile Ile Glu Trp Val Asn Asn Thr Ala Gly
2140 2145 2150
TTG AGA CCT ATT CTG ACC AAA CTA TAT AAA GAA AAG GGA GTG TAT ATG 6833
Leu Arg Pro Ile Leu Thr Lys Leu Tyr Lys Glu Lys Gly Val Tyr Met
2155 2160 2165
ACA GGA AAA GAA CTT CGC CAG TGT ATG CTA CCA AAG TCA GCA GCT TTA 6881
Thr Gly Lys Glu Leu Arg Gin Cys Met Leu Pro Lys Ser Ala Ala Leu
2170 2175 2180
TCT GAA AAA CTC AAA GTA TTC CGA GAA TTT CTC CTG CCC AGG CAT CCT 6929
Ser Glu Lys Leu Lys Val Phe Arg Glu Phe Leu Leu Pro Arg His Pro
2185 2190 2195
CCT ATT TTT CAT GAG TGG TTT CTG AGA ACA TTC CCT GAT CCT ACA TCA 6977
Pro Ile Phe His Glu Trp Phe Leu Arg Thr Phe Pro Asp Pro Thr Ser
2200 2205 2210 2215
TGG TAC AGT AGT AGA TCA GCT TAC TGC CGT TCC ACT GCA GTA ATG TCA 7025
Trp Tyr Ser Ser Arg Ser Ala Tyr Cys Arg Ser Thr Ala Val Met Ser
2220 2225 2230
ATG GTT GGT TAT ATT CTG GGG CTT GGA GAC CGT CAT GGT GAA AAT ATT 7073
Met Val Gly Tyr Ile Leu Gly Leu Gly Asp Arg His Gly Glu Asn Ile
2235 2240 2245
CTC TTT GAT TCT TTG ACT GGT GAA TGC GTA CAT GTA GAT TTC AAT TGT 7121
Leu Phe Asp Ser Leu Thr Gly Glu Cys Val His Val Asp Phe Asn Cys
2250 2255 2260
CTT TTC AAT AAG GGA GAA ACC TTT GAA GTT CCA GAA ATT GTG CCA TTT 7169
Leu Phe Asn Lys Gly Glu Thr Phe Glu Val Pro Glu Ile Val Pro Phe
2265 2270 2275
CGC CTG ACT CAT AAT ATG GTT AAT GGA ATG GGT CCT ATG GGA ACA GAG 7217
Arg Leu Thr His Asn Met Val Asn Gly Met Gly Pro Met Gly Thr Glu
2280 2285 2290 2295
GGT CTT TTT CGA AGA GCA TGT GAA GTT ACA ATG AGG CTG ATG CGT GAT 7265
Gly Leu Phe Arg Arg Ala Cys Glu Val Thr Met Arg Leu Met Arg Asp
2300 2305 2310
CAG CGA GAG CCT TTA ATG AGT GTC TTA AAG ACT TTT CTA CAT GAT CCT 7313
Gln Arg Glu Pro Leu Met Ser Val Leu Lys Thr Phe Leu His Asp Pro
2315 2320 2325
CTT GTG GAA TGG AGT AAA CCA GTG AAA GGG CAT TCC AAA GCG CCA CTG 7361
Leu Val Glu Trp Ser Lys Pro Val Lys Gly His Ser Lys Ala Pro Leu
2330 2335 2340
AAT GAA ACT GGA GAA GTT GTC AAT GAA AAG GCC AAG ACC CAT GTT CTT 7409
Asn Glu Thr Gly Glu Val Val Asn Glu Lys Ala Lys Thr His Val Leu
2345 2350 2355
GAC ATT GAG CAG CGA CTA CAA GGT GTA ATC AAG ACT CGA AAT AGA GTG 7457
Asp Ile Glu Gln Arg Leu Gln Gly Val Ile Lys Thr Arg Asn Arg Val
2360 2365 2370 2375
ACA GGA CTG CCG TTA TCT ATT GAA GGA CAT GTG CAT TAC CTT ATA CAA 7505
Thr Gly Leu Pro Leu Ser Ile Glu Gly His Val His Tyr Leu Ile Gln
2380 2385 2390
GAA GCT ACT GAT GAA AAC TTA CTA TGC CAG ATG TAT CTT GGT TGG ACT 7553
Glu Ala Thr Asp Glu Asn Leu Leu Cys Gln Met Tyr Leu Gly Trp Thr
2395 2400 2405
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CCA TAT ATG TGAAATGAAA TTATGTAAAA GAATATGTTA ATAATCTAAA 7602
Pro Tyr Met
2410
AGTAAAAAAA AAAAAAAAAA AA 7624
(2) INFORMATION FOR SEQ ID NO:24:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2410 amino acids
(B) TYPE: amino acid
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: protein
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:
Met Gly His Ala Val Glu Trp Pro Val Val Met Ser Arg Phe Leu Ser
1 5 10 15
Gln Leu Asp Glu His Met Gly Tyr Leu Gln Ser Ala Pro Leu Gln Leu
20 25 30
Met Ser Met Gln Asn Leu Glu Phe Ile Glu Val Thr Leu Leu Met Val
35 40 45
Leu Thr Arg Ile Ile Ala Ile Val Phe Phe Arg Arg Gln Glu Leu Leu
50 55 60
Leu Trp Gln Ile Gly Cys Val Leu Leu Glu Tyr Gly Ser Pro Lys Ile
65 70 75 80
Lys Ser Leu Ala Ile Ser Phe Leu Thr Glu Leu Phe Gln Leu Gly Gly
85 90 95
Leu Pro Ala Gln Pro Ala Ser Thr Phe Phe Ser Ser Phe Leu Glu Leu
100 105 110
Leu Lys His Leu Val Glu Met Asp Thr Asp Gln Leu Lys Leu Tyr Glu
115 120 125
Glu Pro Leu Ser Lys Leu Ile Lys Thr Leu Phe Pro Phe Glu Ala Glu
130 135 140
Ala Tyr Arg Asn Ile Glu Pro Val Tyr Leu Asn Met Leu Leu Glu Lys
145 150 155 160
Leu Cys Val Met Phe Glu Asp Gly Val Leu Met Arg Leu Lys Ser Asp
165 170 175
Leu Leu Lys Ala Ala Leu Cys His Leu Leu Gln Tyr Phe Leu Lys Phe
180 185 190
Val Pro Ala Gly Tyr Glu Ser Ala Leu Gln Val Arg Lys Val Tyr Val
195 200 205
Arg Asn Ile Cys Lys Ala Leu Leu Asp Val Leu Gly Ile Glu Val Asp
210 215 220
Ala Glu Tyr Leu Leu Gly Pro Leu Tyr Ala Ala Leu Lys Met Glu Ser
225 230 235 240
Met Glu Ile Ile Glu Glu Ile Gln Cys Gln Thr Gln Gln Glu Asn Leu
245 250 255
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Ser Ser Asn Ser Asp Gly Ile Ser Pro Lys Arg Arg Arg Leu Ser Ser
260 265 270
Ser Leu Asn Pro Ser Lys Arg Ala Pro Lys Gln Thr Glu Glu Ile Lys
275 280 285
His Val Asp Met Asn Gln Lys Ser Ile Leu Trp Ser Ala Leu Lys Gln
290 295 300
Lys Ala Glu Ser Leu Gln Ile Ser Leu Glu Tyr Ser Gly Leu Lys Asn
305 310 315 320
Pro Val Ile Glu Met Leu Glu Gly Ile Ala Val Val Leu Gln Leu Thr
325 330 335
Ala Leu Cys Thr Val His Cys Ser His Gln Asn Met Asn Cys Arg Thr
340 345 350
Phe Lys Asp Cys Gin His Lys Ser Lys Lys Lys Pro Ser Val Val Ile
355 360 365
Thr Trp Met Ser Leu Asp Phe Tyr Thr Lys Val Leu Lys Ser Cys Arg
370 375 380
Ser Leu Leu Glu Ser Val Gln Lys Leu Asp Leu Glu Ala Thr Ile Asp
385 390 395 400
Lys Val Val Lys Ile Tyr Asp Ala Leu Ile Tyr Met Gln Val Asn Ser
405 410 415
Ser Phe Glu Asp His Ile Leu Glu Asp Leu Cys Gly Met Leu Ser Leu
420 425 430
Pro Trp Ile Tyr Ser His Ser Asp Asp Gly Cys Leu Lys Leu Thr Thr
435 440 445
Phe Ala Ala Asn Leu Leu Thr Leu Ser Cys Arg Ile Ser Asp Ser Tyr
450 455 460
Ser Pro Gln Ala Gln Ser Arg Cys Val Phe Leu Leu Thr Leu Phe Pro
465 470 475 480
Arg Arg Ile Phe Leu Glu Trp Arg Thr Ala Val Tyr Asn Trp Ala Leu
485 490 495
Gln Ser Ser His Glu Val Ile Arg Ala Ser Cys Val Ser Gly Phe Phe
500 505 510
Ile Leu Leu Gin Gln Gln Asn Ser Cys Asn Arg Val Pro Lys Ile Leu
515 520 525
Ile Asp Lys Val Lys Asp Asp Ser Asp Ile Val Lys Lys Glu Phe Ala
530 535 540
Ser Ile Leu Gly Gln Leu Val Cys Thr Leu His Gly Met Phe Tyr Leu
545 550 555 560
Thr Ser Ser Leu Thr Glu Pro Phe Ser Glu His Gly His Val Asp Leu
565 570 575
Phe Cys Arg Asn Leu Lys Ala Thr Ser Gln His Glu Cys Ser Ser Ser
580 585 590
Gln Leu Lys Ala Ser Val Cys Lys Pro Phe Leu Phe Leu Leu Lys Lys
595 600 605
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Lys Ile Pro Ser Pro Val Lys Leu Ala Phe Ile Asp Asn Leu His His
610 615 620
Leu Cys Lys His Leu Asp Phe Arg Glu Asp Glu Thr Asp Val Lys Ala
625 630 635 640
Val Leu Gly Thr Leu Leu Asn Leu Met Glu Asp Pro Asp Lys Asp Val
645 650 655
Arg Val Ala Phe Ser Gly Asn Ile Lys His Ile Leu Glu Ser Leu Asp
660 665 670
Ser Glu Asp Gly Phe Ile Lys Glu Leu Phe Val Leu Arg Met Lys Glu
675 680 685
Ala Tyr Thr His Ala Gln Ile Ser Arg Asn Asn Glu Leu Lys Asp Thr
690 695 700
Leu Ile Leu Thr Thr Gly Asp Ile Gly Arg Ala Ala Lys Gly Asp Leu
705 710 715 720
Val Pro Phe Ala Leu Leu His Leu Leu His Cys Leu Leu Ser Lys Ser
725 730 735
Ala Ser Val Ser Gly Ala Ala Tyr Thr Glu Ile Arg Ala Leu Val Ala
740 745 750
Ala Lys Ser Val Lys Leu Gln Ser Phe Phe Ser Gln Tyr Lys Lys Pro
755 760 765
Ile Cys Gln Phe Leu Val Glu Ser Leu His Ser Ser Gln Met Thr Ala
770 775 780
Leu Pro Asn Thr Pro Cys Gln Asn Ala Asp Val Arg Lys Gln Asp Val
785 790 795 800
Ala His Gln Arg Glu Met Ala Leu Asn Thr Leu Ser Glu Ile Ala Asn
805 810 815
Val Phe Asp Phe Pro Asp Leu Asn Arg Phe Leu Thr Arg Thr Leu Gln
820 825 830
Val Leu Leu Pro Asp Leu Ala Ala Lys Ala Ser Pro Ala Ala Ser Ala
835 840 845
Leu Ile Arg Thr Leu Gly Lys Gln Leu Asn Val Asn Arg Arg Glu Ile
850 855 860
Leu Ile Asn Asn Phe Lys Tyr Ile Phe Ser His Leu Val Cys Ser Cys
865 870 875 880
Ser Lys Asp Glu Leu Glu Arg Ala Leu His Tyr Leu Lys Asn Glu Thr
885 890 895
Glu Ile Glu Leu Gly Ser Leu Leu Arg Gln Asp Phe Gln Gly Leu His
900 905 910
Asn Glu Leu Leu Leu Arg Ile Gly Glu His Tyr Gln Gln Val Phe Asn
915 920 925
Gly Leu Ser Ile Leu Ala Ser Phe Ala Ser Ser Asp Asp Pro Tyr Gln
930 935 940
Gly Pro Arg Asp Ile Ile Ser Pro Glu Leu Met Ala Asp Tyr Leu Gln
945 950 955 960
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Pro Lys Leu Leu Gly Ile Leu Ala Phe Phe Asn Met Gin Leu Leu Ser
965 970 975
Ser Ser Val Gly Ile Glu Asp Lys Lys Met Ala Leu Asn Ser Leu Met
980 985 990
Ser Leu Met Lys Leu Met Gly Pro Lys His Val Ser Ser Val Arg Val
995 1000 1005
Lys Met Met Thr Thr Leu Arg Thr Gly Leu Arg Phe Lys Asp Asp Phe
1010 1015 1020
Pro Glu Leu Cys Cys Arg Ala Trp Asp Cys Phe Val Arg Cys Leu Asp
1025 1030 1035 1040
His Ala Cys Leu Gly Ser Leu Leu Ser His Val Ile Val Ala Leu Leu
1045 1050 1055
Pro Leu Ile His Ile Gln Pro Lys Glu Thr Ala Ala Ile Phe His Tyr
1060 1065 1070
Leu Ile Ile Glu Asn Arg Asp Ala Val Gln Asp Phe Leu His Glu Ile
1075 1080 1085
Tyr Phe Leu Pro Asp His Pro Glu Leu Lys Lys Ile Lys Ala Val Leu
1090 1095 1100
Gln Glu Tyr Arg Lys Glu Thr Ser Glu Ser Thr Asp Leu Gln Thr Thr
1105 1110 1115 1120
Leu Gln Leu Ser Met Lys Ala Ile Gln His Glu Asn Val Asp Val Arg
1125 1130 1135
Ile His Ala Leu Thr Ser Leu Lys Glu Thr Leu Tyr Lys Asn Gln Glu
1140 1145 1150
Lys Leu Ile Lys Tyr Ala Thr Asp Ser Glu Thr Val Glu Pro Ile Ile
1155 1160 1165
Ser Gln Leu Val Thr Val Leu Leu Lys Gly Cys Gln Asp Ala Asn Ser
1170 1175 1180
Gln Ala Arg Leu Leu Cys Gly Glu Cys Leu Gly Glu Leu Gly Ala Ile
1185 1190 1195 1200
Asp Pro Gly Arg Leu Asp Phe Ser Thr Thr Glu Thr Gln Gly Lys Asp
1205 1210 1215
Phe Thr Phe Val Thr Gly Val Glu Asp Ser Ser Phe Ala Tyr Gly Leu
1220 1225 1230
Leu Met Glu Leu Thr Arg Ala Tyr Leu Ala Tyr Ala Asp Asn Ser Arg
1235 1240 1245
Ala G1n Asp Ser Ala Ala Tyr Ala Ile Gln Glu Leu Leu Ser Ile Tyr
1250 1255 1260
Asp Cys Arg Glu Met Glu Thr Asn Gly Pro Gly His Gln Leu Trp Arg
1265 1270 1275 1280
Arg Phe Pro Glu His Val Arg Glu Ile Leu Glu Pro His Leu Asn Thr
1285 1290 1295
Arg Tyr Lys Ser Ser Gln Lys Ser Thr Asp Trp Ser Gly Val Lys Lys
1300 1305 1310
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Pro Ile Tyr Leu Ser Lys Leu Gly Ser Asn Phe Ala Glu Trp Ser Ala
1315 1320 1325
Ser Trp Ala Gly Tyr Leu Ile Thr Lys Val Arg His Asp Leu Ala Ser
1330 1335 1340
Lys Ile Phe Thr Cys Cys Ser Ile Met Met Lys His Asp Phe Lys Val
1345 1350 1355 1360
Thr Ile Tyr Leu Leu Pro His Ile Leu Val Tyr Val Leu Leu Gly Cys
1365 1370 1375
Asn Gln Glu Asp Gln Gln Glu Val Tyr Ala Glu Ile Met Ala Val Leu
1380 1385 1390
Lys His Asp Asp Gln His Thr Ile Asn Thr Gln Asp Ile Ala Ser Asp
1395 1400 1405
Leu Cys Gln Leu Ser Thr Gln Thr Val Phe Ser Met Leu Asp His Leu
1410 1415 1420
Thr Gln Trp Ala Arg His Lys Phe Gin Ala Leu Lys Ala Glu Lys Cys
1425 1430 1435 1440
Pro His Ser Lys Ser Asn Arg Asn Lys Val Asp Ser Met Val Ser Thr
1445 1450 1455
Val Asp Tyr Glu Asp Tyr Gln Ser Val Thr Arg Phe Leu Asp Leu Ile
1460 1465 1470
Pro Gln Asp Thr Leu Ala Val Ala Ser Phe Arg Ser Lys Ala Tyr Thr
1475 1480 1485
Arg Ala Val Met His Phe Glu Ser Phe Ile Thr Glu Lys Lys Gln Asn
1490 1495 1500
Ile Gln GIu His Leu Gly Phe Leu Gln Lys Leu Tyr Ala Ala Met His
1505 1510 1515 1520
Glu Pro Asp Gly Val Ala Gly Val Ser Ala Ile Arg Lys Ala Glu Pro
1525 1530 1535
Ser Leu Lys Glu Gln Ile Leu Glu His Glu Ser Leu Gly Leu Leu Arg
1540 1545 1550
Asp Ala Thr Ala Cys Tyr Asp Arg Ala Ile Gln Leu Glu Pro Asp Gln
1555 1560 1565
Ile Ile His Tyr His Gly Val Val Lys Ser Met Leu Gly Leu Gly Gln
1570 1575 1580
Leu Ser Thr Val Ile Thr Gln Val Asn Gly Val His Ala Asn Arg Ser
1585 1590 1595 1600
Glu Trp Thr Asp Glu Leu Asn Thr Tyr Arg Val Glu Ala Ala Trp Lys
1605 1610 1615
Leu Ser Gln Trp Asp Leu Val Glu Asn Tyr Leu Ala Ala Asp Gly Lys
1620 1625 1630
Ser Thr Thr Trp Ser Val Arg Leu Gly Gln Leu Leu Leu Ser Ala Lys
1635 1640 1645
Lys Arg Asp Ile Thr Ala Phe Tyr Asp Ser Leu Lys Leu Val Arg Ala
1650 1655 1660
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Glu Gln Ile Val Pro Leu Ser Ala Ala Ser Phe Glu Arg Gly Ser Tyr
1665 1670 1675 1680
Gln Arg Gly Tyr Glu Tyr Ile Val Arg Leu His Met Leu Cys Glu Leu
1685 1690 1695
Glu His Ser Ile Lys Pro Leu Phe Gln His Ser Pro Gly Asp Ser Ser
1700 1705 1710
Gln Glu Asp Ser Leu Asn Trp Val Ala Arg Leu Glu Met Thr Gln Asn
1715 1720 1725
Ser Tyr Arg Ala Lys Glu Pro Ile Leu Ala Leu Arg Arg Ala Leu Leu
1730 1735 1740
Ser Leu Asn Lys Arg Pro Asp Tyr Asn Glu Met Val Gly Glu Cys Trp
1745 1750 1755 1760
Leu Gin Ser Ala Arg Val Ala Arg Lys Ala Gly His His Gln Thr Ala
1765 1770 1775
Tyr Asn Ala Leu Leu Asn Ala Gly Glu Ser Arg Leu Ala Glu Leu Tyr
1780 1785 1790
Val Glu Arg Ala Lys Trp Leu Trp Ser Lys Gly Asp Val His Gln Ala
1795 1800 1805
Leu Ile Val Leu Gln Lys Gly Val Glu Leu Cys Phe Pro Glu Asn Glu
1810 1815 1820
Thr Pro Pro Glu Gly Lys Asn Met Leu Ile His Gly Arg Ala Met Leu
1825 1830 1835 1840
Leu Val Gly Arg Phe Met Glu Glu Thr Ala Asn Phe Glu Ser Asn Ala
1845 1850 1855
Ile Met Lys Lys Tyr Lys Asp Val Thr Ala Cys Leu Pro Giu Trp Glu
1860 1865 1870
Asp Gly His Phe Tyr Leu Ala Lys Tyr Tyr Asp Lys Leu Met Pro Met
1875 1880 1885
Val Thr Asp Asn Lys Met Glu Lys Gln Gly Asp Leu Ile Arg Tyr Ile
1890 1895 1900
Val Leu His Phe Gly Arg Ser Leu Gln Tyr Gly Asn Gln Phe Ile Tyr
1905 1910 1915 1920
Gln Ser Met Pro Arg Met Leu Thr Leu Trp Leu Asp Tyr Gly Thr Lys
1925 1930 1935
Ala Tyr Glu Trp Glu Lys Ala Gly Arg Ser Asp Arg Val Gln Met Arg
1940 1945 1950
Asn Asp Leu Gly Lys Ile Asn Lys Val Ile Thr Glu His Thr Asn Tyr
1955 1960 1965
Leu Ala Pro Tyr Gln Phe Leu Thr Ala Phe Ser Gln Leu Ile Ser Arg
1970 1975 1980
Ile Cys His Ser His Asp Glu Val Phe Val Val Leu Asp Gly Asn Asn
1985 1990 1995 2000
Ser Gln Val Phe Leu Ala Tyr Pro Gln Gln Ala Met Trp Met Met Thr
2005 2010 2015
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Ala Val Ser Lys Ser Ser Tyr Pro Met Arg Val Asn Arg Cys Lys Glu
2020 2025 2030
Ile Leu Asn Lys Ala Ile His Met Lys Lys Ser Leu Glu Lys Phe Val
2035 2040 2045
Gly Asp Ala Thr Arg Leu Thr Asp Lfs Leu Leu Glu Leu Cys Asn Lys
2050 2055 2060
Pro Val Glu Ile Leu Ala Ser Leu Gln Lys Pro Lys Lys Ile Ser Leu
2065 2070 2075 2080
Lys Gly Ser Asp Gly Lys Phe Tyr Ile Met Met Cys Lys Pro Lys Asp
2085 2090 2095
Asp Leu Arg Lys Asp Cys Arg Leu Met Glu Phe Asn Ser Leu Ile Asn
2100 2105 2110
Lys Cys Leu Arg Lys Asp Ala Glu Ser Arg Arg Arg Glu Leu His Ile
2115 2120 2125
Arg Thr Tyr Ala Val Ile Pro Leu Asn Asp Glu Cys Gly Ile Ile Glu
2130 2135 2140
Trp Val Asn Asn Thr Ala Gly Leu Arg Pro Ile Leu Thr Lys Leu Tyr
2145 2150 2155 2160
Lys Glu Lys Gly Val Tyr Met Thr Gly Lys Glu Leu Arg Gln Cys Met
2165 2170 2175
Leu Pro Lys Ser Ala Ala Leu Ser Glu Lys Leu Lys Val Phe Arg Glu
2180 2185 2190
Phe Leu Leu Pro Arg His Pro Pro Ile Phe His Glu Trp Phe Leu Arg
2195 2200 2205
Thr Phe Pro Asp Pro Thr Ser Trp Tyr Ser Ser Arg Ser Ala Tyr Cys
2210 2215 2220
Arg Ser Thr Ala Val Met Ser Met Val Gly Tyr Ile Leu Gly Leu Gly
2225 2230 2235 2240
Asp Arg His Gly Glu Asn Ile Leu Phe Asp Ser Leu Thr Gly Glu Cys
2245 2250 2255
Val His Val Asp Phe Asn Cys Leu Phe Asn Lys Gly Glu Thr Phe Glu
2260 2265 2270
Val Pro Glu Ile Val Pro Phe Arg Leu Thr His Asn Met Val Asn Gly
2275 2280 2285
Met Gly Pro Met Gly Thr Glu Gly Leu Phe Arg Arg Ala Cys Glu Val
2290 2295 2300
Thr Met Arg Leu Met Arg Asp Gln Arg Glu Pro Leu Met Ser Val Leu
2305 2310 2315 2320
Lys Thr Phe Leu His Asp Pro Leu Val Glu Trp Ser Lys Pro Val Lys
2325 2330 2335
Gly His Ser Lys Ala Pro Leu Asn Glu Thr Gly Glu Val Val Asn Glu
2340 2345 2350
Lys Ala Lys Thr His Val Leu Asp Ile Glu Gln Arg Leu Gln Gly Val
2355 2360 2365
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Ile Lys Thr Arg Asn Arg Val Thr Gly Leu Pro Leu Ser Ile Glu Gly
2370 2375 2380
His Val His Tyr Leu Ile Gln Glu Ala Thr Asp Glu Asn Leu Leu Cys
2385 2390 2395 2400
Gln Met Tyr Leu Gly Trp Thr Pro Tyr Met
2405 2410
(2) INFORMATION FOR SEQ ID NO:25:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 7502 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: cDNA
(ix) FEATURE:
(A) NAME/KEY: CDS
(B) LOCATION: 1..7440
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:
ATG GGT CAT GCT GTG GAA TGG CCA GTG GTC ATG AGC CGA TTT TTA AGT 48
Met Gly His Ala Val Glu Trp Pro Val Val Met Ser Arg Phe Leu Ser
1 5 10 15
CAA TTA GAT GAA CAC ATG GGA TAT TTA CAA TCA GCT CCT TTG CAG TTG 96
Gin Leu Asp Glu His Met Gly Tyr Leu Gln Ser Ala Pro Leu Gln Leu
20 25 30
ATG AGT ATG CAA AAT TTA GAA TTT ATT GAA GTC ACT TTA TTA ATG GTT 144
Met Ser Met Gln Asn Leu Glu Phe Ile Glu Val Thr Leu Leu Met Val
35 40 45
CTT ACT CGT ATT ATT GCA ATT GTG TTT TTT AGA AGG CAA GAA CTC TTA 192
Leu Thr Arg Ile Ile Ala Ile Val Phe Phe Arg Arg Gln Glu Leu Leu
50 55 60
CTT TGG CAG ATA GGT TGT GTT CTG CTA GAG TAT GGT AGT CCA AAA ATT 240
Leu Trp Gln Ile Gly Cys Val Leu Leu Glu Tyr Gly Ser Pro Lys Ile
65 70 75 80
AAA TCC CTA GCA ATT AGC TTT TTA ACA GAA CTT TTT CAG CTT GGA GGA 288
Lys Ser Leu Ala Ile Ser Phe Leu Thr Glu Leu Phe Gln Leu Gly Gly
85 90 95
CTA CCA GCA CAA CCA GCT AGC ACT TTT TTC AGC TCA TTT TTG GAA TTA 336
Leu Pro Ala Gln Pro Ala Ser Thr Phe Phe Ser Ser Phe Leu Glu Leu
100 105 110
TTA AAA CAC CTT GTA GAA ATG GAT ACT GAC CAA TTG AAA CTC TAT GAA 384
Leu Lys His Leu Val Glu Met Asp Thr Asp Gln Leu Lys Leu Tyr Clu
115 120 125
GAG CCA TTA TCA AAG CTG ATA AAG ACA CTA TTT CCC TTT GAA GCA GAA 432
Glu Pro Leu Ser Lys Leu Ile Lys Thr Leu Phe Pro Phe Glu Ala Glu
130 135 140
GCT TAT AGA AAT ATT GAA CCT GTC TAT TTA AAT ATG CTG CTG GAA AAA 480
Ala Tyr Arg Asn Ile Glu Pro Val Tyr Leu Asn Met Leu Leu Glu Lys
145 150 155 160
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CTC TGT GTC ATG TTT GAA GAC GGT GTG CTC ATG CGG CTT AAG TCT GAT 528
Leu Cys Val Met Phe Glu Asp Gly Val Leu Met Arg Leu Lys Ser Asp
165 170 175
TTG CTA AAA GCA GCT TTG TGC CAT TTA CTG CAG TAT TTC CTT AAA TTT 576
Leu Leu Lys Ala Ala Leu Cys His Leu Leu Gln Tyr Phe Leu Lys Phe
180 185 190
GTG CCA GCT GGG TAT GAA TCT GCT TTA CAA GTC AGG AAG GTC TAT GTG 624
Val Pro Ala Gly Tyr Glu Ser Ala Leu Gln Val Arg Lys Val Tyr Val
195 200 205
AGA AAT ATT TGT AAA GCT CTT TTG GAT GTG CTT GGA ATT GAG GTA GAT 672
Arg Asn Ile Cys Lys Ala Leu Leu Asp Val Leu Gly Ile Glu Val Asp
210 215 220
GCA GAG TAC TTG TTG GGC CCA CTT TAT GCA GCT TTG AAA ATG GAA AGT 720
Ala Glu Tyr Leu Leu Gly Pro Leu Tyr Ala Ala Leu Lys Met Glu Ser
225 230 235 240
ATG GAA ATC ATT GAG GAG ATT CAA TGC CAA ACT CAA CAG GAA AAC CTC 768
Met Glu Ile Ile Glu Glu Ile Gln Cys Gln Thr Gln Gln Glu Asn Leu
245 250 255
AGC AGT AAT AGT GAT GGA ATA TCA CCC AAA AGG CGT CGT CTC AGC TCG 816
Ser Ser Asn Ser Asp Gly Ile Ser Pro Lys Arg Arg Arg Leu Ser Ser
260 265 270
TCT CTA AAC CCT TCT AAA AGA GCA CCA AAA CAG ACT GAG GAA ATT AAA 864
Ser Leu Asn Pro Ser Lys Arg Ala Pro Lys Gln Thr Glu Glu Ile Lys
275 280 285
CAT GTG GAC ATG AAC CAA AAG AGC ATA TTA TGG AGT GCA CTG AAA CAG 912
His Val Asp Met Asn Gln Lys Ser Ile Leu Trp Ser Ala Leu Lys Gln
290 295 300
AAA GCT GAA TCC CTT CAG ATT TCC CTT GAA TAC AGT GGC CTA AAG AAT 960
Lys Ala Glu Ser Leu Gln Ile Ser Leu Glu Tyr Ser Gly Leu Lys Asn
305 310 315 320
CCT GTT ATT GAG ATG TTA GAA GGA ATT GCT GTT GTC TTA CAA CTG ACT 1008
Pro Val Ile Glu Met Leu Glu Gly Ile Ala Val Val Leu Gln Leu Thr
325 330 335
GCT CTG TGT ACT GTT CAT TGT TCT CAT CAA AAC ATG AAC TGC CGT ACT 1056
Ala Leu Cys Thr Val His Cys Ser His Gln Asn Met Asn Cys Arg Thr
340 345 350
TTC AAG GAC TGT CAA CAT AAA TCC AAG AAG AAA CCT TCT GTA GTG ATA 1104
Phe Lys Asp Cys Gln His Lys Ser Lys Lys Lys Pro Ser Val Val Ile
355 360 365
ACT TGG ATG TCA TTG GAT TTT TAC ACA AAA GTG CTT AAG AGC TGT AGA 1152
Thr Trp Met Ser Leu Asp Phe Tyr Thr Lys Val Leu Lys Ser Cys Arg
370 375 380
AGT TTG TTA GAA TCT GTT CAG AAA CTG GAC CTG GAG GCA ACC ATT GAT 1200
Ser Leu Leu Glu Ser Val Gln Lys Leu Asp Leu Glu Ala Thr Ile Asp
385 390 395 400
AAG GTG GTG AAA ATT TAT GAT GCT TTG ATT TAT ATG CAA GTA AAC AGT 1248
Lys Val Val Lys Ile Tyr Asp Ala Leu Ile Tyr Met Gln Val Asn Ser
405 410 415
TCA TTT GAA GAT CAT ATC CTG GAA GAT TTA TGT GGA ATG CTC TCA CTT 1296
Ser Phe Glu Asp His Ile Leu Glu Asp Leu Cys Gly Met Leu Ser Leu
420 425 430
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CCA TGG ATT TAT TCC CAT TCT GAT GAT GGC TGT TTA AAG TTG ACC ACA 1344
Pro Trp Ile Tyr Ser His Ser Asp Asp Gly Cys Leu Lys Leu Thr Thr
435 440 445
TTT GCC GCT AAT CTT CTA ACA TTA AGC TGT AGG ATT TCA GAT AGC TAT 1392
Phe Ala Ala Asn Leu Leu Thr Leu Ser Cys Arg Ile Ser Asp Ser Tyr
450 455 460
TCA CCA CAG GCA CAA TCA CGA TGT GTG TTT CTT CTG ACT CTG TTT CCA 1440
Ser Pro Gln Ala Gln Ser Arg Cys Val Phe Leu Leu Thr Leu Phe Pro
465 470 475 480
AGA AGA ATA TTC CTT GAG TGG AGA ACA GCA GTT TAC AAC TGG GCC CTG 1488
Arg Arg Ile Phe Leu Glu Trp Arg Thr Ala Val Tyr Asn Trp Ala Leu
485 490 495
CAG AGC TCC CAT GAA GTA ATC CGG GCT AGT TGT GTT AGT GGA TTT TTT 1536
Gln Ser Ser His Glu Val Ile Arg Ala Ser Cys Val Ser Gly Phe Phe
500 505 510
ATC TTA TTG CAG CAG CAG AAT TCT TGT AAC AGA GTT CCC AAG ATT CTT 1584
Ile Leu Leu Gln Gin Gln Asn Ser Cys Asn Arg Val Pro Lys Ile Leu
515 520 525
ATA GAT AAA GTC AAA GAT GAT TCT GAC ATT GTC AAG AAA GAA TIT GCT 1632
Ile Asp Lys Val Lys Asp Asp Ser Asp Ile Val Lys Lys Glu Phe Ala
530 535 540
TCT ATA CTT GGT CAA CTT GTC TGT ACT CTT CAC GGC ATG T'I'T TAT CTG 1680
Ser Ile Leu Gly Gln Leu Val Cys Thr Leu His Gly Met Phe Tyr Leu
545 550 555 560
ACA AGT TCT TTA ACA GAA CCT TTC TCT GAA CAC GGA CAT GTG GAC CTC 1728
Thr Ser Ser Leu Thr Glu Pro Phe Ser Glu His Gly His Val Asp Leu
565 570 575
TTC TGT AGG AAC TTG AAA GCC ACT TCT CAA CAT GAA TGT TCA TCT TCT 1776
Phe Cys Arg Asn Leu Lys Ala Thr Ser Gin His Glu Cys Ser Ser Ser
580 585 590
CAA CTA AAA GCT TCT GTC TGC AAG CCA TTC CTT TTC CTA CTG AAA AAA 1824
Gln Leu Lys Ala Ser Val Cys Lys Pro Phe Leu Phe Leu Leu Lys Lys
595 600 605
AAA ATA CCT AGT CCA GTA AAA CTT GCT TTC ATA GAT AAT CTA CAT CAT 1872
Lys Ile Pro Ser Pro Val Lys Leu Ala Phe Ile Asp Asn Leu His His
610 615 620
CTT TGT AAG CAT CTT GAT TTT AGA GAA GAT GAA ACA GAT GTA AAA GCA 1920
Leu Cys Lys His Leu Asp Phe Arg Glu Asp Glu Thr Asp Val Lys Ala
625 630 635 640
GTT CTT GGA ACT TTA TTA AAT TTA ATG GAA GAT CCA GAC AAA GAT GTT 1968
Val Leu Gly Thr Leu Leu Asn Leu Met Glu Asp Pro Asp Lys Asp Val
645 650 655
AGA GTG GCT TTT AGT GGA AAT ATC AAG CAC ATA TTG GAA TCC TTG GAC 2016
Arg Val Ala Phe Ser Gly Asn Ile Lys His Ile Leu Glu Ser Leu Asp
660 665 670
TCT GAA GAT GGA Z'TT ATA AAG GAG CTT TTT GTC TTA AGA ATG AAG GAA 2064
Ser Glu Asp Gly Phe Ile Lys Glu Leu Phe Val Leu Arg Met Lys Glu
675 680 685
GCA TAT ACA CAT GCC CAA ATA TCA AGA AAT AAT GAG CTG AAG GAT ACC 2112
Ala Tyr Thr His Ala Gln Ile Ser Arg Asn Asn Glu Leu Lys Asp Thr
690 695 700
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TTG ATT CTT ACA ACA GGG GAT ATT GGA AGG GCC GCA AAA GGA GAT TTG 2160
Leu Ile Leu Thr Thr Gly Asp Ile Gly Arg Ala Ala Lys Gly Asp Leu
705 710 715 720
GTA CCA TTT GCA CTC TTA CAC TTA TTG CAT TGT TTG TTA TCC AAG TCA 2208
Val Pro Phe Ala Leu Leu His Leu Leu His Cys Leu Leu Ser Lys Ser
725 730 735
GCA TCT GTC TCT GGA GCA GCA TAC ACA GAA ATT AGA GCT CTG GTT GCA 2256
Ala Ser Val Ser Gly Ala Ala Tyr Thr Glu Ile Arg Ala Leu Val Ala
740 745 750
GCT AAA AGT GTT AAA CTG CAA AGT TTT TTC AGC CAG TAT AAG AAA CCC 2304
Ala Lys Ser Val Lys Leu Gln Ser Plie Phe Ser Gln Tyr Lys Lys Pro
755 760 765
ATC TGT CAG TTT TTG GTA GAA TCC CTT CAC TCT AGT CAG ATG ACA GCA 2352
Ile Cys Gln Phe Leu Val Glu Ser Leu His Ser Ser Gln Met Thr Ala
770 775 780
CTT CCG AAT ACT CCA TGC CAG AAT GCT GAC GTG CGA AAA CAA GAT GTG 2400
Leu Pro Asn Thr Pro Cys Gln Asn Ala Asp Val Arg Lys Gln Asp Val
785 790 795 800
GCT CAC CAG AGA GAA ATG GCT TTA AAT ACG TTG TCT GAA ATT GCC AAC 2448
Ala His Gln Arg Glu Met Ala Leu Asn Thr Leu Ser Glu Ile Ala Asn
805 810 815
GTT TTC GAC TTT CCT GAT CTT AAT CGT TTT CTT ACT AGG ACA TTA CAA 2496
Val Phe Asp Phe Pro Asp Leu Asn Arg Phe Leu Thr Arg Thr Leu Gln
820 825 830
GTT CTA CTA CCT GAT CTT GCT GCC AAA GCA AGC CCT GCA GCT TCT GCT 2544
Val Leu Leu Pro Asp Leu Ala Ala Lys Ala Ser Pro Ala Ala Ser Ala
835 840 845
CTC ATT CGA ACT TTA GGA AAA CAA TTA AAT GTC AAT CGT AGA GAG ATT 2592
Leu Ile Arg Thr Leu Gly Lys Gln Leu Asn Val Asn Arg Arg Glu Ile
850 855 860
TTA ATA AAC AAC TTC AAA TAT ATT TTT TCT CAT TTG GTC TGT TCT TGT 2640
Leu Ile Asn Asn Phe Lys Tyr Ile Phe Ser His Leu Val Cys Ser Cys
865 870 875 880
TCC AAA GAT GAA TTA GAA CGT GCC CTT CAT TAT CTG AAG AAT GAA ACA 2688
Ser Lys Asp Glu Leu Glu Arg Ala Leu His Tyr Leu Lys Asn Glu Thr
885 890 895
GAA ATT GAA CTG GGG AGC CTG TTG AGA CAA GAT TTC CAA GGA TTG CAT 2736
Glu Ile Glu Leu Gly Ser Leu Leu Arg Gln Asp Phe Gln Gly Leu His
900 905 910
AAT GAA TTA TTG CTG CGT ATT GGA GAA CAC TAT CAA CAG GTT TTT AAT 2784
Asn Glu Leu Leu Leu Arg Ile Gly Glu His Tyr Gln Gln Val Phe Asn
915 920 925
GGT TTG TCA ATA CTT GCC TCA TTT GCA TCC AGT GAT GAT CCA TAT CAG 2832
Gly Leu Ser Ile Leu Ala Ser Phe Ala Ser Ser Asp Asp Pro Tyr Gln
930 935 940
GGC CCG AGA GAT ATC ATA TCA CCT GAA CTG ATG GCT GAT TAT TTA CAA 2880
Gly Pro Arg Asp Ile Ile Ser Pro Glu Leu Met Ala Asp Tyr Leu Gln
945 950 955 960
CCC AAA TTG TTG GGC ATT TTG GCT TTT TTT AAC ATG CAG TTA CTG AGC 2928
Pro Lys Leu Leu Gly Ile Leu Ala Phe Phe Asn Met Gln Leu Leu Ser
965 970 975
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TCT AGT GTT GGC ATT GAA GAT AAG AAA ATG GCC TTG AAC AGT TTG ATG 2976
Ser Ser Val Gly Ile Glu Asp Lys Lys Met Ala Leu Asn Ser Leu Met
980 985 990
TCT TTG ATG AAG TTA ATG GGA CCC AAA CAT GTC AGT TCT GTG AGG GTG 3024
Ser Leu Met Lys Leu Met Gly Pro Lys His Val Ser Ser Val Arg Val
995 1000 1005
AAG ATG ATG ACC ACA CTG AGA ACT GGC CTT CGA TTC AAG GAT GAT TTT 3072
Lys Met Met Thr Thr Leu Arg Thr Gly Leu Arg Phe Lys Asp Asp Phe
1010 1015 1020
CCT GAA TTG TGT TGC AGA GCT TGG GAC TGC TTT GTT CGC TGC CTG GAT 3120
Pro Glu Leu Cys Cys Arg Ala Trp Asp Cys Phe Val Arg Cys Leu Asp
1025 1030 1035 1040
CAT GCT TGT CTG GGC TCC CTT CTC AGT CAT GTA ATA GTA GCT TTG TTA 3168
His Ala Cys Leu Gly Ser Leu Leu Ser His Val Ile Val Ala Leu Leu
1045 1050 1055
CCT CTT ATA CAC ATC CAG CCT AAA GAA ACT GCA GCT ATC TTC CAC TAC 3216
Pro Leu Ile His Ile Gln Pro Lys Glu Thr Ala Ala Ile Phe His Tyr
1060 1065 1070
CTC ATA ATT GAA AAC AGG GAT GCT GTG CAA GAT TTT CTT CAT GAA ATA 3264
Leu Ile Ile Glu Asn Arg Asp Ala Val Gln Asp Phe Leu His Glu Ile
1075 1080 1085
TAT TTT TTA CCT GAT CAT CCA GAA TTA AAA AAG ATA AAA GCC GTT CTC 3312
Tyr Phe Leu Pro Asp His Pro Glu Leu Lys Lys Ile Lys Ala Val Leu
1090 1095 1100
CAG GAA TAC AGA AAG GAG ACC TCT GAG AGC ACT GAT CTT CAG ACA ACT 3360
Gln Glu Tyr Arg Lys Glu Thr Ser Glu Ser Thr Asp Leu Gln Thr Thr
1105 1110 1115 1120
CTT CAG CTC TCT ATG AAG GCC ATT CAA CAT GAA AAT GTC GAT GTT CGT 3408
Leu Gln Leu Ser Met Lys Ala Ile Gln His Glu Asn Val Asp Val Arg
1125 1130 1135
ATT CAT GCT CTT ACA AGC TTG AAG GAA ACC TTG TAT AAA AAT CAG GAA 3456
Ile His Ala Leu Thr Ser Leu Lys Glu Thr Leu Tyr Lys Asn Gln Glu
1140 1145 1150
AAA CTG ATA AAG TAT GCA ACA GAC AGT GAA ACA GTA GAA CCT ATT ATC 3504
Lys Leu Ile Lys Tyr Ala Thr Asp Ser Glu Thr Val Glu Pro Ile Ile
1155 1160 1165
TCA CAG TTG GTG ACA GTG CTT TTG AAA GGT TGC CAA GAT GCA AAC TCT 3552
Ser Gln Leu Val Thr Val Leu Leu Lys Gly Cys Gln Asp Ala Asn Ser
1170 1175 1180
CAA GCT CGG TTG CTC TGT GGG GAA TGT TTA GGG GAA TTG GGG GCG ATA 3600
Gln Ala Arg Leu Leu Cys Gly Glu Cys Leu Gly Glu Leu Gly Ala Ile
1185 1190 1195 1200
GAT CCA GGT CGA TTA GAT TTC TCA ACA ACT GAA ACT CAA GGA AAA GAT 3648
Asp Pro Gly Arg Leu Asp Phe Ser Thr Thr Glu Thr Gln Gly Lys Asp
1205 1210 1215
TTT ACA TTT GTG ACT GGA GTA GAA GAT TCA AGC TTT GCC TAT GGA TTA 3696
Phe Thr Phe Val Thr Gly Val Glu Asp Ser Ser Phe Ala Tyr Gly Leu
1220 1225 1230
TTG ATG GAG CTA ACA AGA GCT TAC CTT GCG TAT GCT GAT AAT AGC CGA 3744
Leu Met Glu Leu Thr Arg Ala Tyr Leu Ala Tyr Ala Asp Asn Ser Arg
1235 1240 1245
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GCT CAA GAT TCA GCT GCC TAT GCC ATT CAG GAG TTG CTT TCT ATT TAT 3792
Ala Gln Asp Ser Ala Ala Tyr Ala Ile Gln Glu Leu Leu Ser Ile Tyr
1250 1255 1260
GAC TGT AGA GAG ATG GAG ACC AAC GGC CCA GGT CAC CAA TTG TGG AGG 3840
Asp Cys Arg Glu Met Glu Thr Asn Gly Pro Gly His Gln Leu Trp Arg
1265 1270 1275 1280
AGA TTT CCT GAG CAT GTT CGG GAA ATA CTA GAA CCT CAT CTA AAT ACC 3888
Arg Phe Pro Glu His Val Arg Glu Ile Leu Glu Pro His Leu Asn Thr
1285 1290 1295
AGA TAC AAG AGT TCT CAG AAG TCA ACC GAT TGG TCT GGA GTA AAG AAG 3936
Arg Tyr Lys Ser Ser Gln Lys Ser Thr Asp Trp Ser Gly Val Lys Lys
1300 1305 1310
CCA ATT TAC TTA AGT AAA TTG GGT AGT AAC TTT GCA GAA TGG TCA GCA 3984
Pro Ile Tyr Leu Ser Lys Leu Gly Ser Asn Phe Ala Glu Trp Ser Ala
1315 1320 1325
TCT TGG GCA GGT TAT CTT ATT ACA AAG GTT CGA CAT GAT CTT GCC AGT 4032
Ser Trp Ala Gly Tyr Leu Ile Thr Lys Val Arg His Asp Leu Ala Ser
1330 1335 1340
AAA ATT TTC ACC TGC TGT AGC ATT ATG ATG AAG CAT GAT TTC AAA GTG 4080
Lys Ile Phe Thr Cys Cys Ser Ile Met Met Lys His Asp Phe Lys Val
1345 1350 1355 1360
ACC ATC TAT CTT CTT CCA CAT ATT CTG GTG TAT GTC TTA CTG GGT TGT 4128
Thr Ile Tyr Leu Leu Pro His Ile Leu Val Tyr Val Leu Leu Gly Cys
1365 1370 1375
AAT CAA GAA GAT CAG CAG GAG GTT TAT GCA GAA ATT ATG GCA GTT CTA 4176
Asn Gln Glu Asp Gln Gln Glu Val Tyr Ala Glu Ile Met Ala Val Leu
1380 1385 1390
AAG CAT GAC GAT CAG CAT ACC ATA AAT ACC CAA GAC ATT GCA TCT GAT 4224
Lys His Asp Asp Gln His Thr Ile Asn Thr Gln Asp Ile Ala Ser Asp
1395 1400 1405
CTG TGT CAA CTC AGT ACA CAG ACT GTG TTC TCC ATG CTT GAC CAT CTC 4272
Leu Cys Gln Leu Ser Thr Gln Thr Val Phe Ser Met Leu Asp His Leu
1410 1415 1420
ACA CAG TGG GCA AGG CAC AAA TTT CAG GCA CTG AAA GCT GAG AAA TGT 4320
Thr Gln Trp Ala Arg His Lys Phe Gln Ala Leu Lys Ala Glu Lys Cys
1425 1430 1435 1440
CCA CAC AGC AAA TCA AAC AGA AAT AAG GTA GAC TCA ATG GTA TCT ACT 4368
Pro His Ser Lys Ser Asn Arg Asn Lys Val Asp Ser Met Val Ser Thr
1445 1450 1455
GTG GAT TAT GAA GAC TAT CAG AGT GTA ACC CGT TT"T CTA GAC CTC ATA 4416
Val Asp Tyr Glu Asp Tyr Gln Ser Val Thr Arg Phe Leu Asp Leu Ile
1460 1465 1470
CCC CAG GAT ACT CTG GCA GTA GCT TCC TTT CGC TCC AAA GCA TAC ACA 4464
Pro Gln Asp Thr Leu Ala Val Ala Ser Phe Arg Ser Lys Ala Tyr Thr
1475 1480 1485
CGA GCT GTA ATG CAC TTT GAA TCA TTT ATT ACA GAA AAG AAG CAA AAT 4512
Arg Ala Val Met His Phe Glu Ser Phe Ile Thr Glu Lys Lys Gln Asn
1490 1495 1500
ATT CAG GAA CAT CTT GGA TTT TTA CAG AAA TTG TAT GCT GCT ATG CAT 4560
Ile Gin Glu His Leu Gly Phe Leu Gln Lys Leu Tyr Ala Ala Met His
1505 1510 1515 1520
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GAA CCT GAT GGA GTG GCC GGA GTC AGT GCA ATT AGA AAG GCA GAA CCA 4608
Glu Pro Asp Gly Val Ala Gly Val Ser Ala Ile Arg Lys Ala Glu Pro
1525 1530 1535
TCT CTA AAA GAA CAG ATC CTT GAA CAT GAA AGC CTT GGC TTG CTG AGG 4656
Ser Leu Lys Glu Gln Ile Leu Glu His Glu Ser Leu Gly Leu Leu Arg
1540 1545 1550
GAT GCC ACT GCT TGT TAT GAC AGG GCT ATT CAG CTA GAA CCA GAC CAG 4704
Asp Ala Thr Ala Cys Tyr Asp Arg Ala Ile Gln Leu Glu Pro Asp Gln
1555 1560 1565
ATC ATT CAT TAC CAT GGT GTA GTA AAG TCC ATG TTA GGT CTT GGT CAG 4752
Ile Ile His Tyr His Gly Val Val Lys Ser Met Leu Gly Leu Gly Gln
1570 1575 1580
CTG TCT ACT GTT ATC ACT CAG GTG AAT GGA GTG CAT GCT AAC AGG TCC 4800
Leu Ser Thr Val Ile Thr Gln Val Asn Gly Val His Ala Asn Arg Ser
1585 1590 1595 1600
GAG TGG ACA GAT GAA TTA AAC ACG TAC AGA GTG GAA GCA GCT TGG AAA 4848
Glu Trp Thr Asp Glu Leu Asn Thr Tyr Arg Val Glu Ala Ala Trp Lys
1605 1610 1615
TTG TCA CAG TGG GAT TTG GTG GAA AAC TAT TTG GCA GCA GAT GGA AAA 4896
Leu Ser Gln Trp Asp Leu Val Glu Asn Tyr Leu Ala Ala Asp Gly Lys
1620 1625 1630
TCT ACA ACA TGG AGT GTC AGA CTG GGA CAG CTA TTA TTA TCA GCC AAA 4944
Ser Thr Thr Trp Ser Val Arg Leu Gly Gln Leu Leu Leu Ser Ala Lys
1635 1640 1645
AAA AGA GAT ATC ACA GCT TTT TAT GAC TCA CTG AAA CTA GTG AGA GCA 4992
Lys Arg Asp Ile Thr Ala Phe Tyr Asp Ser Leu Lys Leu Val Arg Ala
1650 1655 1660
GAA CAA ATT GTA CCT CTT TCA GCT GCA AGC TTT GAA AGA GGC TCC TAC 5040
Glu Gln Ile Val Pro Leu Ser Ala Ala Ser Phe Glu Arg Gly Ser Tyr
1665 1670 1675 1680
CAA CGA GGA TAT GAA TAT ATT GTG AGA TTG CAC ATG TTA TGT GAG TTG 5088
Gln Arg Gly Tyr Glu Tyr Ile Val Arg Leu His Met Leu Cys Glu Leu
1685 1690 1695
GAG CAT AGC ATC AAA CCA CTT TTC CAG CAT TCT CCA GGT GAC AGT TCT 5136
Glu His Ser Ile Lys Pro Leu Phe Gln His Ser Pro Gly Asp Ser Ser
1700 1705 1710
CAA GAA GAT TCT CTA AAC TGG GTA GCT CGA CTA GAA ATG ACC CAG AAT 5184
Gln Glu Asp Ser Leu Asn Trp Val Ala Arg Leu Glu Met Thr Gln Asn
1715 1720 1725
TCC TAC AGA GCC AAG GAG CCT ATC CTG GCT CTC CGG AGG GCT TTA CTA 5232
Ser Tyr Arg Ala Lys Glu Pro Ile Leu Ala Leu Arg Arg Ala Leu Leu
1730 1735 1740
AGC CTC AAC AAA AGA CCA GAT TAC AAT GAA ATG GTT GGA GAA TGC TGG 5280
Ser Leu Asn Lys Arg Pro Asp Tyr Asn Glu Met Val Gly Glu Cys Trp
1745 1750 1755 1760
CTG CAG AGT GCC AGG GTA GCT AGA AAG GCT GGT CAC CAC CAG ACA GCC 5328
Leu Gln Ser Ala Arg Val Ala Arg Lys Ala Gly His His Gln Thr Ala
1765 1770 1775
TAC AAT GCT CTC CTT AAT GCA GGG GAA TCA CGA CTC GCT GAA CTG TAC 5376
Tyr Asn Ala Leu Leu Asn Ala Gly Glu Ser Arg Leu Ala Glu Leu Tyr
1780 1785 1790
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GTG GAA AGG GCA AAG TGG CTC TGG TCC AAG GGT GAT GTT CAC CAG GCA 5424
Val Glu Arg Ala Lys Trp Leu Trp Ser Lys Gly Asp Val His Gln Ala
1795 1800 1805
CTA ATT GTT CTT CAA AAA GGT GTT GAA TTA TGT TTT CCT GAA AAT GAA 5472
Leu Ile Val Leu Gln Lys Gly Val Glu Leu Cys Phe Pro Glu Asn Glu
1810 1815 1820
ACC CCA CCT GAG GGT AAG AAC ATG TTA ATC CAT GGT CGA GCT ATG CTA 5520
Thr Pro Pro Glu Gly Lys Asn Met Leu Ile His Gly Arg Ala Met Leu
1825 1830 1835 1840
CTA GTG GGC CGA TTT ATG GAA GAA ACA GCT AAC TTT GAA AGC AAT GCA 5568
Leu Val Gly Arg Phe Met Glu Glu Thr Ala Asn Phe Glu Ser Asn Ala
1845 1850 1855
ATT ATG AAA AAA TAT AAG GAT GTG ACC GCG TGC CTG CCA GAA TGG GAG 5616
Ile Met Lys Lys Tyr Lys Asp Val Thr Ala Cys Leu Pro Glu Trp Glu
1860 1865 1870
GAT GGG CAT TTT TAC CTT GCC AAG TAC TAT GAC AAA TTG ATG CCC ATG 5664
Asp Gly His Phe Tyr Leu Ala Lys Tyr Tyr Asp Lys Leu Met Pro Met
1875 1880 1885
GTC ACA GAC AAC AAA ATG GAA AAG CAA GGT GAT CTC ATC CGG TAT ATA 5712
Val Thr Asp Asn Lys Met Glu Lys Gln Gly Asp Leu Ile Arg Tyr Ile
1890 1895 1900
GTT CTT CAT TTT GGC AGA TCT CTA CAP. TAT GGA AAT CAG TTC ATA TAT 5760
Val Leu His Phe Gly Arg Ser Leu Gln Tyr Gly Asn Gln Phe Ile Tyr
1905 1910 1915 1920
CAG TCA ATG CCA CGA ATG TTA ACT CTA TGG CTT GAT TAT GGT ACA AAG 5808
Gln Ser Met Pro Arg Met Leu Thr Leu Trp Leu Asp Tyr Gly Thr Lys
1925 1930 1935
GCA TAT GAA TGG GAA AAA GCT GGC CGC TCC GAT CGT GTA CAA ATG AGG 5856
Ala Tyr Glu Trp Glu Lys Ala Gly Arg Ser Asp Arg Val Gin Met Arg
1940 1945 1950
AAT GAT TTG GGT AAA ATA AAC AAG GTT ATC ACA GAG CAT ACA AAC TAT 5904
Asn Asp Leu Gly Lys Ile Asn Lys Val Ile Thr Glu His Thr Asn Tyr
1955 1960 1965
TTA GCT CCA TAT CAA TTT TTG ACT GCT TTT TCA CAA TTG ATC TCT CGA 5952
Leu Ala Pro Tyr Gln Phe Leu Thr Ala Phe Ser Gln Leu Ile Ser Arg
1970 1975 1980
ATT TGT CAT TCT CAC GAT GAA GTT TTT GTT GTG CTT GAT GGA AAT AAT 6000
Ile Cys His Ser His Asp Glu Val Phe Val Val Leu Asp Gly Asn Asn
1985 1990 1995 2000
AGC CAA GTA TTT CTA GCC TAT CCT CAA CAA GCA ATG TGG ATG ATG ACA 6048
Ser Gln Val Phe Leu Ala Tyr Pro Gln Gln Ala Met Trp Met Met Thr
2005 2010 2015
GCT GTG TCA AAG TCA TCT TAT CCC ATG CGT GTG AAC AGA TGC AAG GAA 6096
Ala Val Ser Lys Ser Ser Tyr Pro Met Arg Val Asn Arg Cys Lys Glu
2020 2025 2030
ATC CTC AAT AAA GCT ATT CAT ATG AAA AAA TCC TTA GAG AAG TTT GTT 6144
Ile Leu Asn Lys Ala Ile His Met Lys Lys Ser Leu Glu Lys Phe Val
2035 2040 2045
GGA GAT GCA ACT CGC CTA ACA GAT AAG CTT CTA GAA TTG TGC AAT AAA 6192
Gly Asp Ala Thr Arg Leu Thr Asp Lys Leu Leu Glu Leu Cys Asn Lys
2050 2055 2060
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CCG GTT GAT GGA AGT AGT TCC ACA TTA AGC ATG AGC ACT CAT TTT AAA 6240
Pro Val Asp Gly Ser Ser Ser Thr Leu Ser Met Ser Thr His Phe Lys
2065 2070 2075 2080
ATG CTT AAA AAG CTG GTA GAA GAA GCA ACA TTT AGT GAA ATC CTC ATT 6288
Met Leu Lys Lys Leu Val Glu Glu Ala Thr Phe Ser Glu Ile Leu Ile
2085 2090 2095
CCT CTA CAA TCA GTC ATG ATA CCT ACA CTT CCA TCA ATT CTG GGT ACC 6336
Pro Leu Gln Ser Val Met Ile Pro Thr Leu Pro Ser Ile Leu Gly Thr
2100 2105 2110
CAT GCT AAC CAT GCT AGC CAT GAA CCA TTT CCT GGA CAT TGG GCC TAT 6384
His Ala Asn His Ala Ser His Glu Pro Phe Pro Gly His Trp Ala Tyr
2115 2120 2125
ATT GCA GGG TTT GAT GAT ATG GTG GAA ATT CTT GCT TCT CTT CAG AAA 6432
Ile Ala Gly Phe Asp Asp Met Val Glu Ile Leu Ala Ser Leu Gln Lys
2130 2135 2140
CCA AAG AAG ATT TCT TTA AAA GGC TCA GAT GGA AAG TTC TAC ATC ATG 6480
Pro Lys Lys Ile Ser Leu Lys Gly Ser Asp Gly Lys Phe Tyr Ile Met
2145 2150 2155 2160
ATG TGT AAG CCA AAA GAT GAC CTG AGA AAG GAT TGT AGA CTA ATG GAA 6528
Met Cys Lys Pro Lys Asp Asp Leu Arg Lys Asp Cys Arg Leu Met Glu
2165 2170 2175
TTC AAT TCC TTG ATT AAT AAG TGC TTA AGA AAA GAT GCA GAG TCT CGT 6576
Phe Asn Ser Leu Ile Asn Lys Cys Leu Arg Lys Asp Ala Glu Ser Arg
2180 2185 2190
AGA AGA GAA CTT CAT ATT CGA ACA TAT GCA GTT ATT CCA CTA AAT GAT 6624
Arg Arg Glu Leu His Ile Arg Thr Tyr Ala Val Ile Pro Leu Asn Asp
2195 2200 2205
GAA TGT GGG ATT ATT GAA TGG GTG AAC AAC ACT GCT GGT TTG AGA CCT 6672
Glu Cys Gly Ile Ile Glu Trp Val Asn Asn Thr Ala Gly Leu Arg Pro
2210 2215 2220
ATT CTG ACC AAA CTA TAT AAA GAA AAG GGA GTG TAT ATG ACA GGA AAA 6720
Ile Leu Thr Lys Leu Tyr Lys Glu Lys Gly Val Tyr Met Thr Gly Lys
2225 2230 2235 2240
GAA CTT CGC CAG TGT ATG CTA CCA AAG TCA GCA GCT TTA TCT GAA AAA 6768
Glu Leu Arg Gln Cys Met Leu Pro Lys Ser Ala Ala Leu Ser Glu Lys
2245 2250 2255
CTC AAA GTA TTC CGA GAA TTT CTC CTG CCC AGG CAT CCT CCT ATT TTT 6816
Leu Lys Val Phe Arg Glu Phe Leu Leu Pro Arg His Pro Pro Ile Phe
2260 2265 2270
CAT GAG TGG TTT CTG AGA ACA TTC CCT GAT CCT ACA TCA TGG TAC AGT 6864
His Glu Trp Phe Leu Arg Thr Phe Pro Asp Pro Thr Ser Trp Tyr Ser
2275 2280 2285
AGT AGA TCA GCT TAC TGC CGT TCC ACT GCA GTA ATG TCA ATG GTT GGT 6912
Ser Arg Ser Ala Tyr Cys Arg Ser Thr Ala Val Met Ser Met Val Gly
2290 2295 2300
TAT ATT CTG GGG CTT GGA GAC CGT CAT GGT GAA AAT ATT CTC TTT GAT 6960
Tyr Ile Leu Gly Leu Gly Asp Arg His Gly Glu Asn Ile Leu Phe Asp
2305 2310 2315 2320
TCT TTG ACT GGT GAA TGC GTA CAT GTA GAT TTC AAT TGT CTT TTC AAT 7008
Ser Leu Thr Gly Glu Cys Val His Val Asp Phe Asn Cys Leu Phe Asn
2325 2330 2335
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AAG GGA GAA ACC TTT GAA GTT CCA GAA ATT GTG CCA TTT CGC CTG ACT 7056
Lys Gly Glu Thr Phe Glu Val Pro Glu Ile Val Pro Phe Arg Leu Thr
2340 2345 2350
CAT AAT ATG GTT AAT GGA ATG GGT CCT ATG GGA ACA GAG GGT CTT TTT 7104
His Asn Met Val Asn Gly Met Gly Pro Met Gly Thr Glu Gly Leu Phe
2355 2360 2365
CGA AGA GCA TGT GAA GTT ACA ATG AGG CTG ATG CGT GAT CAG CGA GAG 7152
Arg Arg Ala Cys Glu Val Thr Met Arg Leu Met Arg Asp Gln Arg Glu
2370 2375 2380
CCT TTA ATG AGT GTC TTA AAG ACT TTT CTA CAT GAT CCT CTT GTG GAA 7200
Pro Leu Met Ser Val Leu Lys Thr Phe Leu His Asp Pro Leu Val Glu
2385 2390 2395 2400
TGG AGT AAA CCA GTG AAA GGG CAT TCC AAA GCG CCA CTG AAT GAA ACT 7248
Trp Ser Lys Pro Val Lys Gly His Ser Lys Ala Pro Leu Asn Glu Thr
2405 2410 2415
GGA GAA GTT GTC AAT GAA AAG GCC AAG ACC CAT GTT CTT GAC ATT GAG 7296
Gly Glu Val Val Asn Glu Lys Ala Lys Thr His Val Leu Asp Ile Glu
2420 2425 2430
CAG CGA CTA CAA GGT GTA ATC AAG ACT CGA AAT AGA GTG ACA GGA CTG 7344
Gln Arg Leu Gln Gly Val Ile Lys Thr Arg Asn Arg Val Thr Gly Leu
2435 2440 2445
CCG TTA TCT ATT GAA GGA CAT GTG CAT TAC CTT ATA CAA GAA GCT ACT 7392
Pro Leu Ser Ile Glu Gly His Val His Tyr Leu Ile Gln Glu Ala Thr
2450 2455 2460
GAT GAA AAC TTA CTA TGC CAG ATG TAT CTT GGT TGG ACT CCA TAT ATG 7440
Asp Glu Asn Leu Leu Cys Gln Met Tyr Leu Gly Trp Thr Pro Tyr Met
2465 2470 2475 2480
TGAAATGAAA TTATGTAAAA GAATATGTTA ATAATCTAAA AGTAAAAAAA AAAAAP,AAP,A 7500
AA 7502
(2) INFORMATION FOR SEQ ID NO:26:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2480 amino acids
(B) TYPE: amino acid
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: protein
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:
Met Gly His Ala Val Glu Trp Pro Val Val Met Ser Arg Phe Leu Ser
1 5 10 15
Gln Leu Asp Glu His Met Gly Tyr Leu Gln Ser Ala Pro Leu Gin Leu
20 25 30
Met Ser Met Gln Asn Leu Glu Phe Ile Glu Val Thr Leu Leu Met Val
35 40 45
Leu Thr Arg Ile Ile Ala Ile Val Phe Phe Arg Arg Gln Glu Leu Leu
50 55 60
Leu Trp Gln Ile Gly Cys Val Leu Leu Glu Tyr Gly Ser Pro Lys Ile
65 70 75 80
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Lys Ser Leu Ala Ile Ser Phe Leu Thr Glu Leu Phe Gln Leu Gly Gly
85 90 95
Leu Pro Ala Gln Pro Ala Ser Thr Phe Phe Ser Ser Phe Leu Glu Leu
100 105 110
Leu Lys His Leu Val Glu Met Asp Thr Asp Gln Leu Lys Leu Tyr Glu
115 120 125
Glu Pro Leu Ser Lys Leu Ile Lys Thr Leu Phe Pro Phe Glu Ala Glu
130 135 140
Ala Tyr Arg Asn Ile Glu Pro Val Tyr Leu Asn Met Leu Leu Glu Lys
145 150 155 160
Leu Cys Val Met Phe Glu Asp Gly Val Leu Met Arg Leu Lys Ser Asp
165 170 175
Leu Leu Lys Ala Ala Leu Cys His Leu Leu Gln Tyr Phe Leu Lys Phe
180 185 190
Val Pro Ala Gly Tyr Glu Ser Ala Leu Gln Val Arg Lys Val Tyr Val
195 200 205
Arg Asn Ile Cys Lys Ala Leu Leu Asp Val Leu Gly Ile Glu Val Asp
210 215 220
Ala Glu Tyr Leu Leu Gly Pro Leu Tyr Ala Ala Leu Lys Met Glu Ser
225 230 235 240
Met Glu Ile Ile Glu Glu Ile Gln Cys Gln Thr Gin Gin Glu Asn Leu
245 250 255
Ser Ser Asn Ser Asp Gly Ile Ser Pro Lys Arg Arg Arg Leu Ser Ser
260 265 270
Ser Leu Asn Pro Ser Lys Arg Ala Pro Lys Gln Thr Glu Glu Ile Lys
275 280 285
His Val Asp Met Asn Gln Lys Ser Ile Leu Trp Ser Ala Leu Lys Gln
290 295 300
Lys Ala Glu Ser Leu Gln Ile Ser Leu Glu Tyr Ser Gly Leu Lys Asn
305 310 315 320
Pro Val Ile Glu Met Leu Glu Gly Ile Ala Val Val Leu Gln Leu Thr
325 330 335
Ala Leu Cys Thr Val His Cys Ser His Gin Asn Met Asn Cys Arg Thr
340 345 350
Phe Lys Asp Cys Gln His Lys Ser Lys Lys Lys Pro Ser Val Val Ile
355 360 365
Thr Trp Met Ser Leu Asp Phe Tyr Thr Lys Val Leu Lys Ser Cys Arg
370 375 380
Ser Leu Leu Glu Ser Val Gln Lys Leu Asp Leu Glu Ala Thr Ile Asp
385 390 395 400
Lys Val Val Lys Ile Tyr Asp Ala Leu Ile Tyr Met Gin Val Asn Ser
405 410 415
Ser Phe Glu Asp His Ile Leu Glu Asp Leu Cys Gly Met Leu Ser Leu
420 425 430
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Pro Trp Ile Tyr Ser His Ser Asp Asp Gly Cys Leu Lys Leu Thr Thr
435 440 445
Phe Ala Ala Asn Leu Leu Thr Leu Ser Cys Arg Ile Ser Asp Ser Tyr
450 455 460
Ser Pro Gln Ala Gln Ser Arg Cys Val Phe Leu Leu Thr Leu Phe Pro
465 470 475 480
Arg Arg Ile Phe Leu Glu Trp Arg Thr Ala Val Tyr Asn Trp Ala Leu
485 490 495
Gln Ser Ser His Glu Val Ile Arg Ala Ser Cys Val Ser Gly Phe Phe
500 505 510
Ile Leu Leu Gln Gln Gln Asn Ser Cys Asn Arg Val Pro Lys Ile Leu
515 520 525
Ile Asp Lys Val Lys Asp Asp Ser Asp Ile Val Lys Lys Glu Phe Ala
530 535 540
Ser Ile Leu Gly Gln Leu Val Cys Thr Leu His Gly Met Phe Tyr Leu
545 550 555 560
Thr Ser Ser Leu Thr Glu Pro Phe Ser Glu His Gly His Val Asp Leu
565 570 575
Phe Cys Arg Asn Leu Lys Ala Thr Ser Gln His Glu Cys Ser Ser Ser
580 585 590
Gln Leu Lys Ala Ser Val Cys Lys Pro Phe Leu Phe Leu Leu Lys Lys
595 600 605
Lys Ile Pro Ser Pro Val Lys Leu Ala Phe Ile Asp Asn Leu His His
610 615 620
Leu Cys Lys His Leu Asp Phe Arg Glu Asp Glu Thr Asp Val Lys Ala
625 630 635 640
Val Leu Gly Thr Leu Leu Asn Leu Met Glu Asp Pro Asp Lys Asp Val
645 650 655
Arg Val Ala Phe Ser Gly Asn Ile Lys His Ile Leu Glu Ser Leu Asp
660 665 670
Ser Glu Asp Gly Phe Ile Lys Glu Leu Phe Val Leu Arg Met Lys Glu
675 680 685
Ala Tyr Thr His Ala Gln Ile Ser Arg Asn Asn Glu Leu Lys Asp Thr
690 695 700
Leu Ile Leu Thr Thr Gly Asp Ile Gly Arg Ala Ala Lys Gly Asp Leu
705 710 715 720
Val Pro Phe Ala Leu Leu His Leu Leu His Cys Leu Leu Ser Lys Ser
725 730 735
Ala Ser Val Ser Gly Ala Ala Tyr Thr Glu Ile Arg Ala Leu Val Ala
740 745 750
Ala Lys Ser Val Lys Leu Gln Ser Phe Phe Ser Gln Tyr Lys Lys Pro
755 760 765
Ile Cys Gin Phe Leu Val Glu Ser Leu His Ser Ser Gln Met Thr Ala
770 775 780
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Leu Pro Asn Thr Pro Cys Gln Asn Ala Asp Val Arg Lys Gln Asp Val
785 790 795 800
Ala His Gln Arg Glu Met Ala Leu Asn Thr Leu Ser Glu Ile Ala Asn
805 810 815
Val Phe Asp Phe Pro Asp Leu Asn Arg Phe Leu Thr Arg Thr Leu Gin
820 825 830
Val Leu Leu Pro Asp Leu Ala Ala Lys Ala Ser Pro Ala Ala Ser Ala
835 840 845
Leu Ile Arg Thr Leu Gly Lys Gln Leu Asn Val Asn Arg Arg Glu Ile
850 855 860
Leu Ile Asn Asn Phe Lys Tyr Ile Phe Ser His Leu Val Cys Ser Cys
865 870 875 880
Ser Lys Asp Glu Leu Glu Arg Ala Leu His Tyr Leu Lys Asn Glu Thr
885 890 895
Glu Ile Glu Leu Gly Ser Leu Leu Arg Gln Asp Phe Gln Gly Leu His
900 905 910
Asn Glu Leu Leu Leu Arg Ile Gly Glu His Tyr Gln Gln Val Phe Asn
915 920 925
Gly Leu Ser Ile Leu Ala Ser Phe Ala Ser Ser Asp Asp Pro Tyr Gln
930 935 940
Gly Pro Arg Asp Ile Ile Ser Pro Glu Leu Met Ala Asp Tyr Leu Gln
945 950 955 960
Pro Lys Leu Leu Gly Ile Leu Ala Phe Phe Asn Met Gln Leu Leu Ser
965 970 975
Ser Ser Val Gly Ile Glu Asp Lys Lys Met Ala Leu Asn Ser Leu Met
980 985 990
Ser Leu Met Lys Leu Met Gly Pro Lys His Val Ser Ser Val Arg Val
995 1000 1005
Lys Met Met Thr Thr Leu Arg Thr Gly Leu Arg Phe Lys Asp Asp Phe
1010 1015 1020
Pro Glu Leu Cys Cys Arg Ala Trp Asp Cys Phe Val Arg Cys Leu Asp
1025 1030 1035 1040
His Ala Cys Leu Gly Ser Leu Leu Ser His Val Ile Val Ala Leu Leu
1045 1050 1055
Pro Leu Ile His Ile Gln Pro Lys Glu Thr Ala Ala Ile Phe His Tyr
1060 1065 1070
Leu Ile Ile Glu Asn Arg Asp Ala Val Gln Asp Phe Leu His Glu Ile
1075 1080 1085
Tyr Phe Leu Pro Asp His Pro Glu Leu Lys Lys Ile Lys Ala Val Leu
1090 1095 1100
Gln Glu Tyr Arg Lys Glu Thr Ser Glu Ser Thr Asp Leu Gln Thr Thr
1105 1110 1115 1120
Leu Gln Leu Ser Met Lys Ala Ile Gln His Glu Asn Val Asp Val Arg
1125 1130 1135
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Ile His Ala Leu Thr Ser Leu Lys Glu Thr Leu Tyr Lys Asn Gln Glu
1140 1145 1150
Lys Leu Ile Lys Tyr Ala Thr Asp Ser Glu Thr Val Glu Pro Ile Ile
1155 1160 1165
Ser Gln Leu Val Thr Val Leu Leu Lys Gly Cys Gln Asp Ala Asn Ser
1170 1175 1180
Gln Ala Arg Leu Leu Cys Gly Glu Cys Leu Gly Glu Leu Gly Ala Ile
1185 1190 1195 1200
Asp Pro Gly Arg Leu Asp Phe Ser Thr Thr Glu Thr Gln Gly Lys Asp
1205 1210 1215
Phe Thr Phe Val Thr Gly Val Glu Asp Ser Ser Phe Ala Tyr Gly Leu
1220 1225 1230
Leu Met Glu Leu Thr Arg Ala Tyr Leu Ala Tyr Ala Asp Asn Ser Arg
1235 1240 1245
Ala Gln Asp Ser Ala Ala Tyr Ala Ile Gln Glu Leu Leu Ser Ile Tyr
1250 1255 1260
Asp Cys Arg Glu Met Glu Thr Asn Gly Pro Gly His Gln Leu Trp Arg
1265 1270 1275 1280
Arg Phe Pro Glu His Val Arg Glu Ile Leu Glu Pro His Leu Asn Thr
1285 1290 1295
Arg Tyr Lys Ser Ser Gln Lys Ser Thr Asp Trp Ser Gly Val Lys Lys
1300 1305 1310
Pro Ile Tyr Leu Ser Lys Leu Gly Ser Asn Phe Ala Glu Trp Ser Ala
1315 1320 1325
Ser Trp Ala Gly Tyr Leu Ile Thr Lys Val Arg His Asp Leu Ala Ser
1330 1335 1340
Lys Ile Phe Thr Cys Cys Ser Ile Met Met Lys His Asp Phe Lys Val
1345 1350 1355 1360
Thr Ile Tyr Leu Leu Pro His Ile Leu Val Tyr Val Leu Leu Gly Cys
1365 1370 1375
Asn Gln Glu Asp Gln Gln Glu Val Tyr Ala Glu Ile Met Ala Val Leu
1380 1385 1390
Lys His Asp Asp Gln His Thr Ile Asn Thr Gln Asp Ile Ala Ser Asp
1395 1400 1405
Leu Cys Gln Leu Ser Thr Gln Thr Val Phe Ser Met Leu Asp His Leu
1410 1415 1420
Thr Gln Trp Ala Arg His Lys Phe Gln Ala Leu Lys Ala Glu Lys Cys
1425 1430 1435 1440
Pro His Ser Lys Ser Asn Arg Asn Lys Val Asp Ser Met Val Ser Thr
1445 1450 1455
Val Asp Tyr Glu Asp Tyr Gln Ser Val Thr Arg Phe Leu Asp Leu Ile
1460 1465 1470
Pro Gln Asp Thr Leu Ala Val Ala Ser Phe Arg Ser Lys Ala Tyr Thr
1475 1480 1485
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Arg Ala Val Met His Phe Glu Ser Phe Ile Thr Glu Lys Lys Gln Asn
1490 1495 1500
Ile Gln Glu His Leu Gly Phe Leu Gln Lys Leu Tyr Ala Ala Met His
1505 7.510 1515 1520
Glu Pro Asp Gly Val Ala Gly Val Ser Ala Ile Arg Lys Ala Glu Pro
1525 1530 1535
Ser Leu Lys Glu Gln Ile Leu Glu His Glu Ser Leu Gly Leu Leu Arg
1540 1545 1550
Asp Ala Thr Ala Cys Tyr Asp Arg Ala Ile Gln Leu Glu Pro Asp Gln
1555 1560 1565
Ile Ile His Tyr His Gly Val Val Lys Ser Met Leu Gly Leu Gly Gin
1570 1575 1580
Leu Ser Thr Val Ile Thr Gln Val Asn Gly Val His Ala Asn Arg Ser
1585 1590 1595 1600
Glu Trp Thr Asp Glu Leu Asn Thr Tyr Arg Val Glu Ala Ala Trp Lys
1605 1610 1615
Leu Ser Gln Trp Asp Leu Val Glu Asn Tyr Leu Ala Ala Asp Gly Lys
1620 1625 1630
Ser Thr Thr Trp Ser Val Arg Leu Gly Gln Leu Leu Leu Ser Ala Lys
1635 1640 1645
Lys Arg Asp Ile Thr Ala Phe Tyr Asp Ser Leu Lys Leu Val Arg Ala
1650 1655 1660
Glu Gln Ile Val Pro Leu Ser Ala Ala Ser Phe Glu Arg Gly Ser Tyr
1665 1670 1675 1680
Gln Arg Gly Tyr Glu Tyr Ile Val Arg Leu His Met Leu Cys Glu Leu
1685 1690 1695
Glu His Ser Ile Lys Pro Leu Phe Gln His Ser Pro Gly Asp Ser Ser
1700 1705 1710
Gin Glu Asp Ser Leu Asn Trp Val Ala Arg Leu Glu Met Thr Gln Asn
1715 1720 1725
Ser Tyr Arg Ala Lys Glu Pro Ile Leu Ala Leu Arg Arg Ala Leu Leu
1730 1735 1740
Ser Leu Asn Lys Arg Pro Asp Tyr Asn Glu Met Val Gly Glu Cys Trp
1745 1750 1755 1760
Leu Gln Ser Ala Arg Val Ala Arg Lys Ala Gly His His Gln Thr Ala
1765 1770 1775
Tyr Asn Ala Leu Leu Asn Ala Gly Glu Ser Arg Leu Ala Glu Leu Tyr
1780 1785 1790
Val Glu Arg Ala Lys Trp Leu Trp Ser Lys Gly Asp Val His Gln Ala
1795 1800 1805
Leu Ile Val Leu Gln Lys Gly Val Glu Leu Cys Phe Pro Glu Asn Glu
1810 1815 1820
Thr Pro Pro Glu Gly Lys Asn Met Leu Ile His Gly Arg Ala Met Leu
1825 1830 1835 1840
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Leu Val Gly Arg Phe Met Glu Glu Thr Ala Asn Phe Glu Ser Asn Ala
1845 1850 1855
Ile Met Lys Lys Tyr Lys Asp Val Thr Ala Cys Leu Pro Glu Trp Glu
1860 1865 1870
Asp Gly His Phe Tyr Leu Ala Lys Tyr Tyr Asp Lys Leu Met Pro Met
1875 1880 1885
Val Thr Asp Asn Lys Met Glu Lys Gln Gly Asp Leu Ile Arg Tyr Ile
1890 1895 1900
Val Leu His Phe Gly Arg Ser Leu Gln Tyr Gly Asn Gln Phe Ile Tyr
1905 1910 1915 1920
Gln Ser Met Pro Arg Met Leu Thr Leu Trp Leu Asp Tyr Gly Thr Lys
1925 1930 1935
Ala Tyr Glu Trp Glu Lys Ala Gly Arg Ser Asp Arg Val Gln Met Arg
1940 1945 1950
Asn Asp Leu Gly Lys Ile Asn Lys Val Ile Thr Glu His Thr Asn Tyr
1955 1960 1965
Leu Ala Pro Tyr Gln Phe Leu Thr Ala Phe Ser Gln Leu Ile Ser Arg
1970 1975 1980
Ile Cys His Ser His Asp Glu Val Phe Val Val Leu Asp Gly Asn Asn
1985 1990 1995 2000
Ser Gln Val Phe Leu Ala Tyr Pro Gln Gln Ala Met Trp Met Met Thr
2005 2010 2015
Ala Val Ser Lys Ser Ser Tyr Pro Met Arg Val Asn Arg Cys Lys Glu
2020 2025 2030
Ile Leu Asn Lys Ala Ile His Met Lys Lys Ser Leu Glu Lys Phe Val
2035 2040 2045
Gly Asp Ala Thr Arg Leu Thr Asp Lys Leu Leu Glu Leu Cys Asn Lys
2050 2055 2060
Pro Val Asp Gly Ser Ser Ser Thr Leu Ser Met Ser Thr His Phe Lys
2065 2070 2075 2080
Met Leu Lys Lys Leu Val Glu Glu Ala Thr Phe Ser Glu Ile Leu Ile
2085 2090 2095
Pro Leu Gln Ser Val Met Ile Pro Thr Leu Pro Ser Ile Leu Gly Thr
2100 2105 2110
His Ala Asn His Ala Ser His Glu Pro Phe Pro Gly His Trp Ala Tyr
2115 2120 2125
Ile Ala Gly Phe Asp Asp Met Val Glu Ile Leu Ala Ser Leu Gln Lys
2130 2135 2140
Pro Lys Lys Ile Ser Leu Lys Gly Ser Asp Gly Lys Phe Tyr Ile Met
2145 2150 2155 2160
Met Cys Lys Pro Lys Asp Asp Leu Arg Lys Asp Cys Arg Leu Met Glu
2165 2170 2175
Phe Asn Ser Leu Ile Asn Lys Cys Leu Arg Lys Asp Ala Glu Ser Arg
2180 2185 2190
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Arg Arg Glu Leu His Ile Arg Thr Tyr Ala Val Ile Pro Leu Asn Asp
2195 2200 2205
Glu Cys Gly Ile Ile Glu Trp Val Asn Asn Thr Ala Gly Leu Arg Pro
2210 2215 2220
Ile Leu Thr Lys Leu Tyr Lys Glu Lys Gly Val Tyr Met Thr Gly Lys
2225 2230 2235 2240
Glu Leu Arg Gln Cys Met Leu Pro Lys Ser Ala Ala Leu Ser Glu Lys
2245 2250 2255
Leu Lys Val Phe Arg Glu Phe Leu Leu Pro Arg His Pro Pro Ile Phe
2260 2265 2270
His Glu Trp Phe Leu Arg Thr Phe Pro Asp Pro Thr Ser Trp Tyr Ser
2275 2280 2285
Ser Arg Ser Ala Tyr Cys Arg Ser Thr Ala Val Met Ser Met Val Gly
2290 2295 2300
Tyr Ile Leu Gly Leu Gly Asp Arg His Gly Glu Asn Ile Leu Phe Asp
2305 2310 2315 2320
Ser Leu Thr Gly Glu Cys Val His Val Asp Phe Asn Cys Leu Phe Asn
2325 2330 2335
Lys Gly Glu Thr Phe Glu Val Pro Glu Ile Val Pro Phe Arg Leu Thr
2340 2345 2350
His Asn Met Val Asn Gly Met Gly Pro Met Gly Thr Glu Gly Leu Phe
2355 2360 2365
Arg Arg Ala Cys Glu Val Thr Met Arg Leu Met Arg Asp Gln Arg Glu
2370 2375 2380
Pro Leu Met Ser Val Leu Lys Thr Phe Leu His Asp Pro Leu Val Glu
2385 2390 2395 2400
Trp Ser Lys Pro Val Lys Gly His Ser Lys Ala Pro Leu Asn Glu Thr
2405 2410 2415
Gly Glu Val Val Asn Glu Lys Ala Lys Thr His Val Leu Asp Ile Glu
2420 2425 2430
Gln Arg Leu Gln Gly Val Ile Lys Thr Arg Asn Arg Val Thr Gly Leu
2435 2440 2445
Pro Leu Ser Ile Glu Gly His Val His Tyr Leu Ile Gln Glu Ala Thr
2450 2455 2460
Asp Glu Asn Leu Leu Cys Gln Met Tyr Leu Gly Trp Thr Pro Tyr Met
2465 2470 2475 2480
(2) INFORMATION FOR SEQ ID NO:27:
(i1 SEQUENCE CHARACTERISTICS:
(A) LENGTH: 878 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: DNA
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:
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ATCCATTGTG TTGGAAAGGA ATGATGAATG TGGGATTATT GAATGGGTGA ACAATACTGC 60
TGGCTTGAGA CCTATTCTGA CCAAAATATA TAAAGAAAAG GGAGTGTATA TGACAGGAAA 120
GGAGCTTCGC CAGTGTATGC TACCAAAGTC AGCAGCTTTA TCTGAAAAAC TCAAAGTATT 180
CCAAGAATTA CTCCTGCCCA GGCATCCTCC TGTTTTTCAT GAGTGGTTTC TGAGAACATT 240
CCCTGATCCT ACATCATGGT ACAGTAGCAG ATCTGCATAT TGCCGCTCTA CTGCAGTCAT 300
GTCAATGGTT GGCTACATCC TGGGGCTTGG AGACCGTCAT GGTGAAAACA TTCTTTTTGA 360
CTCTTTCACT GGTGAATGTG TACATGTAGA TTTCAACTGT CTTTTTAATA AGGGAGAAAC 420
GTTTGAAGTT CCGGAAATTG TACCATTTCG ACTGACTCAT AATATGGTTA ATGGAATGGG 480
TCCTATGGGA ACAGAGGGTC TATTTCGAAG AGCATGTGAA GTTACACTGA GACTGATGAG 540
GGATCAGAGA GAACCTTTAA TGAGTGTCTT AAAGACTTTT CTACACGATC CTCTAGTGGA 600
GTGGAGTAAA CCAGTGAAAG GACACTCCAA AGCACCACTG AATGAAACCG GGGAAGTTGT 660
CAATGAGAAG GCCAAGACCC ATGTTCTTGA CATTGAACAA CGACTACAAG GTGTGATCAA 720
AACCCGAAAT AGAGTAACAG GGCTGCCATT ATCTATTGAA GGACATGTGC ATTACCTCAT 780
ACAAGAAGCT ACTGATGAAA ACTTACTCTG TCAGATGTAC CTTGGTTGGA CCCCATATAT 840
GTAAAATAAA ATTATTTCAA AGAAAAAAAA AAAAAAAA 878
(2) INFORMATION FOR SEQ ID NO:28:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 7935 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: cDNA
(ix) FEATURE:
(A) NAME/KEY: CDS
(B) LOCATION: 1..7932
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:28:
ATG GGG GAA CAT GGC CTG GAG CTG GCT TCC ATG ATC CCC GCC CTG CGG 48
Met Gly Glu His Gly Leu Glu Leu Ala Ser Met Ile Pro Ala Leu Arg
1 5 10 15
GAG CTG GGC AGT GCC ACA CCA GAG GAA TAT AAT ACA GTT GTA CAG AAG 96
Glu Leu Gly Ser Ala Thr Pro Glu Glu Tyr Asn Thr Val Val Gln Lys
20 25 30
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CCA AGA CAA ATT CTG TGT CAA TTC ATT GAC CGG ATA CTT ACA GAT GTA 144
Pro Arg Gln Ile Leu Cys Gln Phe Ile Asp Arg Ile Leu Thr Asp Val
35 40 45
AAT GTT GTT GCT GTA GAA CTT GTA AAG AAA ACT GAC TCT CAG CCA ACC 192
Asn Val Val Ala Val Glu Leu Val Lys Lys Thr Asp Ser Gln Pro Thr
50 55 60
TCC GTG ATG TTG CTT GAT TTC ATC CAG CAT ATC ATG AAA TCC TCC CCA 240
Ser Val Met Leu Leu Asp Phe Ile Gln His Ile Met Lys Ser Ser Pro
65 70 75 80
CTT ATG TTT GTA AAT GTG AGT GGA AGC CAT GAG CGC AAA GGC AGT TGT 288
Leu Met Phe Val Asn Val Ser Giy Ser His Glu Arg Lys Gly Ser Cys
85 90 95
ATT GAA TTC AGT AAT TGG ATC ATA ACG AGA CTT CTG CGG ATT GCA GCA 336
Ile Glu Phe Ser Asn Tzp Ile Ile Thr Arg Leu Leu Arg Ile Ala Ala
100 105 110
ACT CCC TCC TGT CAT TTG TTA CAC AAG AAA ATC TGT GAA GTC ATC TGT 384
Thr Pro Ser Cys His Leu Leu His Lys Lys Ile Cys Glu Val Ile Cys
115 120 125
TCA TTA TTA TTT CTT TTT AAA AGC AAG AGT CCT GCT ATT TTT GGG GTA 432
Ser Leu Leu Phe Leu Phe Lys Ser Lys Ser Pro Ala Ile Phe Gly Val
130 135 140
CTC ACA AAA GAA TTA TTA CAA CTT TTT GAA GAC TTG GTT TAC CTC CAT 480
Leu Thr Lys Glu Leu Leu Gln Leu Phe Glu Asp Leu Val Tyr Leu His
145 150 155 160
AGA AGA AAT GTG ATG GGT CAT GCT GTG GAA TGG CCA GTG GTC ATG AGC 528
Arg Arg Asn Val Met Gly His Ala Val Glu Trp Pro Val Val Met Ser
165 170 175
CGA TTT TTA AGT CAA TTA GAT GAA CAC ATG GGA TAT TTA CAA TCA GCT 576
Arg Phe Leu Ser Gln Leu Asp Glu His Met Gly Tyr Leu Gln Ser Ala
180 185 190
CCT TTG CAG TTG ATG AGT ATG CAA AAT TTA GAA TTT ATT GAA GTC ACT 624
Pro Leu Gln Leu Met Ser Met Gln Asn Leu Glu Phe Ile Glu Val Thr
195 200 205
TTA TTA ATG GTT CTT ACT CGT ATT ATT GCA ATT GTG TTT TTT AGA AGG 672
Leu Leu Met Val Leu Thr Arg Ile Ile Ala Ile Val Phe Phe Arg Arg
210 215 220
CAA GAA CTC TTA CTT TGG CAG ATA GGT TGT GTT CTG CTA GAG TAT GGT 720
Gln Glu Leu Leu Leu Trp Gln Ile Gly Cys Val Leu Leu Glu Tyr Gly
225 230 235 240
AGT CCA AAA ATT AAA TCC CTA GCA ATT AGC TTT TTA ACA GAA CTT TTT 768
Ser Pro Lys Ile Lys Ser Leu Ala Ile Ser Phe Leu Thr Glu Leu Phe
245 250 255
CAG CTT GGA GGA CTA CCA GCA CAA CCA GCT AGC ACT TTT TTC AGC TCA 816
Gln Leu Gly Gly Leu Pro Ala Gln Pro Ala Ser Thr Phe Phe Ser Ser
260 265 270
TTT TTG GAA TTA TTA AAA CAC CTT GTA GAA ATG GAT ACT GAC CAA TTG 864
Phe Leu Glu Leu Leu Lys His Leu Val Glu Met Asp Thr Asp Gln Leu
275 280 285
AAA CTC TAT GAA GAG CCA TTA TCA AAG CTG ATA AAG ACA CTA TTT CCC 912
Lys Leu Tyr Glu Glu Pro Leu Ser Lys Leu Ile Lys Thr Leu Phe Pro
290 295 300
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TTT GAA GCA GAA GCT TAT AGA AAT ATT GAA CCT GTC TAT TTA AAT ATG 960
Phe Glu Ala Glu Ala Tyr Arg Asn Ile Glu Pro Val Tyr Leu Asn Met
305 310 315 320
CTG CTG GAA AAA CTC TGT GTC ATG TTT GAA GAC GGT GTG CTC ATG CGG 1008
Leu Leu Glu Lys Leu Cys Val Met Phe Glu Asp Gly Val Leu Met Arg
325 330 335
CTT AAG TCT GAT TTG CTA AAA GCA GCT TTG TGC CAT TTA CTG CAG TAT 1056
Leu Lys Ser Asp Leu Leu Lys Ala Ala Leu Cys His Leu Leu Gln Tyr
340 345 350
TTC CTT AAA TTT GTG CCA GCT GGG TAT GAA TCT GCT TTA CAA GTC AGG 1104
Phe Leu Lys Phe Val Pro Ala Gly Tyr Glu Ser Ala Leu Gln Val Arg
355 360 365
AAG GTC TAT GTG AGA AAT ATT TGT AAA GCT CTT TTG GAT GTG CTT GGA 1152
Lys Val Tyr Val Arg Asn Ile Cys Lys Ala Leu Leu Asp Val Leu Gly
370 375 380
ATT GAG GTA GAT GCA GAG TAC TTG TTG GGC CCA CTT TAT GCA GCT TTG 1200
Ile Glu Val Asp Ala Glu Tyr Leu Leu Gly Pro Leu Tyr Ala Ala Leu
385 390 395 400
AAA ATG GAA AGT ATG GAA ATC ATT GAG GAG ATT CAA TGC CAA ACT CAA 1248
Lys Met Glu Ser Met Glu Ile Ile Glu Glu Ile Gln Cys Gln Thr Gln
405 410 415
CAG GAA AAC CTC AGC AGT AAT AGT GAT GGA ATA TCA CCC AAA AGG CGT 1296
Gln Glu Asn Leu Ser Ser Asn Ser Asp Gly Ile Ser Pro Lys Arg Arg
420 425 430
CGT CTC AGC TCG TCT CTA AAC CCT TCT AAA AGA GCA CCA AAA CAG ACT 1344
Arg Leu Ser Ser Ser Leu Asn Pro Ser Lys Arg Ala Pro Lys Gln Thr
435 440 445
GAG GAA ATT AAA CAT GTG GAC ATG AAC CAA AAG AGC ATA TTA TGG AGT 1392
Glu Glu Ile Lys His Val Asp Met Asn Gln Lys Ser Ile Leu Trp Ser
450 455 460
GCA CTG AAA CAG AAA GCT GAA TCC CTT CAG ATT TCC CTT GAA TAC AGT 1440
Ala Leu Lys Gln Lys Ala Glu Ser Leu Gln Ile Ser Leu Glu Tyr Ser
465 470 475 480
GGC CTA AAG AAT CCT GTT ATT GAG ATG TTA GAA GGA ATT GCT GTT GTC 1488
Gly Leu Lys Asn Pro Val Ile Glu Met Leu Glu Gly Ile Ala Val Val
485 490 495
TTA CAA CTG ACT GCT CTG TGT ACT GTT CAT TGT TCT CAT CAA AAC ATG 1536
Leu Gln Leu Thr Ala Leu Cys Thr Val His Cys Ser His Gln Asn Met
500 505 510
AAC TGC CGT ACT TTC AAG GAC TGT CAA CAT AAA TCC AAG AAG AAA CCT 1584
Asn Cys Arg Thr Phe Lys Asp Cys Gln His Lys Ser Lys Lys Lys Pro
515 520 525
TCT GTA GTG ATA ACT TGG ATG TCA TTG GAT TTT TAC ACA AAA GTG CTT 1632
Ser Val Val Ile Thr Trp Met Ser Leu Asp Phe Tyr Thr Lys Val Leu
530 535 540
AAG AGC TGT AGA AGT TTG TTA GAA TCT GTT CAG AAA CTG GAC CTG GAG 1680
Lys Ser Cys Arg Ser Leu Leu Glu Ser Val Gln Lys Leu Asp Leu Glu
545 550 555 560
GCA ACC ATT GAT AAG GTG GTG AAA ATT TAT GAT GCT TTG ATT TAT ATG 1728
Ala Thr Ile Asp Lys Val Val Lys Ile Tyr Asp Ala Leu Ile Tyr Met
565 570 575
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CAA GTA AAC AGT TCA TTT GAA GAT CAT ATC CTG GAA GAT TTA TGT GGT 1776
Gln Val Asn Ser Ser Phe Glu Asp His Ile Leu Glu Asp Leu Cys Gly
580 585 590
ATG CTC TCA CTT CCA TGG ATT TAT TCC CAT TCT GAT GAT GGC TGT TTA 1824
Met Leu Ser Leu Pro Trp Ile Tyr Ser His Ser Asp Asp Gly Cys Leu
595 600 605
AAG TTG ACC ACA TTT GCC GCT AAT CTT CTA ACA TTA AGC TGT AGG ATT 1872
Lys Leu Thr Thr Phe Ala Ala Asn Leu Leu Thr Leu Ser Cys Arg Ile
610 615 620
TCA GAT AGC TAT TCA CCA CAG GCA CAA TCA CGA TGT GTG TTT CTT CTG 1920
Ser Asp Ser Tyr Ser Pro Gln Ala Gln Ser Arg Cys Val Phe Leu Leu
625 630 635 640
ACT CTG T'IT CCA AGA AGA ATA TTC CTT GAG TGG AGA ACA GCA GTT TAC 1968
Thr Leu Phe Pro Arg Arg Ile Phe Leu Glu Trp Arg Thr Ala Val Tyr
645 650 655
AAC TGG GCC CTG CAG AGC TCC CAT GAA GTA ATC CGG GCT AGT TGT GTT 2016
Asn Trp Ala Leu Gln Ser Ser His Glu Val Ile Arg Ala Ser Cys Val
660 665 670
AGT GGA TTT TTT ATC TTA TTG CAG CAG CAG AAT TCT TGT AAC AGA GTT 2064
Ser Gly Phe Phe Ile Leu Leu Gln Gln Gln Asn Ser Cys Asn Arg Val
675 680 685
CCC AAG ATT CTT ATA GAT AAA GTC AAA GAT GAT TCT GAC ATT GTC AAG 2112
Pro Lys Ile Leu Ile Asp Lys Val Lys Asp Asp Ser Asp Ile Val Lys
690 695 700
AAA GAA TTT GCT TCT ATA CTT GGT CAA CTT GTC TGT ACT CTT CAC GGC 2160
Lys Glu Phe Ala Ser Ile Leu Gly Gln Leu Val Cys Thr Leu His Gly
705 710 715 720
ATG TTT TAT CTG ACA AGT TCT TTA ACA GAA CCT TTC TCT GAA CAC GGA 2208
Met Phe Tyr Leu Thr Ser Ser Leu Thr Glu Pro Phe Ser Glu His Gly
725 730 735
CAT GTG GAC CTC TTC TGT AGG AAC TTG AAA GCC ACT TCT CAA CAT GAA 2256
His Val Asp Leu Phe Cys Arg Asn Leu Lys Ala Thr Ser Gln His Glu
740 745 750
TGT TCA TCT TCT CAA CTA AAA GCT TCT GTC TGC AAG CCA TTC CTT TTC 2304
Cys Ser Ser Ser Gln Leu Lys Ala Ser Val Cys Lys Pro Phe Leu Phe
755 760 765
CTA CTG AAA AAA AAA ATA CCT AGT CCA GTA AAA CTT GCT TTC ATA GAT 2352
Leu Leu Lys Lys Lys Ile Pro Ser Pro Val Lys Leu Ala Phe Ile Asp
770 775 780
AAT CTA CAT CAT CTT TGT AAG CAT CTT GAT TTT AGA GAA GAT GAA ACA 2400
Asn Leu His His Leu Cys Lys His Leu Asp Phe Arg Glu Asp Glu Thr
785 790 795 800
GAT GTA AAA GCA GTT CTT GGA ACT TTA TTA AAT TTA ATG GAA GAT CCA 2448
Asp Val Lys Ala Val Leu Gly Thr Leu Leu Asn Leu Met Glu Asp Pro
805 810 815
GAC AAA GAT GTT AGA GTG GCT TTT AGT GGA AAT ATC AAG CAC ATA TTG 2496
Asp Lys Asp Val Arg Val Ala Phe Ser Gly Asn Ile Lys His Ile Leu
820 825 830
GAA TCC TTG GAC TCT GAA GAT GGA TTT ATA AAG GAG CTT TTT GTC TTA 2544
Glu Ser Leu Asp Ser Glu Asp Gly Phe Ile Lys Glu Leu Phe Val Leu
835 840 845
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AGA ATG AAG GAA GCA TAT ACA CAT GCC CAA ATA TCA AGA AAT AAT GAG 2592
Arg Met Lys Glu Ala Tyr Thr His Ala Gln Ile Ser Arg Asn Asn Glu
850 855 860
CTG AAG GAT ACC TTG ATT CTT ACA ACA GGG GAT ATT GGA AGG GCC GCA 2640
Leu Lys Asp Thr Leu Ile Leu Thr Thr Gly Asp Ile Gly Arg Ala Ala
865 870 875 880
AAA GGA GAT TTG GTA CCA TTT GCA CTC TTA CAC TTA TTG CAT TGT TTG 2688
Lys Gly Asp Leu Val Pro Phe Ala Leu Leu His Leu Leu His Cys Leu
885 890 895
TTA TCC AAG TCA GCA TCT GTC TCT GGA GCA GCA TAC ACA GAA ATT AGA 2736
Leu Ser Lys Ser Ala Ser Val Ser Gly Ala Ala Tyr Thr Glu Ile Arg
900 905 910
GCT CTG GTT GCA GCT AAA AGT GTT AAA CTG CAA AGT TTT TTC AGC CAG 2784
Ala Leu Val Ala Ala Lys Ser Val Lys Leu Gln Ser Phe Phe Ser Gln
915 920 925
TAT AAG AAP, CCC ATC TGT CAG TTT TTG GTA GAA TCC CTT CAC TCT AGT 2832
Tyr Lys Lys Pro Ile Cys Gln Phe Leu Val Glu Ser Leu His Ser Ser
930 935 940
CAG ATG ACA GCA CTT CCG AAT ACT CCA TGC CAG AAT GCT GAC GTG CGA 2880
Gln Met Thr Ala Leu Pro Asn Thr Pro Cys Gln Asn Ala Asp Val Arg
945 950 955 960
AAA CAA GAT GTG GCT CAC CAG AGA GAA ATG GCT TTA AAT ACG TTG TCT 2928
Lys Gln Asp Val Ala His Gln Arg Glu Met Ala Leu Asn Thr Leu Ser
965 970 975
GAA ATT GCC AAC GTT TTC GAC TTT CCT GAT CTT AAT CGT TTT CTT ACT 2976
Glu Ile Ala Asn Val Phe Asp Phe Pro Asp Leu Asn Arg Phe Leu Thr
980 985 990
AGG ACA TTA CAA GTT CTA CTA CCT GAT CTT GCT GCC AAA GCA AGC CCT 3024
Arg Thr Leu Gln Val Leu Leu Pro Asp Leu Ala Ala Lys Ala Ser Pro
995 1000 1005
GCA GCT TCT GCT CTC ATT CGA ACT TTA GGA AAA CAA TTA AAT GTC AAT 3072
Ala Ala Ser Ala Leu Ile Arg Thr Leu Gly Lys Gln Leu Asn Val Asn
1010 1015 1020
CGT AGA GAG ATT TTA ATA AAC AAC TTC AAA TAT ATT TTT TCT CAT TTG 3120
Arg Arg Glu Ile Leu Ile Asn Asn Phe Lys Tyr Ile Phe Ser His Leu
1025 1030 1035 1040
GTC TGT TCT TGT TCC AAA GAT GAA TTA GAA CGT GCC CTT CAT TAT CTG 3168
Val Cys Ser Cys Ser Lys Asp Glu Leu Glu Arg Ala Leu His Tyr Leu
1045 1050 1055
AAG AAT GAA ACA GAA ATT GAA CTG GGG AGC CTG TTG AGA CAA GAT TTC 3216
Lys Asn Glu Thr Glu Ile Glu Leu Gly Ser Leu Leu Arg Gln Asp Phe
1060 1065 1070
CAA GGA TTG CAT AAT GAA TTA TTG CTG CGT ATT GGA GAA CAC TAT CAA 3264
Gln Gly Leu His Asn Glu Leu Leu Leu Arg Ile Gly Glu His Tyr Gln
1075 1080 1085
CAG GTT TTT AAT GGT TTG TCA ATA CTT GCC TCA TTT GCA TCC AGT GAT 3312
Gln Val Phe Asn Gly Leu Ser Ile Leu Ala Ser Phe Ala Ser Ser Asp
1090 1095 1100
GAT CCA TAT CAG GGC CCG AGA GAT ATC ATA TCA CCT GAA CTG ATG GCT 3360
Asp Pro Tyr Gln Gly Pro Arg Asp Ile Ile Ser Pro Glu Leu Met Ala
1105 1110 1115 1120
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GAT TAT TTA CAA CCC AAA TTG TTG GGC ATT TTG GCT TTT TTT AAC ATG 3408
Asp Tyr Leu Gln Pro Lys Leu Leu Gly Ile Leu Ala Phe Phe Asn Met
1125 1130 1135
CAG TTA CTG AGC TCT AGT GTT GGC ATT GAA GAT AAG AAA ATG GCC TTG 3456
Gln Leu Leu Ser Ser Ser Val Gly Ile Glu Asp Lys Lys Met Ala Leu
1140 1145 1150
AAC AGT TTG ATG TCT TTG ATG AAG TTA ATG GGA CCC AAA CAT GTC AGT 3504
Asn Ser Leu Met Ser Leu Met Lys Leu Met Gly Pro Lys His Val Ser
1155 1160 1165
TCT GTG AGG GTG AAG ATG ATG ACC ACA CTG AGA ACT GGC CTT CGA TTC 3552
Ser Val Arg Val Lys Met Met Thr Thr Leu Arg Thr Gly Leu Arg Phe
1170 1175 1180
AAG GAT GAT TTT CCT GAA TTG TGT TGC AGA GCT TGG GAC TGC TTT GTT 3600
Lys Asp Asp Phe Pro Glu Leu Cys Cys Arg Ala Trp Asp Cys Phe Val
1185 1190 1195 1200
CGC TGC CTG GAT CAT GCT TGT CTG GGC TCC CTT CTC AGT CAT GTA ATA 3648
Arg Cys Leu Asp His Ala Cys Leu Gly Ser Leu Leu Ser His Val Ile
1205 1210 1215
GTA GCT TTG TTA CCT CTT ATA CAC ATC CAG CCT AAA GAA ACT GCA GCT 3696
Val Ala Leu Leu Pro Leu Ile His Ile Gln Pro Lys Glu Thr Ala Ala
1220 1225 1230
ATC TTC CAC TAC CTC ATA ATT GAA AAC AGG GAT GCT GTG CAA GAT TTT 3744
Ile Phe His Tyr Leu Ile Ile Glu Asn Arg Asp Ala Val Gln Asp Phe
1235 1240 1245
CTT CAT GAA ATA TAT TTT TTA CCT GAT CAT CCA GAA TTA AAA AAG ATA 3792
Leu His Giu Ile Tyr Phe Leu Pro Asp His Pro Glu Leu Lys Lys Ile
1250 1255 1260
AAA GCC GTT CTC CAG GAA TAC AGA AAG GAG ACC TCT GAG AGC ACT GAT 3840
Lys Ala Val Leu Gln Glu Tyr Arg Lys Glu Thr Ser Glu Ser Thr Asp
1265 1270 1275 1280
CTT CAG ACA ACT CTT CAG CTC TCT ATG AAG GCC ATT CAA CAT GAA AAT 3888
Leu Gln Thr Thr Leu Gln Leu Ser Met Lys Ala Ile Gln His Glu Asn
1285 1290 1295
GTC GAT GTT CGT ATT CAT GCT CTT ACA AGC TTG AAG GAA ACC TTG TAT 3936
Val Asp Val Arg Ile His Ala Leu Thr Ser Leu Lys Glu Thr Leu Tyr
1300 1305 1310
AAA AAT CAG GAA AAA CTG ATA AAG TAT GCA ACA GAC AGT GAA ACA GTA 3984
Lys Asn Gln Glu Lys Leu Ile Lys Tyr Ala Thr Asp Ser Glu Thr Val
1315 1320 1325
GAA CCT ATT ATC TCA CAG TTG GTG ACA GTG CTT TTG AAA GGT TGC CAA 4032
Glu Pro Ile Ile Ser Gln Leu Val Thr Val Leu Leu Lys Gly Cys Gln
1330 1335 1340
GAT GCA AAC TCT CAA GCT CGG TTG CTC TGT GGG GAA TGT TTA GGG GAA 4080
Asp Ala Asn Ser Gln Ala Arg Leu Leu Cys Gly Glu Cys Leu Gly Glu
1345 1350 1355 1360
TTG GGG GCG ATA GAT CCA GGT CGA TTA GAT TTC TCA ACA ACT GAA ACT 4128
Leu Gly Ala Ile Asp Pro Gly Arg Leu Asp Phe Ser Thr Thr Glu Thr
1365 1370 1375
CAA GGA AAA GAT TTT ACA TTT GTG ACT GGA GTA GAA GAT TCA AGC TTT 4176
Gln Gly Lys Asp Phe Thr Phe Val Thr Gly Val Glu Asp Ser Ser Phe
1380 1385 1390
CA 02210650 1997-07-16
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GCC TAT GGA TTA TTG ATG GAG CTA ACA AGA GCT TAC CTT GCG TAT GCT 4224
Ala Tyr Gly Leu Leu Met Glu Leu Thr Arg Ala Tyr Leu Ala Tyr Ala
1395 1400 1405
GAT AAT AGC CGA GCT CAA GAT TCA GCT GCC TAT GCC ATT CAG GAG TTG 4272
Asp Asn Ser Arg Ala Gin Asp Ser Ala Ala Tyr Ala Ile Gln Glu Leu
1410 1415 1420
CTT TCT ATT TAT GAC TGT AGA GAG ATG GAG ACC AAC GGC CCA GGT CAC 4320
Leu Ser Ile Tyr Asp Cys Arg Glu Met Glu Thr Asn Gly Pro Gly His
1425 1430 1435 1440
CAA TTG TGG AGG AGA TTT CCT GAG CAT GTT CGG GAA ATA CTA GAA CCT 4368
Gln Leu Trp Arg Arg Phe Pro Glu His Val Arg Glu Ile Leu Glu Pro
1445 1450 1455
CAT CTA AAT ACC AGA TAC AAG AGT TCT CAG AAG TCA ACC GAT TGG TCT 4416
His Leu Asn Thr Arg Tyr Lys Ser Ser Gln Lys Ser Thr Asp Trp Ser
1460 1465 1470
GGA GTA AAG AAG CCA ATT TAC TTA AGT AAA TTG GGT AGT AAC TTT GCA 4464
Gly Val Lys Lys Pro Ile Tyr Leu Ser Lys Leu Gly Ser Asn Phe Ala
1475 1480 1485
GAA TGG TCA GCA TCT TGG GCA GGT TAT CTT ATT ACA AAG GTT CGA CAT 4512
Glu Trp Ser Ala Ser Trp Ala Gly Tyr Leu Ile Thr Lys Val Arg His
1490 1495 1500
GAT CTT GCC AGT AAA ATT TTC ACC TGC TGT AGC ATT ATG ATG AAG CAT 4560
Asp Leu Ala Ser Lys Ile Phe Thr Cys Cys Ser Ile Met Met Lys His
1505 1510 1515 1520
GAT TTC AAA GTG ACC ATC TAT CTT CTT CCA CAT ATT CTG GTG TAT GTC 4608
Asp Phe Lys Val Thr Ile Tyr Leu Leu Pro His Ile Leu Val Tyr Val
1525 1530 1535
TTA CTG GGT TGT AAT CAA GAA GAT CAG CAG GAG GTT TAT GCA GAA ATT 4656
Leu Leu Gly Cys Asn Gln Glu Asp Gln Gln Glu Val Tyr Ala Glu Ile
1540 1545 1550
ATG GCA GTT CTA AAG CAT GAC GAT CAG CAT ACC ATA AAT ACC CAA GAC 4704
Met Ala Val Leu Lys His Asp Asp Gln His Thr Ile Asn Thr Gln Asp
1555 1560 1565
ATT GCA TCT GAT CTG TGT CAA CTC AGT ACA CAG ACT GTG TTC TCC ATG 4752
Ile Ala Ser Asp Leu Cys Gln Leu Ser Thr Gin Thr Val Phe Ser Met
1570 1575 1580
CTT GAC CAT CTC ACA CAG TGG GCA AGG CAC AAA TTT CAG GCA CTG AAA 4800
Leu Asp His Leu Thr Gln Trp Ala Arg His Lys Phe Gln Ala Leu Lys
1585 1590 1595 1600
GCT GAG AAA TGT CCA CAC AGC AAA TCA AAC AGA AAT AAG GTA GAC TCA 4848
Ala Glu Lys Cys Pro His Ser Lys Ser Asn Arg Asn Lys Val Asp Ser
1605 1610 1615
ATG GTA TCT ACT GTG GAT TAT GAA GAC TAT CAG AGT GTA ACC CGT TTT 4896
Met Val Ser Thr Val Asp Tyr Glu Asp Tyr Gln Ser Val Thr Arg Phe
1620 1625 1630
CTA GAC CTC ATA CCC CAG GAT ACT CTG GCA GTA GCT TCC TTT CGC TCC 4944
Leu Asp Leu Ile Pro Gln Asp Thr Leu Ala Val Ala Ser Phe Arg Ser
1635 1640 1645
AAA GCA TAC ACA CGA GCT GTA ATG CAC TTT GAA TCA TTT ATT ACA GAA 4992
Lys Ala Tyr Thr Arg Ala Val Met His Phe Glu Ser Phe Ile Thr Glu
1650 1655 1660
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AAG AAG CAA AAT ATT CAG GAA CAT CTT GGA TTT TTA CAG AAA TTG TAT 5040
Lys Lys Gln Asn Ile Gln Glu His Leu Gly Phe Leu Gln Lys Leu Tyr
1665 1670 1675 1680
GCT GCT ATG CAT GAA CCT GAT GGA GTG GCC GGA GTC AGT GCA ATT AGA 5088
Ala Ala Met His Glu Pro Asp Gly Val Ala Gly Val Ser Ala Ile Arg
1685 1690 1695
AAG GCA GAA CCA TCT CTA AAA GAA CAG ATC CTT GAA CAT GAA AGC CTT 5136
Lys Ala Glu Pro Ser Leu Lys Glu Gln Ile Leu Glu His Glu Ser Leu
1700 1705 1710
GGC TTG CTG AGG GAT GCC ACT GCT TGT TAT GAC AGG GCT ATT CAG CTA 5184
Gly Leu Leu Arg Asp Ala Thr Ala Cys Tyr Asp Arg Ala Ile Gln Leu
1715 1720 1725
GAA CCA GAC CAG ATC ATT CAT TAT CAT GGT GTA GTA AAG TCC ATG TTA 5232
Glu Pro Asp Gln Ile Ile His Tyr His Gly Val Val Lys Ser Met Leu
1730 1735 1740
GGT CTT GGT CAG CTG TCT ACT GTT ATC ACT CAG GTG AAT GGA GTG CAT 5280
Gly Leu Gly Gln Leu Ser Thr Val Ile Thr Gin Val Asn Gly Val His
1745 1750 1755 1760
GCT AAC AGG TCC GAG TGG ACA GAT GAA TTA AAC ACG TAC AGA GTG GAA 5328
Ala Asn Arg Ser Glu Trp Thr Asp Glu Leu Asn Thr Tyr Arg Val Glu
1765 1770 1775
GCA GCT TGG AAA TTG TCA CAG TGG GAT TTG GTG GAA AAC TAT TTG GCA 5376
Ala Ala Trp Lys Leu Ser Gln Trp Asp Leu Val Glu Asn Tyr Leu Ala
1780 1785 1790
GCA GAT GGA AAA TCT ACA ACA TGG AGT GTC AGA CTG GGA CAG CTA TTA 5424
Ala Asp Gly Lys Ser Thr Thr Trp Ser Val Arg Leu Gly Gln Leu Leu
1795 1800 1805
TTA TCA GCC AAA AAA AGA GAT ATC ACA GCT TTT TAT GAC TCA CTG AAA 5472
Leu Ser Ala Lys Lys Arg Asp Ile Thr Ala Phe Tyr Asp Ser Leu Lys
1810 1815 1820
CTA GTG AGA GCA GAA CAA ATT GTA CCT CTT TCA GCT GCA AGC TTT GAA 5520
Leu Val Arg Ala Glu Gln Ile Val Pro Leu Ser Ala Ala Ser Phe Glu
1825 1830 1835 1840
AGA GGC TCC TAC CAA CGA GGA TAT GAA TAT ATT GTG AGA TTG CAC ATG 5568
Arg Gly Ser Tyr Gln Arg Gly Tyr Glu Tyr Ile Val Arg Leu His Met
1845 1850 1855
TTA TGT GAG TTG GAG CAT AGC ATC AAA CCA CTT TTC CAG CAT TCT CCA 5616
Leu Cys Glu Leu Glu His Ser Ile Lys Pro Leu Phe Gln His Ser Pro
1860 1865 1870
GGT GAC AGT TCT CAA GAA GAT TCT CTA AAC TGG GTA GCT CGA CTA GAA 5664
Gly Asp Ser Ser Gln Glu Asp Ser Leu Asn Trp Val Ala Arg Leu Glu
1875 1880 1885
ATG ACC CAG AAT TCC TAC AGA GCC AAG GAG CCT ATC CTG GCT CTC CGG 5712
Met Thr Gln Asn Ser Tyr Arg Ala Lys Glu Pro Ile Leu Ala Leu Arg
1890 1895 1900
AGG GCT TTA CTA AGC CTC AAC AAA AGA CCA GAT TAC AAT GAA ATG GTT 5760
Arg Ala Leu Leu Ser Leu Asn Lys Arg Pro Asp Tyr Asn Glu Met Val
1905 1910 1915 1920
GGA GAA TGC TGG CTG CAG AGT GCC AGG GTA GCT AGA AAG GCT GGT CAC 5808
Gly Glu Cys Trp Leu Gln Ser Ala Arg Val Ala Arg Lys Ala Gly His
1925 1930 1935
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CAC CAG ACA GCC TAC AAT GCT CTC CTT AAT GCA GGG GAA TCA CGA CTC 5856
His Gln Thr Ala Tyr Asn Ala Leu Leu Asn Ala Gly Glu Ser Arg Leu
1940 1945 1950
GCT GAA CTG TAC GTG GAA AGG GCA AAG TGG CTC TGG TCC AAG GGT GAT 5904
Ala Glu Leu Tyr Val Glu Arg Ala Lys Trp Leu Trp Ser Lys Gly Asp
1955 1960 1965
GTT CAC CAG GCA CTA ATT GTT CTT CAA AAA GGT GTT GAA TTA TGT TTT 5952
Val His Gln Ala Leu Ile Val Leu Gln Lys Gly Val Glu Leu Cys Phe
1970 1975 1980
CCT GAA AAT GAA ACC CCA CCT GAG GGT AAG AAC ATG TTA ATC CAT GGT 6000
Pro Glu Asn Glu Thr Pro Pro Glu Gly Lys Asn Met Leu Ile His Gly
1985 1990 1995 2000
CGA GCT ATG CTA CTA GTG GGC CGA TTT ATG GAA GAA ACA GCT AAC TTT 6048
Arg Ala Met Leu Leu Val Gly Arg Phe Met Glu Glu Thr Ala Asn Phe
2005 2010 2015
GAA AGC AAT GCA ATT ATG AAA AAA TAT AAG GAT GTG ACC GCG TGC CTG 6096
Glu Ser Asn Ala Ile Met Lys Lys Tyr Lys Asp Val Thr Ala Cys Leu
2020 2025 2030
CCA GAA TGG GAG GAT GGG CAT TTT TAC CTT GCC AAG TAC TAT GAC AAA 6144
Pro Glu Trp Glu Asp Gly His Phe Tyr Leu Ala Lys Tyr Tyr Asp Lys
2035 2040 2045
TTG ATG CCC ATG GTC ACA GAC AAC AAA ATG GAA AAG CAA GGT GAT CTC 6192
Leu Met Pro Met Val Thr Asp Asn Lys Met Glu Lys Gln Gly Asp Leu
2050 2055 2060
ATC CGG TAT ATA GTT CTT CAT TTT GGC AGA TCT CTA CAA TAT GGA AAT 6240
Ile Arg Tyr Ile Val Leu His Phe Gly Arg Ser Leu Gln Tyr Gly Asn
2065 2070 2075 2080
CAG TTC ATA TAT CAG TCA ATG CCA CGA ATG TTA ACT CTA TGG CTT GAT 6288
Gln Phe Ile Tyr Gln Ser Met Pro Arg Met Leu Thr Leu Trp Leu Asp
2085 2090 2095
TAT GGT ACA AAG GCA TAT GAA TGG GAA AAA GCT GGC CGC TCC GAT CGT 6336
Tyr Gly Thr Lys Ala Tyr Glu Trp Glu Lys Ala Gly Arg Ser Asp Arg
2100 2105 2110
GTA CAA ATG AGG AAT GAT TTG GGT AAA ATA AAC AAG GTT ATC ACA GAG 6384
Val Gln Met Arg Asn Asp Leu Gly Lys Ile Asn Lys Val Ile Thr Glu
2115 2120 2125
CAT ACA AAC TAT TTA GCT CCA TAT CAA TTT TTG ACT GCT TTT TCA CAA 6432
His Thr Asn Tyr Leu Ala Pro Tyr Gln Phe Leu Thr Ala Phe Ser Gln
2130 2135 2140
TTG ATC TCT CGA ATT TGT CAT TCT CAC GAT GAA GTT TTT GTT GTC TTG 6480
Leu Ile Ser Arg Ile Cys His Ser His Asp Glu Val Phe Val Val Leu
2145 2150 2155 2160
ATG GAA ATA ATA GCC AAA GTA TTT CTA GCC TAT CCT CAA CAA GCA ATG 6528
Met Glu Ile Ile Ala Lys Val Phe Leu Ala Tyr Pro Gln Gln Ala Met
2165 2170 2175
TGG ATG ATG ACA GCT GTG TCA AAG TCA TCT TAT CCC ATG CGT GTG AAC 6576
Trp Met Met Thr Ala Val Ser Lys Ser Ser Tyr Pro Met Arg Val Asn
2180 2185 2190
AGA TGC AAG GAA ATC CTC AAT AAA GCT ATT CAT ATG AAA AAA TCC TTA 6624
Arg Cys Lys Glu Ile Leu Asn Lys Ala Ile His Met Lys Lys Ser Leu
2195 2200 2205
CA 02210650 1997-07-16
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-139-
GAG AAG TTT GTT GGA GAT GCA ACT CGC CTA ACA GAT AAG CTT CTA GAA 6672
Glu Lys Phe Val Gly Asp Ala Thr Arg Leu Thr Asp Lys Leu Leu Glu
2210 2215 2220
TTG TGC AAT AAA CCG GTT GAT GGA AC,T AGT TCC ACA TTA AGC ATG AGC 6720
Leu Cys Asn Lys Pro Val Asp Gly Ser Ser Ser Thr Leu Ser Met Ser
2225 2230 2235 2240
ACT CAT TTT AAA ATG CTT AAA AAG CTG GTA GAA GAA GCA ACA TTT AGT 6768
Thr His Phe Lys Met Leu Lys Lys Leu Val Glu Glu Ala Thr Phe Ser
2245 2250 2255
GAA ATC CTC ATT CCT CTA CAA TCA GTC ATG ATA CCT ACA CTT CCA TCA 6816
Glu Ile Leu Ile Pro Leu Gln Ser Val Met Ile Pro Thr Leu Pro Ser
2260 2265 2270
ATT CTG GGT ACC CAT GCT AAC CAT GCT AGC CAT GAA CCA TTT CCT GGA 6864
Ile Leu Gly Thr His Ala Asn His Ala Ser His Glu Pro Phe Pro Gly
2275 2280 2285
CAT TGG GCC TAT ATT GCA GGG TTT GAT GAT ATG GTG GAA ATT CTT GCT 6912
His Trp Ala Tyr Ile Ala Gly Phe Asp Asp Met Val Glu Ile Leu Ala
2290 2295 2300
TCT CTT CAG AAA CCA AAG AAG ATT TCT TTA AAA GGC TCA GAT GGA AAG 6960
Ser Leu Gln Lys Pro Lys Lys Ile Ser Leu Lys Gly Ser Asp Gly Lys
2305 2310 2315 2320
TTC TAC ATC ATG ATG TGT AAG CCA AAA GAT GAC CTG AGA AAG GAT TGT 7008
Phe Tyr Ile Met Met Cys Lys Pro Lys Asp Asp Leu Arg Lys Asp Cys
2325 2330 2335
AGA CTA ATG GAA TTC AAT TCC TTG ATT AAT AAG TGC TTA AGA AAA GAT 7056
Arg Leu Met Glu Phe Asn Ser Leu Ile Asn Lys Cys Leu Arg Lys Asp
2340 2345 2350
GCA GAG TCT CGT AGA AGA GAA CTT CAT ATT CGA ACA TAT GCA GTT ATT 7104
Ala Glu Ser Arg Arg Arg Glu Leu His Ile Arg Thr Tyr Ala Val Ile
2355 2360 2365
CCA CTA AAT GAT GAA TGT GGG ATT ATT GAA TGG GTG AAC AAC ACT GCT 7152
Pro Leu Asn Asp Glu Cys Gly Ile Ile Glu Trp Val Asn Asn Thr Ala
2370 2375 2380
GGT TTG AGA CCT ATT CTG ACC AAA CTA TAT AAA GAA AAG GGA GTG TAT 7200
Gly Leu Arg Pro Ile Leu Thr Lys Leu Tyr Lys Glu Lys Gly Val Tyr
2385 2390 2395 2400
ATG ACA GGA AAA GAA CTT CGC CAG TGT ATG CTA CCA AAG TCA GCA GCT 7248
Met Thr Gly Lys Glu Leu Arg Gln Cys Met Leu Pro Lys Ser Ala Ala
2405 2410 2415
TTA TCT GAA AAA CTC AAA GTA TTC CGA GAA TTT CTC CTG CCC AGG CAT 7296
Leu Ser Glu Lys Leu Lys Val Phe Arg Glu Phe Leu Leu Pro Arg His
2420 2425 2430
CCT CCT ATT TTT CAT GAG TGG TTT CTG AGA ACA TTC CCT GAT CCT ACA 7344
Pro Pro Ile Phe His Glu Trp Phe Leu Arg Thr Phe Pro Asp Pro Thr
2435 2440 2445
TCA TGG TAC AGT AGT AGA TCA GCT TAC TGC CGT TCC ACT GCA GTA ATG 7392
Ser Trp Tyr Ser Ser Arg Ser Ala Tyr Cys Arg Ser Thr Ala Val Met
2450 2455 2460
TCA ATG GTT GGT TAT ATT CTG GGG CTT GGA GAC CGT CAT GGT GAA AAT 7440
Ser Met Val Gly Tyr Ile Leu Gly Leu Gly Asp Arg His Gly Glu Asn
2465 2470 2475 2480
CA 02210650 1997-07-16
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-140-
ATT CTC TTT GAT TCT TTG ACT GGT GAA TGC GTA CAT GTA GAT TTC AAT 7488
Ile Leu Phe Asp Ser Leu Thr Gly Glu Cys Val His Val Asp Phe Asn
2485 2490 2495
TGT CTT TTC AAT AAG GGA GAA ACC TTT GAA GTT CCA GAA ATT GTG CCA 7536
Cys Leu Phe Asn Lys Gly Glu Thr Phe Glu Val Pro Glu Ile Val Pro
2500 2505 2510
TTT CGC CTG ACT CAT AAT ATG GTT AAT GGA ATG GGT CCT ATG GGA ACA 7584
Phe Arg Leu Thr His Asn Met Val Asn Gly Met Gly Pro Met Gly Thr
2515 2520 2525
GAG GGT CTT TTT CGA AGA GCA TGT GAA GTT ACA ATG AGG CTG ATG CGT 7632
Glu Gly Leu Phe Arg Arg Ala Cys Glu Val Thr Met Arg Leu Met Arg
2530 2535 2540
GAT CAG CGA GAG CCT TTA ATG AGT GTC TTA AAG ACT TTT CTA CAT GAT 7680
Asp Gln Arg Glu Pro Leu Met Ser Val Leu Lys Thr Phe Leu His Asp
2545 2550 2555 2560
CCT CTT GTG GAA TGG AGT AAA CCA GTG AAA GGG CAT TCC AAA GCG CCA 7728
Pro Leu Val Glu Trp Ser Lys Pro Val Lys Gly His Ser Lys Ala Pro
2565 2570 2575
CTG AAT GAA ACT GGA GAA GTT GTC AAT GAA AAG GCC AAG ACC CAT GTT 7776
Leu Asn Glu Thr Gly Glu Val Val Asn Glu Lys Ala Lys Thr His Val
2580 2585 2590
CTT GAC ATT GAG CAG CGA CTA CAA GGT GTA ATC AAG ACT CGA AAT AGA 7824
Leu Asp Ile Glu Gln Arg Leu Gln Gly Val Ile Lys Thr Arg Asn Arg
2595 2600 2605
GTG ACA GGA CTG CCG TTA TCT ATT GAA GGA CAT GTG CAT TAC CTT ATA 7872
Val Thr Gly Leu Pro Leu Ser Ile Glu Gly His Val His Tyr Leu Ile
2610 2615 2620
CAA GAA GCT ACT GAT GAA AAC TTA CTA TGC CAG ATG TAT CTT GGT TGG 7920
Gln Glu Ala Thr Asp Glu Asn Leu Leu Cys Gln Met Tyr Leu Gly Trp
2625 2630 2635 2640
ACT CCA TAT ATG TGA 7935
Thr Pro Tyr Met
(2) INFORMATION FOR SEQ ID NO:29:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2644 amino acids
(B) TYPE: amino acid
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE; protein
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:29:
Met Gly Glu His Gly Leu Glu Leu Ala Ser Met Ile Pro Ala Leu Arg
1 5 10 15
Glu Leu Gly Ser Ala Thr Pro Glu Glu Tyr Asn Thr Val Val Gln Lys
20 25 30
Pro Arg Gln Ile Leu Cys Gln Phe Ile Asp Arg Ile Leu Thr Asp Val
35 40 45
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Asn Val Val Ala Val Glu Leu Val Lys Lys Thr Asp Ser Gln Pro Thr
50 55 60
Ser Val Met Leu Leu Asp Phe Ile Gln His Ile Met Lys Ser Ser Pro
65 70 75 80
Leu Met Phe Val Asn Val Ser Gly Ser His Glu Arg Lys Gly Ser Cys
85 90 95
Ile Glu Phe Ser Asn Trp Ile Ile Thr Arg Leu Leu Arg Ile Ala Ala
100 105 110
Thr Pro Ser Cys His Leu Leu His Lys Lys Ile Cys Glu Val Ile Cys
115 120 125
Ser Leu Leu Phe Leu Phe Lys Ser Lys Ser Pro Ala Ile Phe Gly Val
130 135 140
Leu Thr Lys Glu Leu Leu Gln Leu Phe Glu Asp Leu Val Tyr Leu His
145 150 155 160
Arg Arg Asn Val Met Gly His Ala Val Glu Trp Pro Val Val Met Ser
165 170 175
Arg Phe Leu Ser Gln Leu Asp Glu His Met Gly Tyr Leu Gln Ser Ala
180 185 190
Pro Leu Gln Leu Met Ser Met Gln Asn Leu Glu Phe Ile Glu Val Thr
195 200 205
Leu Leu Met Val Leu Thr Arg Ile Ile Ala Ile Val Phe Phe Arg Arg
210 215 220
Gln Glu Leu Leu Leu Trp Gln Ile Gly Cys Val Leu Leu Glu Tyr Gly
225 230 235 240
Ser Pro Lys Ile Lys Ser Leu Ala Ile Ser Phe Leu Thr Glu Leu Phe
245 250 255
Gln Leu Gly Gly Leu Pro Ala Gln Pro Ala Ser Thr Phe Phe Ser Ser
260 265 270
Phe Leu Glu Leu Leu Lys His Leu Val Glu Met Asp Thr Asp Gln Leu
275 280 285
Lys Leu Tyr Glu Glu Pro Leu Ser Lys Leu Ile Lys Thr Leu Phe Pro
290 295 300
Phe Glu Ala Glu Ala Tyr Arg Asn Ile Glu Pro Val Tyr Leu Asn Met
305 310 315 320
Leu Leu Glu Lys Leu Cys Val Met Phe Glu Asp Gly Val Leu Met Arg
325 330 335
Leu Lys Ser Asp Leu Leu Lys Ala Ala Leu Cys His Leu Leu Gln Tyr
340 345 350
Phe Leu Lys Phe Val Pro Ala Gly Tyr Glu Ser Ala Leu Gln Val Arg
355 360 365
Lys Val Tyr Val Arg Asn Ile Cys Lys Ala Leu Leu Asp Val Leu Gly
370 375 380
Ile Glu Val Asp Ala Glu Tyr Leu Leu Gly Pro Leu Tyr Ala Ala Leu
385 390 395 400
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Lys Met Glu Ser Met Glu Ile Ile Glu Glu Ile Gln Cys Gln Thr Gln
405 410 415
Gln Glu Asn Leu Ser Ser Asn Ser Asp Gly Ile Ser Pro Lys Arg Arg
420 425 430
Arg Leu Ser Ser Ser Leu Asn Pro Ser Lys Arg Ala Pro Lys Gln Thr
435 440 445
Glu Glu Ile Lys His Val Asp Met Asn Gln Lys Ser Ile Leu Trp Ser
450 455 460
Ala Leu Lys Gln Lys Ala Glu Ser Leu Gln Ile Ser Leu Glu Tyr Ser
465 470 475 480
Gly Leu Lys Asn Pro Val Ile Glu Met Leu Glu Gly Ile Ala Val Val
485 490 495
Leu Gln Leu Thr Ala Leu Cys Thr Val His Cys Ser His Gln Asn Met
500 505 510
Asn Cys Arg Thr Phe Lys Asp Cys Gln His Lys Ser Lys Lys Lys Pro
515 520 525
Ser Val Val Ile Thr Trp Met Ser Leu Asp Phe Tyr Thr Lys Val Leu
530 535 540
Lys Ser Cys Arg Ser Leu Leu Glu Ser Val Gln Lys Leu Asp Leu Glu
545 550 555 560
Ala Thr Ile Asp Lys Val Val Lys Ile Tyr Asp Ala Leu Ile Tyr Met
565 570 575
Gln Val Asn Ser Ser Phe Glu Asp His Ile Leu Glu Asp Leu Cys Gly
580 585 590
Met Leu Ser Leu Pro Trp Ile Tyr Ser His Ser Asp Asp Gly Cys Leu
595 600 605
Lys Leu Thr Thr Phe Ala Ala Asn Leu Leu Thr Leu Ser Cys Arg Ile
610 615 620
Ser Asp Ser Tyr Ser Pro Gln Ala Gln Ser Arg Cys Val Phe Leu Leu
625 630 635 640
Thr Leu Phe Pro Arg Arg Ile Phe Leu Glu Trp Arg Thr Ala Val Tyr
645 650 655
Asn Trp Ala Leu Gin Ser Ser His Glu Val Ile Arg Ala Ser Cys Val
660 665 670
Ser Gly Phe Phe Ile Leu Leu Gln Gln Gln Asn Ser Cys Asn Arg Val
675 680 685
Pro Lys Ile Leu Ile Asp Lys Val Lys Asp Asp Ser Asp Ile Val Lys
690 695 700
Lys Glu Phe Ala Ser Ile Leu Gly Gln Leu Val Cys Thr Leu His Gly
705 710 715 720
Met Phe Tyr Leu Thr Ser Ser Leu Thr Glu Pro Phe Ser Glu His Gly
725 730 735
His Val Asp Leu Phe Cys Arg Asn Leu Lys Ala Thr Ser Gln His Glu
740 745 750
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Cys Ser Ser Ser Gln Leu Lys Ala Ser Val Cys Lys Pro Phe Leu Phe
755 760 765
Leu Leu Lys Lys Lys Ile Pro Ser Pro Val Lys Leu Ala Phe Ile Asp
770 775 780
Asn Leu His His Leu Cys Lys His Leu Asp Phe Arg Glu Asp Glu Thr
785 790 795 800
Asp Val Lys Ala Val Leu Gly Thr Leu Leu Asn Leu Met Glu Asp Pro
805 810 815
Asp Lys Asp Val Arg Val Ala Phe Ser Gly Asn Ile Lys His Ile Leu
820 825 830
Glu Ser Leu Asp Ser Glu Asp Gly Phe Ile Lys Glu Leu Phe Val Leu
835 840 845
Arg Met Lys Glu Ala Tyr Thr His Ala Gln Ile Ser Arg Asn Asn Glu
850 855 860
Leu Lys Asp Thr Leu Ile Leu Thr Thr Gly Asp Ile Gly Arg Ala Ala
865 870 875 880
Lys Gly Asp Leu Val Pro Phe Ala Leu Leu His Leu Leu His Cys Leu
885 890 895
Leu Ser Lys Ser Ala Ser Val Ser Gly Ala Ala Tyr Thr Glu Ile Arg
900 905 910
Ala Leu Val Ala Ala Lys Ser Val Lys Leu Gln Ser Phe Phe Ser Gln
915 920 925
Tyr Lys Lys Pro Ile Cys Gln Phe Leu Val Glu Ser Leu His Ser Ser
930 935 940
Gln Met Thr Ala Leu Pro Asn Thr Pro Cys Gln Asn Ala Asp Val Arg
945 950 955 960
Lys Gln Asp Val Ala His Gln Arg Glu Met Ala Leu Asn Thr Leu Ser
965 970 975
Glu Ile Ala Asn Val Phe Asp Phe Pro Asp Leu Asn Arg Phe Leu Thr
980 985 990
Arg Thr Leu Gin Val Leu Leu Pro Asp Leu Ala Ala Lys Ala Ser Pro
995 1000 1005
Ala Ala Ser Ala Leu Ile Arg Thr Leu Gly Lys Gln Leu Asn Val Asn
1010 1015 1020
Arg Arg Glu Ile Leu Ile Asn Asn Phe Lys Tyr Ile Phe Ser His Leu
1025 1030 1035 1040
Val Cys Ser Cys Ser Lys Asp Glu Leu Glu Arg Ala Leu His Tyr Leu
1045 1050 1055
Lys Asn Glu Thr Glu Ile Glu Leu Gly Ser Leu Leu Arg Gln Asp Phe
1060 1065 1070
Gln Gly Leu His Asn Glu Leu Leu Leu Arg Ile Gly Glu His Tyr Gln
1075 1080 1085
Gln Val Phe Asn Gly Leu Ser Ile Leu Ala Ser Phe Ala Ser Ser Asp
1090 1095 1100
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Asp Pro Tyr Gln Gly Pro Arg Asp Ile Ile Ser Pro Glu Leu Met Ala
1105 1110 1115 1120
Asp Tyr Leu Gln Pro Lys Leu Leu Gly Ile Leu Ala Phe Phe Asn Met
1125 1130 1135
Gln Leu Leu Ser Ser Ser Val Gly Ile Glu Asp Lys Lys Met Ala Leu
1140 1145 1150
Asn Ser Leu Met Ser Leu Met Lys Leu Met Gly Pro Lys His Val Ser
1155 1160 1165
Ser Val Arg Val Lys Met Met Thr Thr Leu Arg Thr Gly Leu Arg Phe
1170 1175 1180
Lys Asp Asp Phe Pro Glu Leu Cys Cys Arg Ala Trp Asp Cys Phe Val
1185 1190 1195 1200
Arg Cys Leu Asp His Ala Cys Leu Gly Ser Leu Leu Ser His Val Ile
1205 1210 1215
Val Ala Leu Leu Pro Leu Ile His Ile Gln Pro Lys Glu Thr Ala Ala
1220 1225 1230
Ile Phe His Tyr Leu Ile Ile Glu Asn Arg Asp Ala Val Gln Asp Phe
1235 1240 1245
Leu His Glu Ile Tyr Phe Leu Pro Asp His Pro Glu Leu Lys Lys Ile
1250 1255 1260
Lys Ala Val Leu Gln Glu Tyr Arg Lys Glu Thr Ser Glu Ser Thr Asp
1265 1270 1275 1280
Leu Gln Thr Thr Leu Gln Leu Ser Met Lys Ala Ile Gln His Glu Asn
1285 1290 1295
Val Asp Val Arg Ile His Ala Leu Thr Ser Leu Lys Glu Thr Leu Tyr
1300 1305 1310
Lys Asn Gln Glu Lys Leu Ile Lys Tyr Ala Thr Asp Ser Glu Thr Val
1315 1320 1325
Glu Pro Ile Ile Ser Gln Leu Val Thr Val Leu Leu Lys Gly Cys Gln
1330 1335 1340
Asp Ala Asn Ser Gln Ala Arg Leu Leu Cys Gly Glu Cys Leu Gly Glu
1345 1350 1355 1360
Leu Gly Ala Ile Asp Pro Gly Arg Leu Asp Phe Ser Thr Thr Glu Thr
1365 1370 1375
Gln Gly Lys Asp Phe Thr Phe Val Thr Gly Val Glu Asp Ser Ser Phe
1380 1385 1390
Ala Tyr Gly Leu Leu Met Glu Leu Thr Arg Ala Tyr Leu Ala Tyr Ala
1395 1400 1405
Asp Asn Ser Arg Ala Gln Asp Ser Ala Ala Tyr Ala Ile Gln Glu Leu
1410 1415 1420
Leu Ser Ile Tyr Asp Cys Arg Glu Met Glu Thr Asn Gly Pro Gly His
1425 1430 1435 1440
Gln Leu Trp Arg Arg Phe Pro Glu His Val Arg Glu Ile Leu Glu Pro
1445 1450 1455
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His Leu Asn Thr Arg Tyr Lys Ser Ser Gln Lys Ser Thr Asp Trp Ser
1460 1465 1470
Gly Val Lys Lys Pro Ile Tyr Leu Ser Lys Leu Gly Ser Asn Phe Ala
1475 1480 1485
Glu Trp Ser Ala Ser Trp Ala Gly Tyr Leu Ile Thr Lys Val Arg His
1490 1495 1500
Asp Leu Ala Ser Lys Ile Phe Thr Cys Cys Ser Ile Met Met Lys His
1505 1510 1515 1520
Asp Phe Lys Val Thr Ile Tyr Leu Leu Pro His Ile Leu Val Tyr Val
1525 1530 1535
Leu Leu Gly Cys Asn Gln Glu Asp Gln Gln Glu Val Tyr Ala Glu Ile
1540 1545 1550
Met Ala Val Leu Lys His Asp Asp Gln His Thr Ile Asn Thr Gln Asp
1555 1560 1565
Ile Ala Ser Asp Leu Cys Gln Leu Ser Thr Gln Thr Val Phe Ser Met
1570 1575 1580
Leu Asp His Leu Thr Gln Trp Ala Arg His Lys Phe Gln Ala Leu Lys
1585 1590 1595 1600
Ala Glu Lys Cys Pro His Ser Lys Ser Asn Arg Asn Lys Val Asp Ser
1605 1610 1615
Met Val Ser Thr Val Asp Tyr Glu Asp Tyr Gln Ser Val Thr Arg Phe
1620 1625 1630
Leu Asp Leu Ile Pro Gln Asp Thr Leu Ala Val Ala Ser Phe Arg Ser
1635 1640 1645
Lys Ala Tyr Thr Arg Ala Val Met His Phe Glu Ser Phe Ile Thr Glu
1650 1655 1660
Lys Lys Gln Asn Ile Gln Glu His Leu Gly Phe Leu Gln Lys Leu Tyr
1665 1670 1675 1680
Ala Ala Met His Glu Pro Asp Gly Val Ala Gly Val Ser Ala Ile Arg
1685 1690 1695
Lys Ala Glu Pro Ser Leu Lys Glu Gln Ile Leu Glu His Glu Ser Leu
1700 1705 1710
Gly Leu Leu Arg Asp Ala Thr Ala Cys Tyr Asp Arg Ala Ile Gln Leu
1715 1720 1725
Glu Pro Asp Gln Ile Ile His Tyr His Gly Val Val Lys Ser Met Leu
1730 1735 1740
Gly Leu Gly Gln Leu Ser Thr Val Ile Thr Gln Val Asn Gly Val His
1745 1750 1755 1760
Ala Asn Arg Ser Glu Trp Thr Asp Glu Leu Asn Thr Tyr Arg Val Glu
1765 1770 1775
Ala Ala Trp Lys Leu Ser Gln Trp Asp Leu Val Glu Asn Tyr Leu Ala
1780 1785 1790
Ala Asp Gly Lys Ser Thr Thr Trp Ser Val Arg Leu Gly Gln Leu Leu
1795 1800 1805
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Leu Ser Ala Lys Lys Arg Asp Ile Thr Ala Phe Tyr Asp Ser Leu Lys
1810 1815 1820
Leu Val Arg Ala Glu Gln Ile Val Pro Leu Ser Ala Ala Ser Phe Glu
1825 1830 1835 1840
Arg Gly Ser Tyr Gin Arg Gly Tyr Glu Tyr Ile Val Arg Leu His Met
1845 1850 1855
Leu Cys Glu Leu Glu His Ser Ile Lys Pro Leu Phe Gln His Ser Pro
1860 1865 1870
Gly Asp Ser Ser Gln Glu Asp Ser Leu Asn Trp Val Ala Arg Leu Glu
1875 1880 1885
Met Thr Gln Asn Ser Tyr Arg Ala Lys Glu Pro Ile Leu Ala Leu Arg
1890 1895 1900
Arg Ala Leu Leu Ser Leu Asn Lys Arg Pro Asp Tyr Asn Glu Met Val
1905 1910 1915 1920
Gly Glu Cys Trp Leu Gln Ser Ala Arg Val Ala Arg Lys Ala Gly His
1925 1930 1935
His Gln Thr Ala Tyr Asn Ala Leu Leu Asn Ala Gly Glu Ser Arg Leu
1940 1945 1950
Ala Glu Leu Tyr Val Glu Arg Ala Lys Trp Leu Trp Ser Lys Gly Asp
1955 1960 1965
Val His Gln Ala Leu Ile Val Leu Gln Lys Gly Val Glu Leu Cys Phe
1970 1975 1980
Pro Glu Asn Glu Thr Pro Pro Glu Gly Lys Asn Met Leu Ile His Gly
1985 1990 1995 2000
Arg Ala Met Leu Leu Val Gly Arg Phe Met Glu Glu Thr Ala Asn Phe
2005 2010 2015
Glu Ser Asn Ala Ile Met Lys Lys Tyr Lys Asp Val Thr Ala Cys Leu
2020 2025 2030
Pro Glu Trp Glu Asp Gly His Phe Tyr Leu Ala Lys Tyr Tyr Asp Lys
2035 2040 2045
Leu Met Pro Met Val Thr Asp Asn Lys Met Glu Lys Gln Gly Asp Leu
2050 2055 2060
Ile Arg Tyr Ile Val Leu His Phe Gly Arg Ser Leu Gln Tyr Gly Asn
2065 2070 2075 2080
Gln Phe Ile Tyr Gln Ser Met Pro Arg Met Leu Thr Leu Trp Leu Asp
2085 2090 2095
Tyr Gly Thr Lys Ala Tyr Glu Trp Glu Lys Ala Gly Arg Ser Asp Arg
2100 2105 2110
Val Gln Met Arg Asn Asp Leu Gly Lys Ile Asn Lys Val Ile Thr Glu
2115 2120 2125
His Thr Asn Tyr Leu Ala Pro Tyr Gln Phe Leu Thr Ala Phe Ser Gln
2130 2135 2140
Leu Ile Ser Arg Ile Cys His Ser His Asp Glu Val Phe Val Val Leu
2145 2150 2155 2160
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Met Glu Ile Ile Ala Lys Val Phe Leu Ala Tyr Pro Gln Gln Ala Met
2165 2170 2175
Trp Met Met Thr Ala Val Ser Lys Ser Ser Tyr Pro Met Arg Val Asn
2180 2185 2190
Arg Cys Lys Glu Ile Leu Asn Lys Ala Ile His Met Lys Lys Ser Leu
2195 2200 2205
Glu Lys Phe Val Gly Asp Ala Thr Arg Leu Thr Asp Lys Leu Leu Glu
2210 2215 2220
Leu Cys Asn Lys Pro Val Asp Gly Ser Ser Ser Thr Leu Ser Met Ser
2225 2230 2235 2240
Thr His Phe Lys Met Leu Lys Lys Leu Val Glu Glu Ala Thr Phe Ser
2245 2250 2255
Glu Ile Leu Ile Pro Leu Gln Ser Val Met Ile Pro Thr Leu Pro Ser
2260 2265 2270
Ile Leu Gly Thr His Ala Asn His Ala Ser His Glu Pro Phe Pro Gly
2275 2280 2285
His Trp Ala Tyr Ile Ala Gly Phe Asp Asp Met Val Glu Ile Leu Ala
2290 2295 2300
Ser Leu Gln Lys Pro Lys Lys Ile Ser Leu Lys Gly Ser Asp Gly Lys
2305 2310 2315 2320
Phe Tyr Ile Met Met Cys Lys Pro Lys Asp Asp Leu Arg Lys Asp Cys
2325 2330 2335
Arg Leu Met Glu Phe Asn Ser Leu Ile Asn Lys Cys Leu Arg Lys Asp
2340 2345 2350
Ala Glu Ser Arg Arg Arg Glu Leu His Ile Arg Thr Tyr Ala Val Ile
2355 2360 2365
Pro Leu Asn Asp Glu Cys Gly Ile Ile Glu Trp Val Asn Asn Thr Ala
2370 2375 2380
Gly Leu Arg Pro Ile Leu Thr Lys Leu Tyr Lys Glu Lys Gly Val Tyr
2385 2390 2395 2400
Met Thr Gly Lys Glu Leu Arg Gln Cys Met Leu Pro Lys Ser Ala Ala
2405 2410 2415
Leu Ser Glu Lys Leu Lys Val Phe Arg Glu Phe Leu Leu Pro Arg His
2420 2425 2430
Pro Pro Ile Phe His Glu Trp Phe Leu Arg Thr Phe Pro Asp Pro Thr
2435 2440 2445
Ser Trp Tyr Ser Ser Arg Ser Ala Tyr Cys Arg Ser Thr Ala Val Met
2450 2455 2460
Ser Met Val Gly Tyr Ile Leu Gly Leu Gly Asp Arg His Gly Glu Asn
2465 2470 2475 2480
Ile Leu Phe Asp Ser Leu Thr Gly Glu Cys Val His Val Asp Phe Asn
2485 2490 2495
Cys Leu Phe Asn Lys Gly Glu Thr Phe Glu Val Pro Glu Ile Val Pro
2500 2505 2510
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Phe Arg Leu Thr His Asn Met Val Asn Gly Met Gly Pro Met Gly Thr
2515 2520 2525
Glu Gly Leu Phe Arg Arg Ala Cys Glu Val Thr Met Arg Leu Met Arg
2530 2535 2540
Asp Gln Arg Glu Pro Leu Met Ser Val Leu Lys Thr Phe Leu His Asp
2545 2550 2555 2560
Pro Leu Val Glu Trp Ser Lys Pro Val Lys Gly His Ser Lys Ala Pro
2565 2570 2575
Leu Asn Glu Thr Gly Glu Val Val Asn Glu Lys Ala Lys Thr His Val
2580 2585 2 590
Leu Asp Ile Glu Gln Arg Leu Gln Gly Val Ile Lys Thr Arg Asn Arg
2595 2600 2605
Val Thr Gly Leu Pro Leu Ser Ile Glu Gly His Val His Tyr Leu Ile
2610 2615 2620
Gln Glu Ala Thr Asp Glu Asn Leu Leu Cys Gln Met Tyr Leu Gly Trp
2625 2630 2635 2640
Thr Pro Tyr Met
(2) INFO[tMATION FOR SEQ ID NO:30:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 7624 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: cDNA
(ix) FEATURE:
(A) NAME/KEY : CDS
(B) LOCATION: 333..7562
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:30:
CTTGTGAAGA GAATGTTI'TA CACTCTTGTT AGTGAAGTTT ATTCT'ITAAA AGTCAATCGT 60
CAAGGATTTA GCAAATGAAT TAGCACTTCG GATATACTTG TTTATTTAAT ATCTTTTTTG 120
TTTATTTCAA AGAATTCAGT AATTGGATCA TAACGAGACT TCTGCGGATT GCAGCAACTC 180
CCTCCTGTCA TTTGTTACAC AAGAAAATCT GTGAAGTCAT CTGTTCATTA TTATTTCTTT 240
TTAARAGCAA GAGTCCTGCT ATTTI"PGGGG TACTCACAAA AGAATTATTA CAACTTTTTG 300
AAGACTTGGT TTACCTCCAT AGAAGAAATG TG ATG GGT CAT GCT GTG GAA TGG 353
Met Gly His Ala Val Glu Trp
1 5
CCA GTG GTC ATG AGC CGA TTT TTA AGT CAA TTA GAT GAA CAC ATG GGA 401
Pro Val Val Met Ser Arg Phe Leu Ser Gln Leu Asp Glu His Met Gly
15 20
TAT TTA CAA TCA GCT CCT TTG CAG TTG ATG AGT ATG CAP, AAT TTA GAA 449
Tyr Leu Gln Ser Ala Pro Leu Gln Leu Met Ser Met Gln Asn Leu Glu
25 30 35
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TTT ATT GAA GTC ACT TTA TTA ATG GTT CTT ACT CGT ATT ATT GCA ATT 497
Phe Ile Glu Val Thr Leu Leu Met Val Leu Thr Arg Ile Ile Ala Ile
40 45 50 55
GTG TTT TTT AGA AGG CAA GAA CTC TTA CTT TGG CAG ATA GGT TGT GTT 545
Val Phe Phe Arg Arg Gln Glu Leu Leu Leu Trp Gln Ile Gly Cys Val
60 65 70
CTG CTA GAG TAT GGT AGT CCA AAA ATT AAA TCC CTA GCA ATT AGC TTT 593
Leu Leu Glu Tyr Gly Ser Pro Lys Ile Lys Ser Leu Ala Ile Ser Phe
75 80 85
TTA ACA GAA CTT TTT CAG CTT GGA GGA CTA CCA GCA CAA CCA GCT AGC 641
Leu Thr Glu Leu Phe Gln Leu Gly Gly Leu Pro Ala Gln Pro Ala Ser
90 95 100
ACT TTT TTC AGC TCA TTT TTG GAA TTA TTA AAA CAC CTT GTA GAA ATG 689
Thr Phe Phe Ser Ser Phe Leu Glu Leu Leu Lys His Leu Val Glu Met
105 110 115
GAT ACT GAC CAA TTG AAA CTC TAT GAA GAG CCA TTA TCA AAG CTG ATA 737
Asp Thr Asp Gln Leu Lys Leu Tyr Glu Glu Pro Leu Ser Lys Leu Ile
120 125 130 135
AAG ACA CTA TTT CCC TTT GAA GCA GAA GCT TAT AGA AAT ATT GAA CCT 785
Lys Thr Leu Phe Pro Phe Glu Ala Glu Ala Tyr Arg Asn Ile Glu Pro
140 145 150
GTC TAT TTA AAT ATG CTG CTG GAA AAA CTC TGT GTC ATG TTT GAA GAC 833
Val Tyr Leu Asn Met Leu Leu Glu Lys Leu Cys Val Met Phe Glu Asp
155 160 165
GGT GTG CTC ATG CGG CTT AAG TCT GAT TTG CTA AAA GCA GCT TTG TGC 881
Gly Val Leu Met Arg Leu Lys Ser Asp Leu Leu Lys Ala Ala Leu Cys
170 175 180
CAT TTA CTG CAG TAT TTC CTT AAA TTT GTG CCA GCT GGG TAT GAA TCT 929
His Leu Leu Gln Tyr Phe Leu Lys Phe Val Pro Ala Gly Tyr Glu Ser
185 190 195
GCT TTA CAA GTC AGG AAG GTC TAT GTG AGA AAT ATT TGT AAA GCT CTT 977
Ala Leu Gin Val Arg Lys Val Tyr Val Arg Asn Ile Cys Lys Ala Leu
200 205 210 215
TTG GAT GTG CTT GGA ATT GAG GTA GAT GCA GAG TAC TTG TTG GGC CCA 1025
Leu Asp Val Leu Gly Ile Glu Val Asp Ala Glu Tyr Leu Leu Gly Pro
220 225 230
CTT TAT GCA GCT TTG AAA ATG GAA AGT ATG GAA ATC ATT GAG GAG ATT 1073
Leu Tyr Ala Ala Leu Lys Met Glu Ser Met Glu Ile Ile Glu Glu Ile
235 240 245
CAA TGC CAA ACT CAA CAG GAA AAC CTC AGC AGT AAT AGT GAT GGA ATA 1121
Gln Cys Gln Thr Gln Gln Glu Asn Leu Ser Ser Asn Ser Asp Gly Ile
250 255 260
TCA CCC AAA AGG CGT CGT CTC AGC TCG TCT CTA AAC CCT TCT AAA AGA 1169
Ser Pro Lys Arg Arg Arg Leu Ser Ser Ser Leu Asn Pro Ser Lys Arg
265 270 275
GCA CCA AAA CAG ACT GAG GAA ATT AAA CAT GTG GAC ATG AAC CAA AAG 1217
Ala Pro Lys Gln Thr Glu Glu Ile Lys His Val Asp Met Asn Gln Lys
280 285 290 295
AGC ATA TTA TGG AGT GCA CTG AAA CAG AAA GCT GAA TCC CTT CAG ATT 1265
Ser Ile Leu Trp Ser Ala Leu Lys Gln Lys Ala Glu Ser Leu Gln Ile
300 305 310
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TCC CTT GAA TAC AGT GGC CTA AAG AAT CCT GTT ATT GAG ATG TTA GAA 1313
Ser Leu Glu Tyr Ser Gly Leu Lys Asn Pro Val Ile Glu Met Leu Glu
315 320 325
GGA ATT GCT GTT GTC TTA CAA CTG ACT GCT CTG TGT ACT GTT CAT TGT 1361
Gly Ile Ala Val Val Leu Gln Leu Thr Ala Leu Cys Thr Val His Cys
330 335 340
TCT CAT CAA AAC ATG AAC TGC CGT ACT TTC AAG GAC TGT CAA CAT AAA 1409
Ser His Gln Asn Met Asn Cys Arg Thr Phe Lys Asp Cys Gln His Lys
345 350 355
TCC AAG AAG AAA CCT TCT GTA GTG ATA ACT TGG ATG TCA TTG GAT TTT 1457
Ser Lys Lys Lys Pro Ser Val Val Ile Thr Trp Met Ser Leu Asp Phe
360 365 370 375
TAC ACA AAA GTG CTT AAG AGC TGT AGA AGT TTG TTA GAA TCT GTT CAG 1505
Tyr Thr Lys Val Leu Lys Ser Cys Arg Ser Leu Leu Glu Ser Val Gln
380 385 390
AAA CTG GAC CTG GAG GCA ACC ATT GAT AAG GTG GTG AAA ATT TAT GAT 1553
Lys Leu Asp Leu Glu Ala Thr Ile Asp Lys Val Val Lys Ile Tyr Asp
395 400 405
GCT TTG ATT TAT ATG CAA GTA AAC AGT TCA TTT GAA GAT CAT ATC CTG 1601
Ala Leu Ile Tyr Met Gln Val Asn Ser Ser Phe Glu Asp His Ile Leu
410 415 420
GAA GAT TTA TGT GGA ATG CTC TCA CTT CCA TGG ATT TAT TCC CAT TCT 1649
Glu Asp Leu Cys Gly Met Leu Ser Leu Pro Trp Ile Tyr Ser His Ser
425 430 435
GAT GAT GGC TGT TTA AAG TTG ACC ACA TTT GCC GCT AAT CTT CTA ACA 1697
Asp Asp Gly Cys Leu Lys Leu Thr Thr Phe Ala Ala Asn Leu Leu Thr
440 445 450 455
TTA AGC TGT AGG ATT TCA GAT AGC TAT TCA CCA CAG GCA CAA TCA CGA 1745
Leu Ser Cys Arg Ile Ser Asp Ser Tyr Ser Pro Gln Ala Gln Ser Arg
460 465 470
TGT GTG TTT CTT CTG ACT CTG TTT CCA AGA AGA ATA TTC CTT GAG TGG 1793
Cys Val Phe Leu Leu Thr Leu Phe Pro Arg Arg Ile Phe Leu Glu Trp
475 480 485
AGA ACA GCA GTT TAC AAC TGG GCC CTG CAG AGC TCC CAT GAA GTA ATC 1841
Arg Thr Ala Val Tyr Asn Trp Ala Leu Gln Ser Ser His Glu Val Ile
490 495 500
CGG GCT AGT TGT GTT AGT GGA TTT TTT ATC TTA TTG CAG CAG CAG AAT 1889
Arg Ala Ser Cys Val Ser Gly Phe Phe Ile Leu Leu Gln Gln Gln Asn
505 510 515
TCT TGT AAC AGA GTT CCC AAG ATT CTT ATA GAT AAA GTC AAA GAT GAT 1937
Ser Cys Asn Arg Val Pro Lys Ile Leu Ile Asp Lys Val Lys Asp Asp
520 525 530 535
TCT GAC ATT GTC AAG AAA GAA TTT GCT TCT ATA CTT GGT CAA CTT GTC 1985
Ser Asp Ile Val Lys Lys Glu Phe Ala Ser Ile Leu Gly Gin Leu Val
540 545 550
TGT ACT CTT CAC GGC ATG TTT TAT CTG ACA AGT TCT TTA ACA GAA CCT 2033
Cys Thr Leu His Gly Met Phe Tyr Leu Thr Ser Ser Leu Thr Glu Pro
555 560 565
TTC TCT GAA CAC GGA CAT GTG GAC CTC TTC TGT AGG AAC TTG AAA GCC 2081
Phe Ser Glu His Gly His Val Asp Leu Phe Cys Arg Asn Leu Lys Ala
570 575 580
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ACT TCT CAA CAT GAA TGT TCA TCT TCT CAA CTA AAA GCT TCT GTC TGC 2129
Thr Ser Gln His Glu Cys Ser Ser Ser Gln Leu Lys Ala Ser Val Cys
585 590 595
AAG CCA TTC CTT TTC CTA CTG AAA AAA AAA ATA CCT AGT CCA GTA AAA 2177
Lys Pro Phe Leu Phe Leu Leu Lys Lys Lys Ile Pro Ser Pro Val Lys
600 605 610 615
CTT GCT TTC ATA GAT AAT CTA CAT CAT CTT TGT AAG CAT CTT GAT TTT 2225
Leu Ala Phe Ile Asp Asn Leu His His Leu Cys Lys His Leu Asp Phe
620 625 630
AGA GAA GAT GAA ACA GAT GTA AAA GCA GTT CTT GGA ACT TTA TTA AAT 2273
Arg Glu Asp Glu Thr Asp Val Lys Ala Val Leu Gly Thr Leu Leu Asn
635 640 645
TTA ATG GAA GAT CCA GAC AAA GAT GTT AGA GTG GCT TTT AGT GGA AAT 2321
Leu Met Glu Asp Pro Asp Lys Asp Val Arg Val Ala Phe Ser Gly Asn
650 655 660
ATC AAG CAC ATA TTG GAA TCC TTG GAC TCT GAA GAT GGA TTT ATA AAG 2369
Ile Lys His Ile Leu Glu Ser Leu Asp Ser Glu Asp Gly Phe Ile Lys
665 670 675
GAG CTT TTT GTC TTA AGA ATG AAG GAA GCA TAT ACA CAT GCC C.AA ATA 2417
Glu Leu Phe Val Leu Arg Met Lys Glu Ala Tyr Thr His Ala Gln Ile
680 685 690 695
TCA AGA AAT AAT GAG CTG AAG GAT ACC TTG ATT CTT ACA ACA GGG GAT 2465
Ser Arg Asn Asn Glu Leu Lys Asp Thr Leu Ile Leu Thr Thr Gly Asp
700 705 710
ATT GGA AGG GCC GCA AAA GGA GAT TTG GTA CCA TIT GCA CTC TTA CAC 2513
Ile Gly Arg Ala Ala Lys Gly Asp Leu Val Pro Phe Ala Leu Leu His
715 720 725
TTA TTG CAT TGT TTG TTA TCC AAG TCA GCA TCT GTC TCT GGA GCA GCA 2561
Leu Leu His Cys Leu Leu Ser Lys Ser Ala Ser Val Ser Gly Ala Ala
730 735 740
TAC ACA GAA ATT AGA GCT CTG GTT GCA GCT AAA AGT GTT AAA CTG CAA 2609
Tyr Thr Glu Ile Arg Ala Leu Val Ala Ala Lys Ser Val Lys Leu Gln
745 750 755
AGT TTT TTC AGC CAG TAT AAG AAA CCC ATC TGT CAG TTT TTG GTA GAA 2657
Ser Phe Phe Ser Gln Tyr Lys Lys Pro Ile Cys Gln Phe Leu Val Glu
760 765 770 775
TCC CTT CAC TCT AGT CAG ATG ACA GCA CTT CCG AAT ACT CCA TGC CAG 2705
Ser Leu His Ser Ser Gln Met Thr Ala Leu Pro Asn Thr Pro Cys Gln
780 785 790
AAT GCT GAC GTG CGA AAA CAA GAT GTG GCT CAC CAG AGA GAA ATG GCT 2753
Asn Ala Asp Val Arg Lys Gln Asp Val Ala His Gln Arg Glu Met Ala
795 800 805
TTA AAT ACG TTG TCT GAA ATT GCC AAC GTT TTC GAC TTT CCT GAT CTT 2801
Leu Asn Thr Leu Ser Glu Ile Ala Asn Val Phe Asp Phe Pro Asp Leu
810 815 820
AAT CGT TTT CTT ACT AGG ACA TTA CAA GTT CTA CTA CCT GAT CTT GCT 2849
Asn Arg Phe Leu Thr Arg Thr Leu Gln Val Leu Leu Pro Asp Leu Ala
825 830 835
GCC AAA GCA AGC CCT GCA GCT TCT GCT CTC ATT CGA ACT TTA GGA AAA 2897
Ala Lys Ala Ser Pro Ala Ala Ser Ala Leu Ile Arg Thr Leu Gly Lys
840 845 850 855
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CAA TTA AAT GTC AAT CGT AGA GAG ATT TTA ATA AAC AAC TTC AAA TAT 2945
Gln Leu Asn Val Asn Arg Arg Glu Ile Leu Ile Asn Asn Phe Lys Tyr
860 865 870
ATT TTT TCT CAT TTG GTC TGT TCT TGT TCC AAA GAT GAA TTA GAA CGT 2993
Ile Phe Ser His Leu Val Cys Ser Cys Ser Lys Asp Glu Leu Glu Arg
875 880 885
GCC CTT CAT TAT CTG AAG AAT GAA ACA GAA ATT GAA CTG GGG AGC CTG 3041
Ala Leu His Tyr Leu Lys Asn Glu Thr Glu Ile Glu Leu Gly Ser Leu
890 895 900
TTG AGA CAA GAT TTC CAA GGA TTG CAT AAT GAA TTA TTG CTG CGT ATT 3089
Leu Arg Gln Asp Phe Gln Gly Leu His Asn Glu Leu Leu Leu Arg Ile
905 910 915
GGA GAA CAC TAT CAA CAG GTT TTT AAT GGT TTG TCA ATA CTT GCC TCA 3137
Gly Glu His Tyr Gln Gln Val Phe Asn Gly Leu Ser Ile Leu Ala Ser
920 925 930 935
TTT GCA TCC AGT GAT GAT CCA TAT CAG GGC CCG AGA GAT ATC ATA TCA 3185
Phe Ala Ser Ser Asp Asp Pro Tyr Gln Gly Pro Arg Asp Ile Ile Ser
940 945 950
CCT GAA CTG ATG GCT GAT TAT TTA CAA CCC AAA TTG TTG GGC ATT TTG 3233
Pro Glu Leu Met Ala Asp Tyr Leu Gin Pro Lys Leu Leu Gly Ile Leu
955 960 965
GCT TTT TTT AAC ATG CAG TTA CTG AGC TCT AGT GTT GGC ATT GAA GAT 3281
Ala Phe Phe Asn Met Gln Leu Leu Ser Ser Ser Val Gly Ile Glu Asp
970 975 980
AAG AAA ATG GCC TTG AAC AGT TTG ATG TCT TTG ATG AAG TTA ATG GGA 3329
Lys Lys Met Ala Leu Asn Ser Leu Met Ser Leu Met Lys Leu Met Gly
985 990 995
CCC AAA CAT GTC AGT TCT GTG AGG GTG AAG ATG ATG ACC ACA CTG AGA 3377
Pro Lys His Val Ser Ser Val Arg Val Lys Met Met Thr Thr Leu Arg
1000 1005 1010 1015
ACT GGC CTT CGA TTC AAG GAT GAT TTT CCT GAA TTG TGT TGC AGA GCT 3425
Thr Gly Leu Arg Phe Lys Asp Asp Phe Pro Glu Leu Cys Cys Arg Ala
1020 1025 1030
TGG GAC TGC TTT GTT CGC TGC CTG GAT CAT GCT TGT CTG GGC TCC CTT 3473
Trp Asp Cys Phe Val Arg Cys Leu Asp His Ala Cys Leu Gly Ser Leu
1035 1040 1045
CTC AGT CAT GTA ATA GTA GCT TTG TTA CCT CTT ATA CAC ATC CAG CCT 3521
Leu Ser His Val Ile Val Ala Leu Leu Pro Leu Ile His Ile Gln Pro
1050 1055 1060
AAA GAA ACT GCA GCT ATC TTC CAC TAC CTC ATA ATT GAA AAC AGG GAT 3569
Lys Glu Thr Ala Ala Ile Phe His Tyr Leu Ile Ile Glu Asn Arg Asp
1065 1070 1075
GCT GTG CAA GAT TTT CTT CAT GAA ATA TAT TTT TTA CCT GAT CAT CCA 3617
Ala Val Gln Asp Phe Leu His Glu Ile 'Iyr Phe Leu Pro Asp His Pro
1080 1085 1090 1095
GAA TTA AAA AAG ATA AAA GCC GTT CTC CAG GAA TAC AGA AAG GAG ACC 3665
Glu Leu Lys Lys Ile Lys Ala Val Leu Gln Glu Tyr Arg Lys Glu Thr
1100 1105 1110
TCT GAG AGC ACT GAT CTT CAG ACA ACT CTT CAG CTC TCT ATG AAG GCC 3713
Ser Glu Ser Thr Asp Leu Gln Thr Thr Leu Gin Leu Ser Met Lys Ala
1115 1120 1125
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ATT CAA CAT GAA AAT GTC GAT GTT CGT ATT CAT GCT CTT ACA AGC TTG 3761
Ile Gln His Glu Asn Val Asp Val Arg Ile His Ala Leu Thr Ser Leu
1130 1135 1140
AAG GAA ACC TTG TAT AAA AAT CAG GAA AAA CTG ATA AAG TAT GCA ACA 3809
Lys Glu Thr Leu Tyr Lys Asn Gln Glu Lys Leu Ile Lys Tyr Ala Thr
1145 1150 1155
GAC AGT GAA ACA GTA GAA CCT ATT ATC TCA CAG TTG GTG ACA GTG CTT 3857
Asp Ser Glu Thr Val Glu Pro Ile Ile Ser Gln Leu Val Thr Val Leu
1160 1165 1170 1175
TTG AAA GGT TGC CAA GAT GCA AAC TCT CAA GCT CGG TTG CTC TGT GGG 3905
Leu Lys Gly Cys Gln Asp Ala Asn Ser Gln Ala Arg Leu Leu Cys Gly
1180 1185 1190
GAA TGT TTA GGG GAA TTG GGG GCG ATA GAT CCA GGT CGA TTA GAT TTC 3953
Glu Cys Leu Gly Glu Leu Gly Ala Ile Asp Pro Gly Arg Leu Asp Phe
1195 1200 1205
TCA ACA ACT GAA ACT CAA GGA AAA GAT TTT ACA TTT GTG ACT GGA GTA 4001
Ser Thr Thr Glu Thr Gln Gly Lys Asp Phe Thr Phe Val Thr Gly Val
1210 1215 1220
GAA GAT TCA AGC TTT GCC TAT GGA TTA TTG ATG GAG CTA ACA AGA GCT 4049
Glu Asp Ser Ser Phe Ala Tyr Gly Leu Leu Met Glu Leu Thr Arg Ala
1225 1230 1235
TAC CTT GCG TAT GCT GAT AAT AGC CGA GCT CAA GAT TCA GCT GCC TAT 4097
Tyr Leu Ala Tyr Ala Asp Asn Ser Arg Ala Gln Asp Ser Ala Ala Tyr
1240 1245 1250 1255
GCC ATT CAG GAG TTG CTT TCT ATT TAT GAC TGT AGA GAG ATG GAG ACC 4145
Ala Ile Gln Glu Leu Leu Ser Ile Tyr Asp Cys Arg Glu Met Glu Thr
1260 1265 1270
AAC GGC CCA GGT CAC CAA TTG TGG AGG AGA TTT CCT GAG CAT GTT CGG 4193
Asn Gly Pro Gly His Gln Leu Trp Arg Arg Phe Pro Glu His Val Arg
1275 1280 1285
GAA ATA CTA GAA CCT CAT CTA AAT ACC AGA TAC AAG AGT TCT CAG AAG 4241
Glu Ile Leu Glu Pro His Leu Asn Thr Arg Tyr Lys Ser Ser Gln Lys
1290 1295 1300
TCA ACC GAT TGG TCT GGA GTA AAG AAG CCA ATT TAC TTA AGT AAA TTG 4289
Ser Thr Asp Trp Ser Gly Val Lys Lys Pro Ile Tyr Leu Ser Lys Leu
1305 1310 1315
GGT AGT AAC TTT GCA GAA TGG TCA GCA TCT TGG GCA GGT TAT CTT ATT 4337
Gly Ser Asn Phe Ala Glu Trp Ser Ala Ser Trp Ala Gly Tyr Leu Ile
1320 1325 1330 1335
ACA AAG GTT CGA CAT GAT CTT GCC AGT AAA ATT TTC ACC TGC TGT AGC 4385
Thr Lys Val Arg His Asp Leu Ala Ser Lys Ile Phe Thr Cys Cys Ser
1340 1345 1350
ATT ATG ATG AAG CAT GAT TTC AAA GTG ACC ATC TAT CTT CTT CCA CAT 4433
Ile Met Met Lys His Asp Phe Lys Val Thr Ile Tyr Leu Leu Pro His
1355 1360 1365
ATT CTG GTG TAT GTC TTA CTG GGT TGT AAT CAA GAA GAT CAG CAG GAG 4481
Ile Leu Val Tyr Val Leu Leu Gly Cys Asn Gln Glu Asp Gln Gln Glu
1370 1375 1380
GTT TAT GCA GAA ATT ATG GCA GTT CTA AAG CAT GAC GAT CAG CAT ACC 4529
Val Tyr Ala Glu Ile Met Ala Val Leu Lys His Asp Asp Gln His Thr
1385 1390 1395
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ATA AAT ACC CAA GAC ATT GCA TCT GAT CTG TGT CAA CTC AGT ACA CAG 4577
Ile Asn Thr Gin Asp Ile Ala Ser Asp Leu Cys Gln Leu Ser Thr Gln
1400 1405 1410 1415
ACT GTG TTC TCC ATG CTT GAC CAT CTC ACA CAG TGG GCA AGG CAC AAA 4625
Thr Val Phe Ser Met Leu Asp His Leu Thr Gln Trp Ala Arg His Lys
1420 1425 1430
TTT CAG GCA CTG AAA GCT GAG AAA TGT CCA CAC AGC AAA TCA AAC AGA 4673
Phe Gln Ala Leu Lys Ala Glu Lys Cys Pro His Ser Lys Ser Asn Arg
1435 1440 1445
AAT AAG GTA GAC TCA ATG GTA TCT ACT GTG GAT TAT GAA GAC TAT CAG 4721
Asn Lys Val Asp Ser Met Val Ser Thr Val Asp Tyr Glu Asp Tyr Gln
1450 1455 1460
AGT GTA ACC CGT TTT CTA GAC CTC ATA CCC CAG GAT ACT CTG GCA GTA 4769
Ser Val Thr Arg Phe Leu Asp Leu Ile Pro Gln Asp Thr Leu Ala Val
1465 1470 1475
GCT TCC TTT CGC TCC AAA GCA TAC ACA CGA GCT GTA ATG CAC TTT GAA 4817
Ala Ser Phe Arg Ser Lys Ala Tyr Thr Arg Ala Val Met His Phe Glu
1480 1485 1490 1495
TCA TTT ATT ACA GAA AAG AAG CAA AAT ATT CAG GAA CAT CTT GGA TTT 4865
Ser Phe Ile Thr Glu Lys Lys Gln Asn Ile Gln Glu His Leu Gly Phe
1500 1505 1510
TTA CAG AAA TTG TAT GCT GCT ATG CAT GAA CCT GAT GGA GTG GCC GGA 4913
Leu Gln Lys Leu Tyr Ala Ala Met His Glu Pro Asp Gly Val Ala Gly
1515 1520 1525
GTC AGT GCA ATT AGA AAG GCA GAA CCA TCT CTA AAA GAA CAG ATC CTT 4961
Val Ser Ala Ile Arg Lys Ala Glu Pro Ser Leu Lys Glu Gin Ile Leu
1530 1535 1540
GAA CAT GAA AGC CTT GGC TTG CTG AGG GAT GCC ACT GCT TGT TAT GAC 5009
Glu His Glu Ser Leu Gly Leu Leu Arg Asp Ala Thr Ala Cys Tyr Asp
1545 1550 1555
AGG GCT ATT CAG CTA GAA CCA GAC CAG ATC ATT CAT TAC CAT GGT GTA 5057
Arg Ala Ile Gln Leu Glu Pro Asp Gln Ile Ile His Tyr His Gly Val
1560 1565 1570 1575
GTA AAG TCC ATG TTA GGT CTT GGT CAG CTG TCT ACT GTT ATC ACT CAG 5105
Val Lys Ser Met Leu Gly Leu Gly Gln Leu Ser Thr Val Ile Thr Gln
1580 1585 1590
GTG AAT GGA GTG CAT GCT AAC AGG TCC GAG TGG ACA GAT GAA TTA AAC 5153
Val Asn Gly Val His Ala Asn Arg Ser Glu Trp Thr Asp Glu Leu Asn
1595 1600 1605
ACG TAC AGA GTG GAA GCA GCT TGG AAA TTG TCA CAG TGG GAT TTG GTG 5201
Thr Tyr Arg Val Glu Ala Ala Trp Lys Leu Ser Gln Trp Asp Leu Val
1610 1615 1620
GAA AAC TAT TTG GCA GCA GAT GGA AAA TCT ACA ACA TGG AGT GTC AGA 5249
Glu Asn Tyr Leu Ala Ala Asp Gly Lys Ser Thr Thr Trp Ser Val Arg
1625 1630 1635
CTG GGA CAG CTA TTA TTA TCA GCC AAA AAA AGA GAT ATC ACA GCT TTT 5297
Leu Gly Gln Leu Leu Leu Ser Ala Lys Lys Arg Asp Ile Thr Ala Phe
1640 1645 1650 1655
TAT GAC TCA CTG AAA CTA GTG AGA GCA GAA CAA ATT GTA CCT CTT TCA 5345
Tyr Asp Ser Leu Lys Leu Val Arg Ala Glu Gln Ile Val Pro Leu Ser
1660 1665 1670
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GCT GCA AGC TTT GAA AGA GGC TCC TAC CAA CGA GGA TAT GAA TAT ATT 5393
Ala Ala Ser Phe Glu Arg Gly Ser Tyr Gln Arg Gly Tyr Glu Tyr Ile
1675 1680 1685
GTG AGA TTG CAC ATG TTA TGT GAG TTG GAG CAT AGC ATC AAA CCA CTT 5441
Val Arg Leu His Met Leu Cys Glu Leu Glu His Ser Ile Lys Pro Leu
1690 1695 1700
TTC CAG CAT TCT CCA GGT GAC AGT TCT CAA GAA GAT TCT CTA AAC TGG 5489
Phe Gln His Ser Pro Gly Asp Ser Ser Gln Glu Asp Ser Leu Asn Trp
1705 1710 1715
GTA GCT CGA CTA GAA ATG ACC CAG AAT TCC TAC AGA GCC AAG GAG CCT 5537
Val Ala Arg Leu Glu Met Thr Gln Asn Ser Tyr Arg Ala Lys Glu Pro
1720 1725 1730 1735
ATC CTG GCT CTC CGG AGG GCT TTA CTA AGC CTC AAC AAA AGA CCA GAT 5585
Ile Leu Ala Leu Arg Arg Ala Leu Leu Ser Leu Asn Lys Arg Pro Asp
1740 1745 1750
TAC AAT GAA ATG GTT GGA GAA TGC TGG CTG CAG AGT GCC AGG GTA GCT 5633
Tyr Asn Glu Met Val Gly Glu Cys Trp Leu Gln Ser Ala Arg Val Ala
1755 1760 1765
AGA AAG GCT GGT CAC CAC CAG ACA GCC TAC AAT GCT CTC CTT AAT GCA 5681
Arg Lys Ala Gly His His Gln Thr Ala Tyr Asn Ala Leu Leu Asn Ala
1770 1775 1780
GGG GAA TCA CGA CTC GCT GAA CTG TAC GTG GAA AGG GCA AAG TGG CTC 5729
Gly Glu Ser Arg Leu Ala Glu Leu Tyr Val Glu Arg Ala Lys Trp Leu
1785 1790 1795
TGG TCC AAG GGT GAT GTT C-AC CAG GCA CTA ATT GTT CTT CAA AAA GGT 5777
Trp Ser Lys Gly Asp Val His Gln Ala Leu Ile Val Leu Gln Lys Gly
1800 1805 1810 1815
GTT GAA TTA TGT TTT CCT GAA AAT GAA ACC CCA CCT GAG GGT AAG AAC 5825
Val Glu Leu Cys Phe Pro Glu Asn Glu Thr Pro Pro Glu Gly Lys Asn
1820 1825 1830
ATG TTA ATC CAT GGT CGA GCT ATG CTA CTA GTG GGC CGA TTT ATG GAA 5873
Met Leu Ile His Gly Arg Ala Met Leu Leu Val Gly Arg Phe Met Glu
1835 1840 1845
GAA ACA GCT AAC TTT GAA AGC AAT GCA ATT ATG AAA AAA TAT AAG GAT 5921
Glu Thr Ala Asn Phe Glu Ser Asn Ala Ile Met Lys Lys Tyr Lys Asp
1850 1855 1860
GTG ACC GCG TGC CTG CCA GAA TGG GAG GAT GGG CAT TTT TAC CTT GCC 5969
Val Thr Ala Cys Leu Pro Glu Trp Glu Asp Gly His Phe Tyr Leu Ala
1865 1870 1875
AAG TAC TAT GAC AAA TTG ATG CCC ATG GTC ACA GAC AAC AAA ATG GAA 6017
Lys Tyr Tyr Asp Lys Leu Met Pro Met Val Thr Asp Asn Lys Met Glu
1880 1885 1890 1895
AAG CAA GGT GAT CTC ATC CGG TAT ATA GTT CTT CAT ZTT GGC AGA TCT 6065
Lys Gln Gly Asp Leu Ile Arg Tyr Ile Val Leu His Phe Gly Arg Ser
1900 1905 1910
CTA CAA TAT GGA AAT CAG TTC ATA TAT CAG TCA ATG CCA CGA ATG TTA 6113
Leu Gln Tyr Gly Asn Gln Phe Ile Tyr Gln Ser Met Pro Arg Met Leu
1915 1920 1925
ACT CTA TGG CTT GAT TAT GGT ACA AAG GCA TAT GAA TGG GAA AAA GCT 6161
Thr Leu Trp Leu Asp Tyr Gly Thr Lys Ala Tyr Glu Trp Glu Lys Ala
1930 1935 1940
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GGC CGC TCC GAT CGT GTA CAA ATG AGG AAT GAT TTG GGT AAA ATA AAC 6209
Gly Arg Ser Asp Arg Val Gln Met Arg Asn Asp Leu Gly Lys Ile Asn
1945 1950 1955
AAG GTT ATC ACA GAG CAT ACA AAC TAT TTA GCT CCA TAT CAA TTT TTG 6257
Lys Val Ile Thr Glu His Thr Asn Tyr Leu Ala Pro Tyr Gln Phe Leu
1960 1965 1970 1975
ACT GCT TTT TCA CAA TTG ATC TCT CGA ATT TGT CAT TCT CAC GAT GAA 6305
Thr Ala Phe Ser Gln Leu Ile Ser Arg Ile Cys His Ser His Asp Glu
1980 1985 1990
GTT TTT GTT GTC TTG ATG GAA ATA ATA GCC AAA GTA TTT CTA GCC TAT 6353
Val Phe Val Val Leu Met Glu Ile Ile Ala Lys Val Phe Leu Ala Tyr
1995 2000 2005
CCT CAA CAA GCA ATG TGG ATG ATG ACA GCT GTG TCA AAG TCA TCT TAT 6401
Pro Gln Gln Ala Met Trp Met Met Thr Ala Val Ser Lys Ser Ser Tyr
2010 2015 2020
CCC ATG CGT GTG AAC AGA TGC AAG GAA ATC CTC AAT AAA GCT ATT CAT 6449
Pro Met Arg Val Asn Arg Cys Lys Glu Ile Leu Asn Lys Ala Ile His
2025 2030 2035
ATG AAA AAA TCC TTA GAG AAG TTT GTT GGA GAT GCA ACT CGC CTA ACA 6497
Met Lys Lys Ser Leu Glu Lys Phe Val Gly Asp Ala Thr Arg Leu Thr
2040 2045 2050 2055
GAT AAG CTT CTA GAA TTG TGC AAT AAA CCG GTG GAA ATT CTT GCT TCT 6545
Asp Lys Leu Leu Glu Leu Cys Asn Lys Pro Val Glu Ile Leu Ala Ser
2060 2065 2070
CTT CAG AAA CCA AAG AAG ATT TCT TTA AAA GGC TCA GAT GGA AAG TTC 6593
Leu Gln Lys Pro Lys Lys Ile Ser Leu Lys Gly Ser Asp Gly Lys Phe
2075 2080 2085
TAC ATC ATG ATG TGT AAG CCA AAA GAT GAC CTG AGA AAG GAT TGT AGA 6641
Tyr Ile Met Met Cys Lys Pro Lys Asp Asp Leu Arg Lys Asp Cys Arg
2090 2095 2100
CTA ATG GAA TTC AAT TCC TTG ATT AAT AAG TGC TTA AGA AAA GAT GCA 6689
Leu Met Glu Phe Asn Ser Leu Ile Asn Lys Cys Leu Arg Lys Asp Ala
2105 2110 2115
GAG TCT CGT AGA AGA GAA CTT CAT ATT CGA ACA TAT GCA GTT ATT CCA 6737
Glu Ser Arg Arg Arg Glu Leu His Ile Arg Thr Tyr Ala Val Ile Pro
2120 2125 2130 2135
CTA AAT GAT GAA TGT GGG ATT ATT GAA TGG GTG AAC AAC ACT GCT GGT 6785
Leu Asn Asp Glu Cys Gly Ile Ile Glu Trp Val Asn Asn Thr Ala Gly
2140 2145 2150
TTG AGA CCT ATT CTG ACC AAA CTA TAT AAA GAA AAG GGA GTG TAT ATG 6833
Leu Arg Pro Ile Leu Thr Lys Leu Tyr Lys Glu Lys Gly Val Tyr Met
2155 2160 2165
ACA GGA AAA GAA CTT CGC CAG TGT ATG CTA CCA AAG TCA GCA GCT TTA 6881
Thr Gly Lys Glu Leu Arg Gln Cys Met Leu Pro Lys Ser Ala Ala Leu
2170 2175 2180
TCT GAA AAA CTC AAA GTA TTC CGA GAA TTT CTC CTG CCC AGG CAT CCT 6929
Ser Glu Lys Leu Lys Val Phe Arg Glu Phe Leu Leu Pro Arg His Pro
2185 2190 2195
CCT ATT TTT CAT GAG TGG TTT CTG AGA ACA TTC CCT GAT CCT ACA TCA 6977
Pro Ile Phe His Glu Trp Phe Leu Arg Thr Phe Pro Asp Pro Thr Ser
2200 2205 2210 2215
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TGG TAC AGT AGT AGA TCA GCT TAC TGC CGT TCC ACT GCA GTA ATG TCA 7025
Trp Tyr Ser Ser Arg Ser Ala Tyr Cys Arg Ser Thr Ala Val Met Ser
2220 2225 2230
ATG GTT GGT TAT ATT CTG GGG CTT GGA GAC CGT CAT GGT GAA AAT ATT 7073
Met Val Gly Tyr Ile Leu Gly Leu Gly Asp Arg His Gly Glu Asn Ile
2235 2240 2245
CTC TTT GAT TCT TTG ACT GGT GAA TGC GTA CAT GTA GAT TTC AAT TGT 7121
Leu Phe Asp Ser Leu Thr Gly Glu Cys Val His Val Asp Phe Asn Cys
2250 2255 2260
CTT TTC AAT AAG GGA GAA ACC TTT GAA GTT CCA GAA ATT GTG CCA TTT 7169
Leu Phe Asn Lys Gly Glu Thr Phe Glu Val Pro Glu Ile Val Pro Phe
2265 2270 2275
CGC CTG ACT CAT AAT ATG GTT AAT GGA ATG GGT CCT ATG GGA ACA GAG 7217
Arg Leu Thr His Asn Met Val Asn Gly Met Gly Pro Met Gly Thr Glu
2280 2285 2290 2295
GGT CTT TTT CGA AGA GCA TGT GAA GTT ACA ATG AGG CTG ATG CGT GAT 7265
Gly Leu Phe Arg Arg Ala Cys Glu Val Thr Met Arg Leu Met Arg Asp
2300 2305 2310
CAG CGA GAG CCT TTA ATG AGT GTC TTA AAG ACT TTT CTA CAT GAT CCT 7313
Gln Arg Glu Pro Leu Met Ser Val Leu Lys Thr Phe Leu His Asp Pro
2315 2320 2325
CTT GTG GAA TGG AGT AAA CCA GTG AAA GGG CAT TCC AAA GCG CCA CTG 7361
Leu Val Glu Trp Ser Lys Pro Val Lys Gly His Ser Lys Ala Pro Leu
2330 2335 2340
AAT GAA ACT GGA GAA GTT GTC AAT GAA AAG GCC AAG ACC CAT GTT CTT 7409
Asn Glu Thr Gly Glu Val Val Asn Glu Lys Ala Lys Thr His Val Leu
2345 2350 2355
GAC ATT GAG CAG CGA CTA CAA GGT GTA ATC AAG ACT CGA AAT AGA GTG 7457
Asp Ile Glu Gln Arg Leu Gln Gly Val Ile Lys Thr Arg Asn Arg Val
2360 2365 2370 2375
ACA GGA CTG CCG TTA TCT ATT GAA GGA CAT GTG CAT TAC CTT ATA CAA 7505
Thr Gly Leu Pro Leu Ser Ile Glu Gly His Val His Tyr Leu Ile Gln
2380 2385 2390
GAA GCT ACT GAT GAA AAC TTA CTA TGC CAG ATG TAT CTT GGT TGG ACT 7553
Glu Ala Thr Asp Glu Asn Leu Leu Cys Gln Met Tyr Leu Gly Trp Thr
2395 2400 2405
CCA TAT ATG TGAAATGAAA TTATGTAAAA GAATATGTTA ATAATCTAAA 7602
Pro Tyr Met
2410
AGTAAAAAAA AAAAAAAAAA AA 7624
(2) INFORMATION FOR SEQ ID NO:31:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2410 amino acids
(B) TYPE: amino acid
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: protein
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:31:
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Met Gly His Ala Val Glu Trp Pro Val Val Met Ser Arg Phe Leu Ser
1 5 10 15
Gln Leu Asp Glu His Met Gly Tyr Leu Gln Ser Ala Pro Leu Gln Leu
20 25 30
Met Ser Met Gln Asn Leu Glu Phe Ile Glu Val Thr Leu Leu Met Val
35 40 45
Leu Thr Arg Ile Ile Ala Ile Val Phe Phe Arg Arg Gin Glu Leu Leu
50 55 60
Leu Trp Gln Ile Gly Cys Val Leu Leu Glu Tyr Gly Ser Pro Lys Ile
65 70 75 80
Lys Ser Leu Ala Ile Ser Phe Leu Thr Glu Leu Phe Gln Leu Gly Gly
85 90 95
Leu Pro Ala Gln Pro Ala Ser Thr Phe Phe Ser Ser Phe Leu Glu Leu
100 105 110
Leu Lys His Leu Val Glu Met Asp Thr Asp Gln Leu Lys Leu Tyr Glu
115 120 125
Glu Pro Leu Ser Lys Leu Ile Lys Thr Leu Phe Pro Phe Glu Ala Glu
130 135 140
Ala Tyr Arg Asn Ile Glu Pro Val Tyr Leu Asn Met Leu Leu Glu Lys
145 150 155 160
Leu Cys Val Met Phe Glu Asp Gly Val Leu Met Arg Leu Lys Ser Asp
165 170 175
Leu Leu Lys Ala Ala Leu Cys His Leu Leu Gln Tyr Phe Leu Lys Phe
180 185 190
Val Pro Ala Gly Tyr Glu Ser Ala Leu Gln Val Arg Lys Val Tyr Val
195 200 205
Arg Asn Ile Cys Lys Ala Leu Leu Asp Val Leu Gly Ile Glu Val Asp
210 215 220
Ala Glu Tyr Leu Leu Gly Pro Leu Tyr Ala Ala Leu Lys Met Glu Ser
225 230 235 240
Met Glu Ile Ile Glu Glu Ile Gln Cys Gln Thr Gln Gln Glu Asn Leu
245 250 255
Ser Ser Asn Ser Asp Gly Ile Ser Pro Lys Arg Arg Arg Leu Ser Ser
260 265 270
Ser Leu Asn Pro Ser Lys Arg Ala Pro Lys Gln Thr Glu Glu Ile Lys
275 280 285
His Val Asp Met Asn Gln Lys Ser Ile Leu Trp Ser Ala Leu Lys Gln
290 295 300
Lys Ala Glu Ser Leu Gln Ile Ser Leu Glu Tyr Ser Gly Leu Lys Asn
305 310 315 320
Pro Val Ile Glu Met Leu Glu Gly Ile Ala Val Val Leu Gln Leu Thr
325 330 335
Ala Leu Cys Thr Val His Cys Ser His Gln Asn Met Asn Cys Arg Thr
340 345 350
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Phe Lys Asp Cys Gln His Lys Ser Lys Lys Lys Pro Ser Val Val Ile
355 360 365
Thr Trp Met Ser Leu Asp Phe Tyr Thr Lys Val Leu Lys Ser Cys Arg
370 375 380
Ser Leu Leu Glu Ser Val Gln Lys Leu Asp Leu Glu Ala Thr Ile Asp
385 390 395 400
Lys Val Val Lys Ile Tyr Asp Ala Leu Ile Tyr Met Gln Val Asn Ser
405 410 415
Ser Phe Glu Asp His Ile Leu Glu Asp Leu Cys Gly Met Leu Ser Leu
420 425 430
Pro Trp Ile Tyr Ser His Ser Asp Asp Gly Cys Leu Lys Leu Thr Thr
435 440 445
Phe Ala Ala Asn Leu Leu Thr Leu Ser Cys Arg Ile Ser Asp Ser Tyr
450 455 460
Ser Pro Gln Ala Gln Ser Arg Cys Val Phe Leu Leu Thr Leu Phe Pro
465 470 475 480
Arg Arg Ile Phe Leu Glu Trp Arg Thr Ala Val Tyr Asn Trp Ala Leu
485 490 495
Gln Ser Ser His Glu Val Ile Arg Ala Ser Cys Val Ser Gly Phe Phe
500 505 510
Ile Leu Leu Gln Gln Gln Asn Ser Cys Asn Arg Val Pro Lys Ile Leu
515 520 525
Ile Asp Lys Val Lys Asp Asp Ser Asp Ile Val Lys Lys Glu Phe Ala
530 535 540
Ser Ile Leu Gly Gin Leu Val Cys Thr Leu His Gly Met Phe Tyr Leu
545 550 555 560
Thr Ser Ser Leu Thr Glu Pro Phe Ser Glu His Gly His Val Asp Leu
565 570 575
Phe Cys Arg Asn Leu Lys Ala Thr Ser Gln His Glu Cys Ser Ser Ser
580 585 590
Gln Leu Lys Ala Ser Val Cys Lys Pro Phe Leu Phe Leu Leu Lys Lys
595 600 605
Lys Ile Pro Ser Pro Val Lys Leu Ala Phe Ile Asp Asn Leu His His
610 615 620
Leu Cys Lys His Leu Asp Phe Arg Glu Asp Glu Thr Asp Val Lys Ala
625 630 635 640
Val Leu Gly Thr Leu Leu Asn Leu Met Glu Asp Pro Asp Lys Asp Val
645 650 655
Arg Val Ala Phe Ser Gly Asn Ile Lys His Ile Leu Glu Ser Leu Asp
660 665 670
Ser Glu Asp Gly Phe Ile Lys Glu Leu Phe Val Leu Arg Met Lys Glu
675 680 685
Ala Tyr Thr His Ala Gln Ile Ser Arg Asn Asn Glu Leu Lys Asp Thr
690 695 700
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Leu Ile Leu Thr Thr Gly Asp Ile Gly Arg Ala Ala Lys Gly Asp Leu
705 710 715 720
Val Pro Phe Ala Leu Leu His Leu Leu His Cys Leu Leu Ser Lys Ser
725 730 735
Ala Ser Val Ser Gly Ala Ala Tyr Thr Glu Ile Arg Ala Leu Val Ala
740 745 750
Ala Lys Ser Val Lys Leu Gln Ser Phe Phe Ser Gln Tyr Lys Lys Pro
755 760 765
Ile Cys Gln Phe Leu Val Glu Ser Leu His Ser Ser Gln Met Thr Ala
770 775 780
Leu Pro Asn Thr Pro Cys Gln Asn Ala Asp Val Arg Lys Gln Asp Val
785 790 795 800
Ala His Gln Arg Glu Met Ala Leu Asn Thr Leu Ser Glu Ile Ala Asn
805 810 815
Val Phe Asp Phe Pro Asp Leu Asn Arg Phe Leu Thr Arg Thr Leu Gln
820 825 830
Val Leu Leu Pro Asp Leu Ala Ala Lys Ala Ser Pro Ala Ala Ser Ala
835 840 845
Leu Ile Arg Thr Leu Gly Lys Gln Leu Asn Val Asn Arg Arg Glu Ile
850 855 860
Leu Ile Asn Asn Phe Lys Tyr Ile Phe Ser His Leu Val Cys Ser Cys
865 870 875 880
Ser Lys Asp Glu Leu Glu Arg Ala Leu His Tyr Leu Lys Asn Glu Thr
885 890 895
Glu Ile Glu Leu Gly Ser Leu Leu Arg Gln Asp Phe Gln Gly Leu His
900 905 910
Asn Glu Leu Leu Leu Arg Ile Gly Glu His Tyr Gln Gln Val Phe Asn
915 920 925
Gly Leu Ser Ile Leu Ala Ser Phe Ala Ser Ser Asp Asp Pro Tyr Gln
930 935 940
Gly Pro Arg Asp Ile Ile Ser Pro Glu Leu Met Ala Asp Tyr Leu Gln
945 950 955 960
Pro Lys Leu Leu Gly Ile Leu Ala Phe Phe Asn Met Gln Leu Leu Ser
965 970 975
Ser Ser Val Gly Ile Glu Asp Lys Lys Met Ala Leu Asn Ser Leu Met
980 985 990
Ser Leu Met Lys Leu Met Gly Pro Lys His Val Ser Ser Val Arg Val
995 1000 1005
Lys Met Met Thr Thr Leu Arg Thr Gly Leu Arg Phe Lys Asp Asp Phe
1010 1015 1020
Pro Glu Leu Cys Cys Arg Ala Trp Asp Cys Phe Val Arg Cys Leu Asp
1025 1030 1035 1040
His Ala Cys Leu Gly Ser Leu Leu Ser His Val Ile Val Ala Leu Leu
1045 1050 1055
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Pro Leu Ile His Ile Gln Pro Lys Glu Thr Ala Ala Ile Phe His Tyr
1060 1065 1070
Leu Ile Ile Glu Asn Arg Asp Ala Val Gln Asp Phe Leu His Glu Ile
1075 1080 1085
Tyr Phe Leu Pro Asp His Pro Glu Leu Lys Lys Ile Lys Ala Val Leu
1090 1095 1100
Gln Glu Tyr Arg Lys Glu Thr Ser Glu Ser Thr Asp Leu Gln Thr Thr
1105 1110 1115 1120
Leu Gln Leu Ser Met Lys Ala Ile Gln His Giu Asn Val Asp Val Arg
1125 1130 1135
Ile His Ala Leu Thr Ser Leu Lys Glu Thr Leu Tyr Lys Asn Gln Glu
1140 1145 1150
Lys Leu Ile Lys Tyr Ala Thr Asp Ser Glu Thr Val Glu Pro Ile Ile
1155 1160 1165
Ser Gln Leu Val Thr Val Leu Leu Lys Gly Cys Gln Asp Ala Asn Ser
1170 1175 1180
Gln Ala Arg Leu Leu Cys Gly Glu Cys Leu Gly Glu Leu Gly Ala Ile
1185 1190 1195 1200
Asp Pro Gly Arg Leu Asp Phe Ser Thr Thr Glu Thr Gln Gly Lys Asp
1205 1210 1215
Phe Thr Phe Val Thr Gly Val Glu Asp Ser Ser Phe Ala Tyr Gly Leu
1220 1225 1230
Leu Met Glu Leu Thr Arg Ala Tyr Leu Ala Tyr Ala Asp Asn Ser Arg
1235 1240 1245
Ala Gln Asp Ser Ala Ala Tyr Ala Ile Gln Glu Leu Leu Ser Ile Tyr
1250 1255 1260
Asp Cys Arg Glu Met Glu Thr Asn Gly Pro Gly His Gln Leu Trp Arg
1265 1270 1275 1280
Arg Phe Pro Glu His Val Arg Glu Ile Leu Glu Pro His Leu Asn Thr
1285 1290 1295
Arg Tyr Lys Ser Ser Gln Lys Ser Thr Asp Trp Ser Gly Val Lys Lys
1300 1305 1310
Pro Ile Tyr Leu Ser Lys Leu Gly Ser Asn Phe Ala Glu Trp Ser Ala
1315 1320 1325
Ser Trp Ala Gly Tyr Leu Ile Thr Lys Val Arg His Asp Leu Ala Ser
1330 1335 1340
Lys Ile Phe Thr Cys Cys Ser Ile Met Met Lys His Asp Phe Lys Val
1345 1350 1355 1360
Thr Ile Tyr Leu Leu Pro His Ile Leu Val Tyr Val Leu Leu Gly Cys
1365 1370 1375
Asn Gln Glu Asp Gin Gln Glu Val Tyr Ala Glu Ile Met Ala Val Leu
1380 1385 1390
Lys His Asp Asp Gln His Thr Ile Asn Thr G1n Asp Ile Ala Ser Asp
1395 1400 1405
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Leu Cys Gln Leu Ser Thr Gln Thr Val Phe Ser Met Leu Asp His Leu
1410 1415 1420
Thr Gln Trp Ala Arg His Lys Phe Gin Ala Leu Lys Ala Glu Lys Cys
1425 1430 1435 1440
Pro His Ser Lys Ser Asn Arg Asn Lys Val Asp Ser Met Val Ser Thr
1445 1450 1455
Val Asp Tyr Glu Asp Tyr Gln Ser Val Thr Arg Phe Leu Asp Leu Ile
1460 1465 1470
Pro Gln Asp Thr Leu Ala Val Ala Ser Phe Arg Ser Lys Ala Tyr Thr
1475 1480 1485
Arg Ala Val Met His Phe Glu Ser Phe Ile Thr Glu Lys Lys Gin Asn
1490 1495 1500
Ile Gln Glu His Leu Gly Phe Leu Gln Lys Leu Tyr Ala Ala Met His
1505 1510 1515 1520
Glu Pro Asp Gly Val Ala Gly Val Ser Ala Ile Arg Lys Ala Glu Pro
1525 1530 1535
Ser Leu Lys Glu Gln Ile Leu Glu His Glu Ser Leu Gly Leu Leu Arg
1540 1545 1550
Asp Ala Thr Ala Cys Tyr Asp Arg Ala Ile Gln Leu Glu Pro Asp Gln
1555 1560 1565
Ile Ile His Tyr His Gly Val Val Lys Ser Met Leu Gly Leu Gly Gln
1570 1575 1580
Leu Ser Thr Val Ile Thr Gin Val Asn Gly Val His Ala Asn Arg Ser
1585 1590 1595 1600
Glu Trp Thr Asp Glu Leu Asn Thr Tyr Arg Val Glu Ala Ala Trp Lys
1605 1610 1615
Leu Ser Gln Trp Asp Leu Val Glu Asn Tyr Leu Ala Ala Asp Gly Lys
1620 1625 1630
Ser Thr Thr Trp Ser Val Arg Leu Gly Gln Leu Leu Leu Ser Ala Lys
1635 1640 1645
Lys Arg Asp Ile Thr Ala Phe Tyr Asp Ser Leu Lys Leu Val Arg Ala
1650 1655 1660
Glu Gln Ile Val Pro Leu Ser Ala Ala Ser Phe Glu Arg Gly Ser Tyr
1665 1670 1675 1680
Gln Arg Gly Tyr Glu Tyr Ile Val Arg Leu His Met Leu Cys Glu Leu
1685 1690 1695
Glu His Ser Ile Lys Pro Leu Phe Gln His Ser Pro Gly Asp Ser Ser
1700 1705 1710
Gln Glu Asp Ser Leu Asn Trp Val Ala Arg Leu Glu Met Thr Gln Asn
1715 1720 1725
Ser Tyr Arg Ala Lys Glu Pro Ile Leu Ala Leu Arg Arg Ala Leu Leu
1730 1735 1740
Ser Leu Asn Lys Arg Pro Asp Tyr Asn Glu Met Val Gly Glu Cys Trp
1745 1750 1755 1760
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Leu Gln Ser Ala Arg Val Ala Arg Lys Ala Gly His His Gln Thr Ala
1765 1770 1775
Tyr Asn Ala Leu Leu Asn Ala Gly Glu Ser Arg Leu Ala Glu Leu Tyr
1780 1785 1790
Val Glu Arg Ala Lys Trp Leu Trp Ser Lys Gly Asp Val His Gln Ala
1795 1800 1805
Leu Ile Val Leu Gln Lys Gly Val Glu Leu Cys Phe Pro Glu Asn Glu
1810 1815 1820
Thr Pro Pro Glu Gly Lys Asn Met Leu Ile His Gly Arg Ala Met Leu
1825 1830 1835 1840
Leu Val Gly Arg Phe Met Glu Glu Thr Ala Asn Phe Glu Ser Asn Ala
1845 1850 1855
Ile Met Lys Lys Tyr Lys Asp Val Thr Ala Cys Leu Pro Glu Trp Glu
1860 1865 1870
Asp Gly His Phe Tyr Leu Ala Lys Tyr Tyr Asp Lys Leu Met Pro Met
1875 1880 1885
Val Thr Asp Asn Lys Met Glu Lys Gln Gly Asp Leu Ile Arg Tyr Ile
1890 1895 1900
Val Leu His Phe Gly Arg Ser Leu Gln Tyr Gly Asn Gln Phe Ile Tyr
1905 1910 1915 1920
Gln Ser Met Pro Arg Met Leu Thr Leu Trp Leu Asp Tyr Gly Thr Lys
1925 1930 1935
Ala Tyr Glu Trp Glu Lys Ala Gly Arg Ser Asp Arg Val Gln Met Arg
1940 1945 1950
Asn Asp Leu Gly Lys Ile Asn Lys Val Ile Thr Giu His Thr Asn Tyr
1955 1960 1965
Leu Ala Pro Tyr Gln Phe Leu Thr Ala Phe Ser Gln Leu Ile Ser Arg
1970 1975 1980
Ile Cys His Ser His Asp Glu Val Phe Val Val Leu Met Glu Ile Ile
1985 1990 1995 2000
Ala Lys Val Phe Leu Ala Tyr Pro Gln Gln Ala Met Trp Met Met Thr
2005 2010 2015
Ala Val Ser Lys Ser Ser Tyr Pro Met Arg Val Asn Arg Cys Lys Glu
2020 2025 2030
Ile Leu Asn Lys Ala Ile His Met Lys Lys Ser Leu Glu Lys Phe Val
2035 2040 2045
Gly Asp Ala Thr Arg Leu Thr Asp Lys Leu Leu Glu Leu Cys Asn Lys
2050 2055 2060
Pro Val Glu Ile Leu Ala Ser Leu Gln Lys Pro Lys Lys Ile Ser Leu
2065 2070 2075 2080
Lys Gly Ser Asp Gly Lys Phe Tyr Ile Met Met Cys Lys Pro Lys Asp
2085 2090 2095
Asp Leu Arg Lys Asp Cys Arg Leu Met Glu Phe Asn Ser Leu Ile Asn
2100 2105 2110
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Lys Cys Leu Arg Lys Asp Ala Glu Ser Arg Arg Arg Glu Leu His Ile
2115 2120 2125
Arg Thr Tyr Ala Val Ile Pro Leu Asn Asp Glu Cys Gly Ile Ile Glu
2130 2135 2140
Trp Val Asn Asn Thr Ala Gly Leu Arg Pro Ile Leu Thr Lys Leu Tyr
2145 2150 2155 2160
Lys Glu Lys Gly Val Tyr Met Thr Gly Lys Glu Leu Arg Gin Cys Met
2165 2170 2175
Leu Pro Lys Ser Ala Ala Leu Ser Glu Lys Leu Lys Val Phe Arg Glu
2180 2185 2190
Phe Leu Leu Pro Arg His Pro Pro Ile Phe His Glu Trp Phe Leu Arg
2195 2200 2205
Thr Phe Pro Asp Pro Thr Ser Trp Tyr Ser Ser Arg Ser Ala Tyr Cys
2210 2215 2220
Arg Ser Thr Ala Val Met Ser Met Val Gly Tyr Ile Leu Gly Leu Gly
2225 2230 2235 2240
Asp Arg His Gly Glu Asn Ile Leu Phe Asp Ser Leu Thr Gly Glu Cys
2245 2250 2255
Val His Val Asp Phe Asn Cys Leu Phe Asn Lys Gly Glu Thr Phe Glu
2260 2265 2270
Val Pro Glu Ile Val Pro Phe Arg Leu Thr His Asn Met Val Asn Gly
2275 2280 2285
Met Gly Pro Met Gly Thr Glu Gly Leu Phe Arg Arg Ala Cys Glu Val
2290 2295 2300
Thr Met Arg Leu Met Arg Asp Gln Arg Glu Pro Leu Met Ser Val Leu
2305 2310 2315 2320
Lys Thr Phe Leu His Asp Pro Leu Val Glu Trp Ser Lys Pro Val Lys
2325 2330 2335
Gly His Ser Lys Ala Pro Leu Asn Glu Thr Gly Glu Val Val Asn Glu
2340 2345 2350
Lys Ala Lys Thr His Val Leu Asp Ile Glu Gln Arg Leu Gln Gly Val
2355 2360 2365
Ile Lys Thr Arg Asn Arg Val Thr Gly Leu Pro Leu Ser Ile Glu Gly
2370 2375 2380
His Val His Tyr Leu Ile Gln Glu Ala Thr Asp Glu Asn Leu Leu Cys
2385 2390 2395 2400
Gln Met Tyr Leu Gly Trp Thr Pro Tyr Met
2405 2410
(2) INFORMATION FOR SEQ ID NO:32:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 7502 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
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(ii) MOLECULE TYPE: cDNA
(ix) FEATURE:
(A) NAME/KEY: CDS
(B) LOCATION: 1..7440
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:32:
ATG GGT CAT GCT GTG GAA TGG CCA GTG GTC ATG AGC CGA TTT TTA AGT 48
Met Gly His Ala Val Glu Trp Pro Val Val Met Ser Arg Phe Leu Ser
1 5 10 15
CAA TTA GAT GAA CAC ATG GGA TAT TTA CAA TCA GCT CCT TTG CAG TTG 96
Gln Leu Asp Glu His Met Gly Tyr Leu Gln Ser Ala Pro Leu Gln Leu
20 25 30
ATG AGT ATG CAA AAT TTA GAA TTT ATT GAA GTC ACT TTA TTA ATG GTT 144
Met Ser Met Gln Asn Leu Glu Phe Ile Glu Val Thr Leu Leu Met Val
35 40 45
CTT ACT CGT ATT ATT GCA ATT GTG TTT TTT AGA AGG CAA GAA CTC TTA 192
Leu Thr Arg Ile Ile Ala Ile Val Phe Phe Arg Arg Gln Glu Leu Leu
50 55 60
CTT TGG CAG ATA GGT TGT GTT CTG CTA GAG TAT GGT AGT CCA AAA ATT 240
Leu Trp Gln Ile Gly Cys Val Leu Leu Glu Tyr Gly Ser Pro Lys Ile
65 70 75 80
AAA TCC CTA GCA ATT AGC TTT TTA ACA GAA CTT TT'T CAG CTT GGA GGA 288
Lys Ser Leu Ala Ile Ser Phe Leu Thr Glu Leu Phe Gln Leu Gly Gly
85 90 95
CTA CCA GCA CAA CCA GCT AGC ACT TTT TTC AGC TCA TTT TTG GAA TTA 336
Leu Pro Ala Gln Pro Ala Ser Thr Phe Phe Ser Ser Phe Leu Glu Leu
100 105 110
TTA AAA CAC CTT GTA GAA ATG GAT ACT GAC CAA TTG AAA CTC TAT GAA 384
Leu Lys His Leu Val Glu Met Asp Thr Asp Gln Leu Lys Leu Tyr Glu
115 120 125
GAG CCA TTA TCA AAG CTG ATA AAG ACA CTA TTT CCC TTT GAA GCA GAA 432
Glu Pro Leu Ser Lys Leu Ile Lys Thr Leu Phe Pro Phe Glu Ala Glu
130 135 140
GCT TAT AGA AAT ATT GAA CCT GTC TAT TTA AAT ATG CTG CTG GAA AAA 480
Ala Tyr Arg Asn Ile Glu Pro Val Tyr Leu Asn Met Leu Leu Glu Lys
145 150 155 160
CTC TGT GTC ATG TTT GAA GAC GGT GTG CTC ATG CGG CTT AAG TCT GAT 528
Leu Cys Val Met Phe Glu Asp Gly Val Leu Met Arg Leu Lys Ser Asp
165 170 175
TTG CTA AAA GCA GCT TTG TGC CAT TTA CTG CAG TAT TTC CTT AAA TTT 576
Leu Leu Lys Ala Ala Leu Cys His Leu Leu Gln Tyr Phe Leu Lys Phe
180 185 190
GTG CCA GCT GGG TAT GAA TCT GCT TTA CAA GTC AGG AAG GTC TAT GTG 624
Val Pro Ala Gly Tyr Glu Ser Ala Leu Gln Vai Arg Lys Val Tyr Val
195 200 205
AGA AAT ATT TGT AAA GCT CTT TTG GAT GTG CTT GGA ATT GAG GTA GAT 672
Arg Asn Ile Cys Lys Ala Leu Leu Asp Val Leu Gly Ile Glu Val Asp
210 215 220
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GCA GAG TAC TTG TTG GGC CCA CTT TAT GCA GCT TTG AAA ATG GAA AGT 720
Ala Glu Tyr Leu Leu Gly Pro Leu Tyr Ala Ala Leu Lys Met Glu Ser
225 230 235 240
ATG GAA ATC ATT GAG GAG ATT CAA TGC CAA ACT CAA CAG GAA AAC CTC 768
Met Glu Ile ILe Glu Glu Ile Gln Cys Gln Thr Gln Gln Glu Asn Leu
245 250 255
AGC AGT AAT AGT GAT GGA ATA TCA CCC AAA AGG CGT CGT CTC AGC TCG 816
Ser Ser Asn Ser Asp Gly Ile Ser Pro Lys Arg Arg Arg Leu Ser Ser
260 265 270
TCT CTA AAC CCT TCT AAA AGA GCA CCA AAA CAG ACT GAG GAA ATT AAA 864
Ser Leu Asn Pro Ser Lys Arg Ala Pro Lys Gln Thr Glu Glu Ile Lys
275 280 285
CAT GTG GAC ATG AAC CAA AAG AGC ATA TTA TGG AGT GCA CTG AAA CAG 912
His Val Asp Met Asn Gln Lys Ser Ile Leu Trp Ser Ala Leu Lys Gln
290 295 300
AAA GCT GAA TCC CTT CAG ATT TCC C'TT GAA TAC AGT GGC CTA AAG AAT 960
Lys Ala Glu Ser Leu Gln Ile Ser Leu Glu Tyr Ser Gly Leu Lys Asn
305 310 315 320
CCT GTT ATT GAG ATG TTA GAA GGA ATT GCT GTT GTC TTA CAA CTG ACT 1008
Pro Val Ile Glu Met Leu Glu Gly Ile Ala Val Val Leu Gln Leu Thr
325 330 335
GCT CTG TGT ACT GTT CAT TGT TCT CAT CAA AAC ATG AAC TGC CGT ACT 1056
Ala Leu Cys Thr Val His Cys Ser His Gln Asn Met Asn Cys Arg Thr
340 345 350
TTC AAG GAC TGT CAA CAT AAA TCC AAG AAG AAA CCT TCT GTA GTG ATA 1104
Phe Lys Asp Cys Gln His Lys Ser Lys Lys Lys Pro Ser Val Val Ile
355 360 365
ACT TGG ATG TCA TTG GAT TTT TAC ACA AAA GTG CTT AAG AGC TGT AGA 1152
Thr Trp Met Ser Leu Asp Phe Tyr Thr Lys Val Leu Lys Ser Cys Arg
370 375 380
AGT TTG TTA GAA TCT GTT CAG AAA CTG GAC CTG GAG GCA ACC ATT GAT 1200
Ser Leu Leu Glu Ser Val Gln Lys Leu Asp Leu Glu Ala Thr Ile Asp
385 390 395 400
AAG GTG GTG AAA ATT TAT GAT GCT TTG ATT TAT ATG CAA GTA AAC AGT 1248
Lys Val Val Lys Ile Tyr Asp Ala Leu Ile Tyr Met Gln Val Asn Ser
405 410 415
TCA TTT GAA GAT CAT ATC CTG GAA GAT TTA TGT GGA ATG CTC TCA CTT 1296
Ser Phe Glu Asp His Ile Leu Glu Asp Leu Cys Gly Met Leu Ser Leu
420 425 430
CCA TGG ATT TAT TCC CAT TCT GAT GAT GGC TGT TTA AAG TTG ACC ACA 1344
Pro Trp Ile Tyr Ser His Ser Asp Asp Gly Cys Leu Lys Leu Thr Thr
435 440 445
TTT GCC GCT AAT CTT CTA ACA TTA AGC TGT AGG ATT TCA GAT AGC TAT 1392
Phe Ala Ala Asn Leu Leu Thr Leu Ser Cys Arg Ile Ser Asp Ser Tyr
450 455 460
TCA CCA CAG GCA CAA TCA CGA TGT GTG Z"TT CTT CTG ACT CTG TTT CCA 1440
Ser Pro Gln Ala Gln Ser Arg Cys Val Phe Leu Leu Thr Leu Phe Pro
465 470 475 480
AGA AGA ATA TTC CTT GAG TGG AGA ACA GCA GTT TAC AAC TGG GCC CTG 1488
Arg Arg Ile Phe Leu Glu Trp Arg Thr Ala Val Tyr Asn Trp Ala Leu
485 490 495
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CAG AGC TCC CAT GAA GTA ATC CGG GCT AGT TGT GTT AGT GGA TTT TTT 1536
Gln Ser Ser His Glu Val Ile Arg Ala Ser Cys Val Ser Gly Phe Phe
500 505 510
ATC TTA TTG CAG CAG CAG AAT TCT TGT AAC AGA GTT CCC AAG ATT CTT 1584
Ile Leu Leu Gln Gin Gln Asn Ser Cys Asn Arg Val Pro Lys Ile Leu
515 520 525
ATA GAT AAA GTC AAA GAT GAT TCT GAC ATT GTC AAG AAA GAA TTT GCT 1632
Ile Asp Lys Val Lys Asp Asp Ser Asp Ile Val Lys Lys Glu Phe Ala
530 535 540
TCT ATA CTT GGT CAA CTT GTC TGT ACT CTT CAC GGC ATG TTT TAT CTG 1680
Ser Ile Leu Gly Gln Leu Val Cys Thr Leu His Gly Met Phe Tyr Leu
545 550 555 560
ACA AGT TCT TTA ACA GAA CCT TTC TCT GAA CAC GGA CAT GTG GAC CTC 1728
Thr Ser Ser Leu Thr Glu Pro Phe Ser Glu His Gly His Val Asp Leu
565 570 575
TTC TGT AGG AAC TTG AAA GCC ACT TCT CAA CAT GAA TGT TCA TCT TCT 1776
Phe Cys Arg Asn Leu Lys Ala Thr Ser Gln His Glu Cys Ser Ser Ser
580 585 590
CAA CTA AAA GCT TCT GTC TGC AAG CCA TTC CTT TTC CTA CTG AAA AAA 1824
Gln Leu Lys Ala Ser Val Cys Lys Pro Phe Leu Phe Leu Leu Lys Lys
595 600 605
AAA ATA CCT AGT CCA GTA AAA CTT GCT TTC ATA GAT AAT CTA CAT CAT 1872
Lys Ile Pro Ser Pro Val Lys Leu Ala Phe Ile Asp Asn Leu His His
610 615 620
CTT TGT AAG CAT CTT GAT TTT AGA GAA GAT GAA ACA GAT GTA AAA GCA 1920
Leu Cys Lys His Leu Asp Phe Arg Glu Asp Glu Thr Asp Val Lys Ala
625 630 635 640
GTT CTT GGA ACT TTA TTA AAT TTA ATG GAA GAT CCA GAC AAA GAT GTT 1968
Val Leu Gly Thr Leu Leu Asn Leu Met Glu Asp Pro Asp Lys Asp Val
645 650 655
AGA GTG GCT TTT AGT GGA AAT ATC AAG CAC ATA TTG GAA TCC TTG GAC 2016
Arg Val Ala Phe Ser Gly Asn Ile Lys His Ile Leu Glu Ser Leu Asp
660 665 670
TCT GAA GAT GGA T'i'T ATA AAG GAG CTT TTT GTC TTA AGA ATG AAG GAA 2064
Ser Glu Asp Gly Phe Ile Lys Glu Leu Phe Val Leu Arg Met Lys Glu
675 680 685
GCA TAT ACA CAT GCC CAA ATA TCA AGA AAT AAT GAG CTG AAG GAT ACC 2112
Ala Tyr Thr His Ala Gln Ile Ser Arg Asn Asn Glu Leu Lys Asp Thr
690 695 700
TTG ATT CTT ACA ACA GGG GAT ATT GGA AGG GCC GCA AAA GGA GAT TTG 2160
Leu Ile Leu Thr Thr Gly Asp Ile Gly Arg Ala Ala Lys Gly Asp Leu
705 710 715 720
GTA CCA TTT GCA CTC TTA CAC TTA TTG CAT TGT TTG TTA TCC AAG TCA 2208
Val Pro Phe Ala Leu Leu His Leu Leu His Cys Leu Leu Ser Lys Ser
725 730 735
GCA TCT GTC TCT GGA GCA GCA TAC ACA GAA ATT AGA GCT CTG GTT GCA 2256
Ala Ser Val Ser Gly Ala Ala Tyr Thr Glu Ile Arg Ala Leu Val Ala
740 745 750
GCT AAA AGT GTT AAA CTG CAA AGT TTT TTC AGC CAG TAT AAG AAA CCC 2304
Ala Lys Ser Val Lys Leu Gln Ser Phe Phe Ser Gln Tyr Lys Lys Pro
755 760 765
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ATC TGT CAG TTT TTG GTA GAA TCC CTT CAC TCT AGT CAG ATG ACA GCA 2352
Ile Cys Gln Phe Leu Val Glu Ser Leu His Ser Ser Gln Met Thr Ala
770 775 780
CTT CCG AAT ACT CCA TGC CAG AAT GCT GAC GTG CGA AAA CAA GAT GTG 2400
Leu Pro Asn Thr Pro Cys Gln Asn Ala Asp Val Arg Lys Gln Asp Val
785 790 795 800
GCT CAC CAG AGA GAA ATG GCT TTA AAT ACG TTG TCT GAA ATT GCC AAC 2448
Ala His Gln Arg Glu Met Ala Leu Asn Thr Leu Ser Glu Ile Ala Asn
805 810 815
GTT TTC GAC TTT CCT GAT CTT AAT CGT TTT CTT ACT AGG ACA TTA CAA 2496
Val Phe Asp Phe Pro Asp Leu Asn Arg Phe Leu Thr Arg Thr Leu Gln
820 825 830
GTT CTA CTA CCT GAT CTT GCT GCC AAA GCA AGC CCT GCA GCT TCT GCT 2544
Val Leu Leu Pro Asp Leu Ala Ala Lys Ala Ser Pro Ala Ala Ser Ala
835 840 845
CTC ATT CGA ACT TTA GGA AAA CAA TTA AAT GTC AAT CGT AGA GAG ATT 2592
Leu Ile Arg Thr Leu Gly Lys Gln Leu Asn Val Asn Arg Arg Glu Ile
850 855 860
TTA ATA AAC AAC TTC AAA TAT ATT TTT TCT CAT TTG GTC TGT TCT TGT 2640
Leu Ile Asn Asn Phe Lys Tyr Ile Phe Ser His Leu Val Cys Ser Cys
865 870 875 880
TCC AAA GAT GAA TTA GAA CGT GCC CTT CAT TAT CTG AAG AAT GAA ACA 2688
Ser Lys Asp Glu Leu Glu Arg Ala Leu His Tyr Leu Lys Asn Glu Thr
885 890 895
GAA ATT GAA CTG GGG AGC CTG TTG AGA CAA GAT TTC CAA GGA TTG CAT 2736
Glu Ile Glu Leu Gly Ser Leu Leu Arg Gln Asp Phe Gln Gly Leu His
900 905 910
AAT GAA TTA TTG CTG CGT ATT GGA GAA CAC TAT CAA CAG GTT TTT AAT 2784
Asn Giu Leu Leu Leu Arg Ile Gly Glu His Tyr Gln Gln Val Phe Asn
915 920 925
GGT TTG TCA ATA CTT GCC TCA TTT GCA TCC AGT GAT GAT CCA TAT CAG 2832
Gly Leu Ser Ile Leu Ala Ser Phe Ala Ser Ser Asp Asp Pro Tyr Gln
930 935 940
GGC CCG AGA GAT ATC ATA TCA CCT GAA CTG ATG GCT GAT TAT TTA CAA 2880
Gly Pro Arg Asp Ile Ile Ser Pro Glu Leu Met Ala Asp Tyr Leu Gln
945 950 955 960
CCC AAA TTG TTG GGC ATT TTG GCT TTT TTT AAC ATG CAG TTA CTG AGC 2928
Pro Lys Leu Leu Gly Ile Leu Ala Phe Phe Asn Met Gln Leu Leu Ser
965 970 975
TCT AGT GTT GGC ATT GAA GAT AAG AAA ATG GCC TTG AAC AGT TTG ATG 2976
Ser Ser Val Gly Ile Glu Asp Lys Lys Met Ala Leu Asn Ser Leu Met
980 985 990
TCT TTG ATG AAG TTA ATG GGA CCC AAA CAT GTC AGT TCT GTG AGG GTG 3024
Ser Leu Met Lys Leu Met Gly Pro Lys His Val Ser Ser Val Arg Val
995 1000 1005
AAG ATG ATG ACC ACA CTG AGA ACT GGC CTT CGA TTC AAG GAT GAT TTT 3072
Lys Met Met Thr Thr Leu Arg Thr Gly Leu Arg Phe Lys Asp Asp Phe
1010 1015 1020
CCT GAA TTG TGT TGC AGA GCT TGG GAC TGC TTT GTT CGC TGC CTG GAT 3120
Pro Glu Leu Cys Cys Arg Ala Trp Asp Cys Phe Val Arg Cys Leu Asp
1025 1030 1035 1040
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CAT GCT TGT CTG GGC TCC CTT CTC AGT CAT GTA ATA GTA GCT TTG TTA 3168
His Ala Cys Leu Gly Ser Leu Leu Ser His Val Ile Val Ala Leu Leu
1045 1050 1055
CCT CTT ATA CAC ATC CAG CCT AAA GAA ACT GCA GCT ATC TTC CAC TAC 3216
Pro Leu Ile His Ile Gln Pro Lys Glu Thr Ala Ala Ile Phe His Tyr
1060 1065 1070
CTC ATA ATT GAA AAC AGG GAT GCT GTG CAA GAT TTT CTT CAT GAA ATA 3264
Leu Ile Ile Glu Asn Arg Asp Ala Val Gin Asp Phe Leu His Glu Ile
1075 1080 1085
TAT TTT TTA CCT GAT CAT CCA GAA TTA AAA AAG ATA AAA GCC GTT CTC 3312
Tyr Phe Leu Pro Asp His Pro Glu Leu Lys Lys Ile Lys Ala Val Leu
1090 1095 1100
CAG GAA TAC AGA AAG GAG ACC TCT GAG AGC ACT GAT CTT CAG ACA ACT 3360
Gln Glu Tyr Arg Lys Glu Thr Ser Glu Ser Thr Asp Leu Gln Thr Thr
1105 1110 1115 1120
CTT CAG CTC TCT ATG AAG GCC ATT CAA CAT GAA AAT GTC GAT GTT CGT 3408
Leu Gln Leu Ser Met Lys Ala Ile Gln His Glu Asn Val Asp Val Arg
1125 1130 1135
ATT CAT GCT CTT ACA AGC TTG AAG GAA ACC TTG TAT AAA AAT CAG GAA 3456
Ile His Ala Leu Thr Ser Leu Lys Glu Thr Leu Tyr Lys Asn Gln Giu
1140 1145 1150
AAA CTG ATA AAG TAT GCA ACA GAC AGT GAA ACA GTA GAA CCT ATT ATC 3504
Lys Leu Ile Lys Tyr Ala Thr Asp Ser Glu Thr Val Glu Pro Ile Ile
1155 1160 1165
TCA CAG TTG GTG ACA GTG CTT TTG AAA GGT TGC CAA GAT GCA AAC TCT 3552
Ser Gln Leu Val Thr Val Leu Leu Lys Gly Cys Gln Asp Ala Asn Ser
1170 1175 1180
CAA GCT CGG TTG CTC TGT GGG GAA TGT TTA GGG GAA TTG GGG GCG ATA 3600
Gln Ala Arg Leu Leu Cys Gly Glu Cys Leu Gly Glu Leu Gly Ala Ile
1185 1190 1195 1200
GAT CCA GGT CGA TTA GAT TTC TCA ACA ACT GAA ACT CAA GGA AAA GAT 3648
Asp Pro Gly Arg Leu Asp Phe Ser Thr Thr Glu Thr Gln Gly Lys Asp
1205 1210 1215
TTT ACA TTT GTG ACT GGA GTA GAA GAT TCA AGC TTT GCC TAT GGA TTA 3696
Phe Thr Phe Val Thr Gly Val Glu Asp Ser Ser Phe Ala Tyr Gly Leu
1220 1225 1230
TTG ATG GAG CTA ACA AGA GCT TAC CTT GCG TAT GCT GAT AAT AGC CGA 3744
Leu Met Glu Leu Thr Arg Ala Tyr Leu Ala Tyr Ala Asp Asn Ser Arg
1235 1240 1245
GCT CAA GAT TCA GCT GCC TAT GCC ATT CAG GAG TTG CTT TCT ATT TAT 3792
Ala Gln Asp Ser Ala Ala Tyr Ala Ile Gln Glu Leu Leu Ser Ile Tyr
1250 1255 1260
GAC TGT AGA GAG ATG GAG ACC AAC GGC CCA GGT CAC CAA TTG TGG AGG 3840
Asp Cys Arg Glu Met Glu Thr Asn Gly Pro Gly His Gln Leu Trp Arg
1265 1270 1275 1280
AGA TTT CCT GAG CAT GTT CGG GAA ATA CTA GAA CCT CAT CTA AAT ACC 3888
Arg Phe Pro Glu His Val Arg Glu Ile Leu Glu Pro His Leu Asn Thr
1285 1290 1295
AGA TAC AAG AGT TCT CAG AAG TCA ACC GAT TGG TCT GGA GTA AAG AAG 3936
Arg Tyr Lys Ser Ser Gln Lys Ser Thr Asp Trp Ser Gly Val Lys Lys
1300 1305 1310
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CCA ATT TAC TTA AGT AAA TTG GGT AGT AAC TTT GCA GAA TGG TCA GCA 3984
Pro Ile Tyr Leu Ser Lys Leu Gly Ser Asn Phe Ala Glu Trp Ser Ala
1315 1320 1325
TCT TGG GCA GGT TAT CTT ATT ACA AAG GTT CGA CAT GAT CTT GCC AGT 4032
Ser Trp Ala Gly Tyr Leu Ile Thr Lys Val Arg His Asp Leu Ala Ser
1330 1335 1340
AAA ATT TTC ACC TGC TGT AGC ATT ATG ATG AAG CAT GAT TTC AAA GTG 4080
Lys Ile Phe Thr Cys Cys Ser Ile Met Met Lys His Asp Phe Lys Val
1345 1350 1355 1360
ACC ATC TAT CTT CTT CCA CAT ATT CTG GTG TAT GTC TTA CTG GGT TGT 4128
Thr Ile Tyr Leu Leu Pro His Ile Leu Val Tyr Val Leu Leu Gly Cys
1365 1370 1375
AAT CAA GAA GAT CAG CAG GAG GTT TAT GCA GAA ATT ATG GCA GTT CTA 4176
Asn Gln Glu Asp Gln Gin Glu Val Tyr Ala Glu Ile Met Ala Val Leu
1380 1385 1390
AAG CAT GAC GAT CAG CAT ACC ATA AAT ACC CAA GAC ATT GCA TCT GAT 4224
Lys His Asp Asp Gln His Thr Ile Asn Thr Gln Asp Ile Ala Ser Asp
1395 1400 1405
CTG TGT CAA CTC AGT ACA CAG ACT GTG TTC TCC ATG CTT GAC CAT CTC 4272
Leu Cys Gln Leu Ser Thr Gln Thr Val Phe Ser Met Leu Asp His Leu
1410 1415 1420
ACA CAG TGG GCA AGG CAC AAA TTT CAG GCA CTG AAA GCT GAG AAA TGT 4320
Thr Gln Trp Ala Arg His Lys Phe Gln Ala Leu Lys Ala Glu Lys Cys
1425 1430 1435 1440
CCA CAC AGC AAA TCA AAC AGA AAT AAG GTA GAC TCA ATG GTA TCT ACT 4368
Pro His Ser Lys Ser Asn Arg Asn Lys Val Asp Ser Met Val Ser Thr
1445 1450 1455
GTG GAT TAT GAA GAC TAT CAG AGT GTA ACC CGT TTT CTA GAC CTC ATA 4416
Val Asp Tyr Glu Asp Tyr Gln Ser Val Thr Arg Phe Leu Asp Leu Ile
1460 1465 1470
CCC CAG GAT ACT CTG GCA GTA GCT TCC TTT CGC TCC AAA GCA TAC ACA 4464
Pro Gln Asp Thr Leu Ala Val Ala Ser Phe Arg Ser Lys Ala Tyr Thr
1475 1480 1485
CGA GCT GTA ATG CAC TTT GAA TCA TTT ATT ACA GAA AAG AAG CAA AAT 4512
Arg Ala Val Met His Phe Glu Ser Phe Ile Thr Glu Lys Lys Gln Asn
1490 1495 1500
ATT CAG GAA CAT CTT GGA TTT TTA CAG AAA TTG TAT GCT GCT ATG CAT 4560
Ile Gln Giu His Leu Gly Phe Leu Gln Lys Leu Tyr Ala Ala Met His
1505 1510 1515 1520
GAA CCT GAT GGA GTG GCC GGA GTC AGT GCA ATT AGA AAG GCA GAA CCA 4608
Glu Pro Asp Gly Val Ala Gly Val Ser Ala Ile Arg Lys Ala Glu Pro
1525 1530 1535
TCT CTA AAA GAA CAG ATC CTT GAA CAT GAA AGC CTT GGC TTG CTG AGG 4656
Ser Leu Lys Glu Gln Ile Leu Glu His Glu Ser Leu Gly Leu Leu Arg
1540 1545 1550
GAT GCC ACT GCT TGT TAT GAC AGG GCT ATT CAG CTA GAA CCA GAC CAG 4704
Asp Ala Thr Ala Cys Tyr Asp Arg Ala Ile Gln Leu Glu Pro Asp Gln
1555 1560 1565
ATC ATT CAT TAC CAT GGT GTA GTA AAG TCC ATG TTA GGT CTT GGT CAG 4752
Ile Ile His Tyr His Gly Val Val Lys Ser Met Leu Gly Leu Gly Gln
1570 1575 1580
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CTG TCT ACT GTT ATC ACT CAG GTG AAT GGA GTG CAT GCT AAC AGG TCC 4800
Leu Ser Thr Val Ile Thr Gln Val Asn Gly Val His Ala Asn Arg Ser
1585 1590 1595 1600
GAG TGG ACA GAT GAA TTA AAC ACG TAC AGA GTG GAA GCA GCT TGG AAA 4848
Glu Trp Thr Asp Glu Leu Asn Thr Tyr Arg Val Glu Ala Ala Trp Lys
1605 1610 1615
TTG TCA CAG TGG GAT TTG GTG GAA AAC TAT TTG GCA GCA GAT GGA AAA 4896
Leu Ser Gln Trp Asp Leu Val Glu Asn Tyr Leu Ala Ala Asp Gly Lys
1620 1625 1630
TCT ACA ACA TGG AGT GTC AGA CTG GGA CAG CTA TTA TTA TCA GCC AAA 4944
Ser Thr Thr Trp Ser Val Arg Leu Gly Gln Leu Leu Leu Ser Ala Lys
1635 1640 1645
AAA AGA GAT ATC ACA GCT TTT TAT GAC TCA CTG AAA CTA GTG AGA GCA 4992
Lys Arg Asp Ile Thr Ala Phe Tyr Asp Ser Leu Lys Leu Val Arg Ala
1650 1655 1660
GAA CAA ATT GTA CCT CTT TCA GCT GCA AGC TTT GAA AGA GGC TCC TAC 5040
Glu Gln Ile Val Pro Leu Ser Ala Ala Ser Phe Glu Arg Gly Ser Tyr
1665 1670 1675 1680
CAA CGA GGA TAT GAA TAT ATT GTG AGA TTG CAC ATG TTA TGT GAG TTG 5088
Gln Arg Gly Tyr Glu Tyr Ile Val Arg Leu His Met Leu Cys Glu Leu
1685 1690 1695
GAG CAT AGC ATC AAA CCA CTT TTC CAG CAT TCT CCA GGT GAC AGT TCT 5136
Glu His Ser Ile Lys Pro Leu Phe Gln His Ser Pro Gly Asp Ser Ser
1700 1705 1710
CAA GAA GAT TCT CTA AAC TGG GTA GCT CGA CTA GAA ATG ACC CAG AAT 5184
Gln Glu Asp Ser Leu Asn Trp Val Ala Arg Leu Glu Met Thr Gln Asn
1715 1720 1725
TCC TAC AGA GCC AAG GAG CCT ATC CTG GCT CTC CGG AGG GCT TTA CTA 5232
Ser Tyr Arg Ala Lys Glu Pro Ile Leu Ala Leu Arg Arg Ala Leu Leu
1730 1735 1740
AGC CTC AAC AAA AGA CCA GAT TAC AAT GAA ATG GTT GGA GAA TGC TGG 5280
Ser Leu Asn Lys Arg Pro Asp Tyr Asn Glu Met Val Gly Glu Cys Trp
1745 1750 1755 1760
CTG CAG AGT GCC AGG GTA GCT AGA AAG GCT GGT CAC CAC CAG ACA GCC 5328
Leu Gln Ser Ala Arg Val Ala Arg Lys Ala Gly His His Gln Thr Ala
1765 1770 1775
TAC AAT GCT CTC CTT AAT GCA GGG GAA TCA CGA CTC GCT GAA CTG TAC 5376
Tyr Asn Ala Leu Leu Asn Ala Gly Glu Ser Arg Leu Ala Glu Leu Tyr
1780 1785 1790
GTG GAA AGG GCA AAG TGG CTC TGG TCC AAG GGT GAT GTT CAC CAG GCA 5424
Val Glu Arg Ala Lys Trp Leu Trp Ser Lys Gly Asp Val His Gln Ala
1795 1800 1805
CTA ATT GTT CTT CAA AAA GGT GTT GAA TTA TGT TTT CCT GAA AAT GAA 5472
Leu Ile Val Leu Gln Lys Gly Val Glu Leu Cys Phe Pro Glu Asn Glu
1810 1815 1820
ACC CCA CCT GAG GGT AAG AAC ATG TTA ATC CAT GGT CGA GCT ATG CTA 5520
Thr Pro Pro Glu Gly Lys Asn Met Leu Ile His Gly Arg Ala Met Leu
1825 1830 1835 1840
CTA GTG GGC CGA TTT ATG GAA GAA ACA GCT AAC TTT GAA AGC AAT GCA 5568
Leu Val Gly Arg Phe Met Glu Glu Thr Ala Asn Phe Glu Ser Asn Ala
1845 1850 1855
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ATT ATG AAA AAA TAT AAG GAT GTG ACC GCG TGC CTG CCA GAA TGG GAG 5616
Ile Met Lys Lys Tyr Lys Asp Val Thr Ala Cys Leu Pro Glu Trp Glu
1860 1865 1870
GAT GGG CAT TTT TAC CTT GCC AAG TAC TAT GAC AAA TTG ATG CCC ATG 5664
Asp Gly His Phe Tyr Leu Ala Lys Tyr Tyr Asp Lys Leu Met Pro Met
1875 1880 1885
GTC ACA GAC AAC AAA ATG GAA AAG CAA GGT GAT CTC ATC CGG TAT ATA 5712
Val Thr Asp Asn Lys Met Glu Lys Gln Gly Asp Leu Ile Arg Tyr Ile
1890 1895 1900
GTT CTT CAT TTT GGC AGA TCT CTA CAA TAT GGA AAT CAG TTC ATA TAT 5760
Val Leu His Phe Gly Arg Ser Leu Gln Tyr Gly Asn Gln Phe Ile Tyr
1905 1910 1915 1920
CAG TCA ATG CCA CGA ATG TTA ACT CTA TGG CTT GAT TAT GGT ACA AAG 5808
Gln Ser Met Pro Arg Met Leu Thr Leu Trp Leu Asp Tyr Gly Thr Lys
1925 1930 1935
GCA TAT GAA TGG GAA AAA GCT GGC CGC TCC GAT CGT GTA CAA ATG AGG 5856
Ala Tyr Glu Trp Glu Lys Ala Gly Arg Ser Asp Arg Val Gln Met Arg
1940 1945 1950
AAT GAT TTG GGT AAA ATA AAC AAG GTT ATC ACA GAG CAT ACA AAC TAT 5904
Asn Asp Leu Gly Lys Ile Asn Lys Val Ile Thr Glu His Thr Asn Tyr
1955 1960 1965
TTA GCT CCA TAT CAA TTT TTG ACT GCT TTT TCA CAA TTG ATC TCT CGA 5952
Leu Ala Pro Tyr Gln Phe Leu Thr Ala Phe Ser Gln Leu Ile Ser Arg
1970 1975 1980
ATT TGT CAT TCT CAC GAT GAA GTT TTT GTT GTC TTG ATG GAA ATA ATA 6000
Ile Cys His Ser His Asp Glu Val Phe Val Val Leu Met Glu Ile Ile
1985 1990 1995 2000
GCC AAA GTA TTT CTA GCC TAT CCT CAA CAA GCA ATG TGG ATG ATG ACA 6048
Ala Lys Val Phe Leu Ala Tyr Pro Gln Gln Ala Met Trp Met Met Thr
2005 2010 2015
GCT GTG TCA AAG TCA TCT TAT CCC ATG CGT GTG AAC AGA TGC AAG GAA 6096
Ala Val Ser Lys Ser Ser Tyr Pro Met Arg Val Asn Arg Cys Lys Glu
2020 2025 2030
ATC CTC AAT AAA GCT ATT CAT ATG AAA AAA TCC TTA GAG AAG TTT GTT 6144
Ile Leu Asn Lys Ala Ile His Met Lys Lys Ser Leu Glu Lys Phe Val
2035 2040 2045
GGA GAT GCA ACT CGC CTA ACA GAT AAG CTT CTA GAA TTG TGC AAT AAA 6192
Gly Asp Ala Thr Arg Leu Thr Asp Lys Leu Leu Glu Leu Cys Asn Lys
2050 2055 2060
CCG GTT GAT GGA AGT AGT TCC ACA TTA AGC ATG AGC ACT CAT TTT AAA 6240
Pro Val Asp Gly Ser Ser Ser Thr Leu Ser Met Ser Thr His Phe Lys
2065 2070 2075 2080
ATG CTT AAA AAG CTG GTA GAA GAA GCA ACA TTT AGT GAA ATC CTC ATT 6288
Met Leu Lys Lys Leu Val Glu Glu Ala Thr Phe Ser Glu Ile Leu Ile
2085 2090 2095
CCT CTA CAA TCA GTC ATG ATA CCT ACA CTT CCA TCA ATT CTG GGT ACC 6336
Pro Leu Gln Ser Val Met Ile Pro Thr Leu Pro Ser Ile Leu Gly Thr
2100 2105 2110
CAT GCT AAC CAT GCT AGC CAT GAA CCA TTT CCT GGA CAT TGG GCC TAT 6384
His Ala Asn His Ala Ser His Glu Pro Phe Pro Gly His Trp Ala Tyr
2115 2120 2125
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ATT GCA GGG TTT GAT GAT ATG GTG GAA ATT CTT GCT TCT CTT CAG AAA 6432
Ile Ala Gly Phe Asp Asp Met Val Glu Ile Leu Ala Ser Leu Gln Lys
2130 2135 2140
CCA AAG AAG ATT TCT TTA AAA GGC TCA GAT GGA AAG TTC TAC ATC ATG 6480
Pro Lys Lys Ile Ser Leu Lys Gly Ser Asp Gly Lys Phe Tyr Ile Met
2145 2150 2155 2160
ATG TGT AAG CCA AAA GAT GAC CTG AGA AAG GAT TGT AGA CTA ATG GAA 6528
Met Cys Lys Pro Lys Asp Asp Leu Arg Lys Asp Cys Arg Leu Met Glu
2165 2170 2175
TTC AAT TCC TTG ATT AAT AAG TGC TTA AGA AAA GAT GCA GAG TCT CGT 6576
Phe Asn Ser Leu Ile Asn Lys Cys Leu Arg Lys Asp Ala Glu Ser Arg
2180 2185 2190
AGA AGA GAA CTT CAT ATT CGA ACA TAT GCA GTT ATT CCA CTA AAT GAT 6624
Arg Arg Glu Leu His Ile Arg Thr Tyr Ala Val Ile Pro Leu Asn Asp
2195 2200 2205
GAA TGT GGG ATT ATT GAA TGG GTG AAC AAC ACT GCT GGT TTG AGA CCT 6672
Glu Cys Gly Ile Ile Glu Trp Val Asn Asn Thr Ala Gly Leu Arg Pro
2210 2215 2220
ATT CTG ACC AAA CTA TAT AAA GAA AAG GGA GTG TAT ATG ACA GGA AAA 6720
Ile Leu Thr Lys Leu Tyr Lys Glu Lys Gly Val Tyr Met Thr Gly Lys
2225 2230 2235 2240
GAA CTT CGC CAG TGT ATG CTA CCA AAG TCA GCA GCT TTA TCT GAA AAA 6768
Glu Leu Arg Gln Cys Met Leu Pro Lys Ser Ala Ala Leu Ser Glu Lys
2245 2250 2255
CTC AAA GTA TTC CGA GAA TTT CTC CTG CCC AGG CAT CCT CCT ATT TTT 6816
Leu Lys Val Phe Arg Glu Phe Leu Leu Pro Arg His Pro Pro Ile Phe
2260 2265 2270
CAT GAG TGG TTT CTG AGA ACA TTC CCT GAT CCT ACA TCA TGG TAC AGT 6864
His Glu Trp Phe Leu Arg Thr Phe Pro Asp Pro Thr Ser Trp Tyr Ser
2275 2280 2285
AGT AGA TCA GCT TAC TGC CGT TCC ACT GCA GTA ATG TCA ATG GTT GGT 6912
Ser Arg Ser Ala Tyr Cys Arg Ser Thr Ala Val Met Ser Met Val Gly
2290 2295 2300
TAT ATT CTG GGG CTT GGA GAC CGT CAT GGT GAA AAT ATT CTC TTT GAT 6960
Tyr Ile Leu Gly Leu Gly Asp Arg His Gly Glu Asn Ile Leu Phe Asp
2305 2310 2315 2320
TCT TTG ACT GGT GAA TGC GTA CAT GTA GAT TTC AAT TGT CTT TTC AAT 7008
Ser Leu Thr Gly Glu Cys Val His Val Asp Phe Asn Cys Leu Phe Asn
2325 2330 2335
AAG GGA GAA ACC TTT GAA GTT CCA GAA ATT GTG CCA TTT CGC CTG ACT 7056
Lys Gly Glu Thr Phe Glu Val Pro Glu Ile Val Pro Phe Arg Leu Thr
2340 2345 2350
CAT AAT ATG GTT AAT GGA ATG GGT CCT ATG GGA ACA GAG GGT CTT TTT 7104
His Asn Met Val Asn Gly Met Gly Pro Met Gly Thr Glu Giy Leu Phe
2355 2360 2365
CGA AGA GCA TGT GAA GTT ACA ATG AGG CTG ATG CGT GAT CAG CGA GAG 7152
Arg Arg Ala Cys Glu Val Thr Met Arg Leu Met Arg Asp Gln Arg Glu
2370 2375 2380
CCT TTA ATG AGT GTC TTA AAG ACT TTT CTA CAT GAT CCT CTT GTG GAA 7200
Pro Leu Met Ser Val Leu Lys Thr Phe Leu His Asp Pro Leu Val Glu
2385 2390 2395 2400
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TGG AGT AAA CCA GTG AAA GGG CAT TCC AAA GCG CCA CTG AAT GAA ACT 7248
Trp Ser Lys Pro Val Lys Gly His Ser Lys Ala Pro Leu Asn Glu Thr
2405 2410 2415
GGA GAA GTT GTC AAT GAA AAG GCC AAG ACC CAT GTT CTT GAC ATT GAG 7296
Gly Glu Val Val Asn Glu Lys Ala Lys Thr His Val Leu Asp Ile Glu
2420 2425 2430
CAG CGA CTA CAA GGT GTA ATC AAG ACT CGA AAT AGA GTG ACA GGA CTG 7344
Gln Arg Leu Gin Gly Val Ile Lys Thr Arg Asn Arg Val Thr Gly Leu
2435 2440 2445
CCG TTA TCT ATT GAA GGA CAT GTG CAT TAC CTT ATA CAA GAA GCT ACT 7392
Pro Leu Ser Ile Glu Gly His Val His Tyr Leu Ile Gln Glu Ala Thr
2450 2455 2460
GAT GAA AAC TTA CTA TGC CAG ATG TAT CTT GGT TGG ACT CCA TAT ATG 7440
Asp Glu Asn Leu Leu Cys Gln Met Tyr Leu Gly Trp Thr Pro Tyr Met
2465 2470 2475 2480
TGAAATGAAA TTATGTAAAA GAATATGTTA ATAATCTAAA AGTAAAAAAA AAAAAAAAAA 7500
AA 7502
(2) INFORMATION FOR SEQ ID NO:33:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2480 amino acids
(B) TYPE: amino acid
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: protein
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:33:
Met Gly His Ala Val Glu Trp Pro Val Val Met Ser Arg Phe Leu Ser
1 5 10 15
Gln Leu Asp Glu His Met Gly Tyr Leu Gin Ser Ala Pro Leu Gln Leu
20 25 30
Met Ser Met Gln Asn Leu Glu Phe Ile Glu Val Thr Leu Leu Met Val
35 40 45
Leu Thr Arg Ile Ile Ala Ile Val Phe Phe Arg Arg Gin Glu Leu Leu
50 55 60
Leu Trp Gln Ile Gly Cys Val Leu Leu Glu Tyr Gly Ser Pro Lys Ile
65 70 75 80
Lys Ser Leu Ala Ile Ser Phe Leu Thr Glu Leu Phe Gln Leu Gly Gly
85 90 95
Leu Pro Ala Gln Pro Ala Ser Thr Phe Phe Ser Ser Phe Leu Glu Leu
100 105 110
Leu Lys His Leu Val Glu Met Asp Thr Asp Gln Leu Lys Leu Tyr Glu
115 120 125
Glu Pro Leu Ser Lys Leu Ile Lys Thr Leu Phe Pro Phe Glu Ala Glu
130 135 140
Ala Tyr Arg Asn Ile Glu Pro Val Tyr Leu Asn Met Leu Leu Glu Lys
145 15D 155 160
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Leu Cys Val Met Phe Glu Asp Gly Val Leu Met Arg Leu Lys Ser Asp
165 170 175
Leu Leu Lys Ala Ala Leu Cys His Leu Leu Gin Tyr Phe Leu Lys Phe
180 185 190
Val Pro Ala Gly Tyr Glu Ser Ala Leu Gln Val Arg Lys Val Tyr Val
195 200 205
Arg Asn Ile Cys Lys Ala Leu Leu Asp Val Leu Gly Ile Glu Val Asp
210 215 220
Ala Glu Tyr Leu Leu Gly Pro Leu Tyr Ala Ala Leu Lys Met Glu Ser
225 230 235 240
Met Glu Ile Ile Glu Glu Ile Gin Cys Gln Thr Gln Gin Glu Asn Leu
245 250 255
Ser Ser Asn Ser Asp Gly Ile Ser Pro Lys Arg Arg Arg Leu Ser Ser
260 265 270
Ser Leu Asn Pro Ser Lys Arg Ala Pro Lys Gln Thr Glu Glu Ile Lys
275 280 285
His Val Asp Met Asn Gln Lys Ser Ile Leu Trp Ser Ala Leu Lys Gln
290 295 300
Lys Ala Glu Ser Leu Gln Ile Ser Leu Glu Tyr Ser Gly Leu Lys Asn
305 310 315 320
Pro Val Ile Glu Met Leu Glu Gly Ile Ala Val Val Leu Gln Leu Thr
325 330 335
Ala Leu Cys Thr Val His Cys Ser His Gln Asn Met Asn Cys Arg Thr
340 345 350
Phe Lys Asp Cys Gln His Lys Ser Lys Lys Lys Pro Ser Val Val Ile
355 360 365
Thr Trp Met Ser Leu Asp Phe Tyr Thr Lys Val Leu Lys Ser Cys Arg
370 375 380
Ser Leu Leu Glu Ser Val Gln Lys Leu Asp Leu Glu Ala Thr Ile Asp
385 390 395 400
Lys Val Val Lys Ile Tyr Asp Ala Leu Ile Tyr Met Gln Val Asn Ser
405 410 415
Ser Phe Glu Asp His Ile Leu Glu Asp Leu Cys Gly Met Leu Ser Leu
420 425 430
Pro Trp Ile Tyr Ser His Ser Asp Asp Giy Cys Leu Lys Leu Thr Thr
435 440 445
Phe Ala Ala Asn Leu Leu Thr Leu Ser Cys Arg Ile Ser Asp Ser Tyr
450 455 460
Ser Pro Gln Ala Gln Ser Arg Cys Val Phe Leu Leu Thr Leu Phe Pro
465 470 475 480
Arg Arg Ile Phe Leu Glu Trp Arg Thr Ala Val Tyr Asn Trp Ala Leu
485 490 495
Gln Ser Ser His Glu Val Ile Arg Ala Ser Cys Val Ser Gly Phe Phe
500 505 510
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Ile Leu Leu Gln Gln Gln Asn Ser Cys Asn Arg Val Pro Lys Ile Leu
515 520 525
Ile Asp Lys Val Lys Asp Asp Ser Asp Ile Val Lys Lys Glu Phe Ala
530 535 540
Ser Ile Leu Gly Gln Leu Val Cys Thr Leu His Gly Met Phe Tyr Leu
545 550 555 560
Thr Ser Ser Leu Thr Glu Pro Phe Ser Glu His Gly His Val Asp Leu
565 570 575
Phe Cys Arg Asn Leu Lys Ala Thr Ser Gln His Glu Cys Ser Ser Ser
580 585 590
Gln Leu Lvs Ala Ser Val Cys Lys Pro Phe Leu Phe Leu Leu Lys Lys
595 600 605
Lys Ile Pxo Ser Pro Val Lys Leu Ala Phe Ile Asp Asn Leu His His
610 615 620
Leu Cys Lys His Leu Asp Phe Arg Glu Asp Glu Thr Asp Val Lys Ala
625 630 635 640
Val Leu Gly Thr Leu Leu Asn Leu Met Glu Asp Pro Asp Lys Asp Val
645 650 655
Arg Val Ala Phe Ser Gly Asn Ile Lys His Ile Leu Glu Ser Leu Asp
660 665 670
Ser Glu Asp Gly Phe Ile Lys Glu Leu Phe Val Leu Arg Met Lys Glu
6?5 680 685
Ala Tyr Thr His Ala Gln Ile Ser Arg Asn Asn Glu Leu Lys Asp Thr
690 695 700
Leu Ile Leu Thr Thr Gly Asp Ile Gly Arg Ala Ala Lys Gly Asp Leu
705 710 715 720
Val Pro Phe Ala Leu Leu His Leu Leu His Cys Leu Leu Ser Lys Ser
725 730 735
Ala Ser Val Ser Gly Ala Ala Tyr Thr Glu Ile Arg Ala Leu Val Ala
740 745 750
Ala Lys Ser Val Lys Leu Gln Ser Phe Phe Ser Gln Tyr Lys Lys Pro
755 760 765
Ile Cys Gln Phe Leu Val Glu Ser Leu His Ser Ser Gln Met Thr Ala
770 775 780
Leu Pro Asn Thr Pro Cys Gln Asn Ala Asp Val Arg Lys Gln Asp Val
785 790 795 800
Ala His Gln Arg Glu Met Ala Leu Asn Thr Leu Ser Glu Ile Ala Asn
805 910 815
Val Phe Asp Phe Pro Asp Leu Asn Arg Phe Leu Thr Arg Thr Leu Gln
820 825 830
Val Leu Leu Pro Asp Leu Ala Ala Lys Ala Ser Pro Ala Ala Ser Ala
835 840 845
Leu Ile Arg Thr Leu Gly Lys Gln Leu Asn Val Asn Arg Arg Glu Ile
850 855 860
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Leu Ile Asn Asn Phe Lys Tyr Ile Phe Ser His Leu Val Cys Ser Cys
865 870 875 880
Ser Lys Asp Glu Leu Glu Arg Ala Leu His Tyr Leu Lys Asn Glu Thr
885 890 895
Glu Ile Glu Leu Gly Ser Leu Leu Arg Gln Asp Phe Gln Gly Leu His
900 905 910
Asn Glu Leu Leu Leu Arg Ile Gly Glu His Tyr Gln Gln Val Phe Asn
915 920 925
Gly Leu Ser Ile Leu Ala Ser Phe Ala Ser Ser Asp Asp Pro Tyr Gln
930 935 940
Gly Pro Arg Asp Ile Ile Ser Pro Glu Leu Met Ala Asp Tyr Leu Gln
945 950 955 960
Pro Lys Leu Leu Gly Ile Leu Ala Phe Phe Asn Met Gln Leu Leu Ser
965 970 975
Ser Ser Val Gly Ile Glu Asp Lys Lys Met Ala Leu Asn Ser Leu Met
980 985 990
Ser Leu Met Lys Leu Met Gly Pro Lys His Val Ser Ser Val Arg Val
995 1000 1005
Lys Met Met Thr Thr Leu Arg Thr Gly Leu Arg Phe Lys Asp Asp Phe
1010 1015 1020
Pro Glu Leu Cys Cys Arg Ala Trp Asp Cys Phe Val Arg Cys Leu Asp
1025 1030 1035 1040
His Ala Cys Leu Gly Ser Leu Leu Ser His Val Ile Val Ala Leu Leu
1045 1050 1055
Pro Leu Ile His Ile Gln Pro Lys Glu Thr Ala Ala Ile Phe His Tyr
1060 1065 1070
Leu Ile Ile Glu Asn Arg Asp Ala Val Gln Asp Phe Leu His Glu Ile
1075 1080 1085
Tyr Phe Leu Pro Asp His Pro Glu Leu Lys Lys Ile Lys Ala Val Leu
1090 1095 1100
Gln Glu Tyr Arg Lys Glu Thr Ser Glu Ser Thr Asp Leu Gln Thr Thr
1105 1110 1115 1120
Leu Gln Leu Ser Met Lys Ala Ile Gln His Glu Asn Val Asp Val Arg
1125 1130 1135
Ile His Ala Leu Thr Ser Leu Lys Glu Thr Leu Tyr Lys Asn Gln Glu
1140 1145 1150
Lys Leu Ile Lys Tyr Ala Thr Asp Ser Glu Thr Val Glu Pro Ile Ile
1155 1160 1165
Ser Gln Leu Val Thr Val Leu Leu Lys Gly Cys Gln Asp Ala Asn Ser
1170 1175 1180
Gln Ala Arg Leu Leu Cys Gly Glu Cys Leu Gly Glu Leu Gly Ala Ile
1185 1190 1195 1200
Asp Pro Gly Arg Leu Asp Phe Ser Thr Thr Glu Thr Gln Gly Lys Asp
1205 1210 1215
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Phe Thr Phe Val Thr Gly Val Glu Asp Ser Ser Phe Ala Tyr Gly Leu
1220 1225 1230
Leu Met Glu Leu Thr Arg Ala Tyr Leu Ala Tyr Ala Asp Asn Ser Arg
1235 1240 1245
Ala Gln Asp Ser Ala Ala Tyr Ala Ile Gln Glu Leu Leu Ser Ile Tyr
1250 1255 1260
Asp Cys Arg Glu Met Glu Thr Asn Gly Pro Gly His Gln Leu Trp Arg
1265 1270 1275 1280
Arg Phe Pro Glu His Val Arg Glu Ile Leu Glu Pro His Leu Asn Thr
1285 1290 1295
Arg Tyr Lys Ser Ser Gin Lys Ser Thr Asp Trp Ser Gly Val Lys Lys
1300 1305 1310
Pro Ile Tyr Leu Ser Lys Leu Gly Ser Asn Phe Ala Glu Trp Ser Ala
1315 1320 1325
Ser Trp Ala Gly Tyr Leu Ile Thr Lys Val Arg His Asp Leu Ala Ser
1330 1335 1340
Lys Ile Phe Thr Cys Cys Ser Ile Met Met Lys His Asp Phe Lys Val
1345 1350 1355 1360
Thr Ile Tyr Leu Leu Pro His Ile Leu Val Tyr Val Leu Leu Gly Cys
1365 1370 1375
Asn Gln Glu Asp Gln Gln Glu Val Tyr Ala Glu Ile Met Ala Val Leu
1380 1385 1390
Lys His Asp Asp Gln His Thr Ile Asn Thr Gln Asp Ile Ala Ser Asp
1395 1400 1405
Leu Cys Gln Leu Ser Thr Gln Thr Val Phe Ser Met Leu Asp His Leu
1410 1415 1420
Thr Gln Trp Ala Arg His Lys Phe Gln Ala Leu Lys Ala Glu Lys Cys
1425 1430 1435 1440
Pro His Ser Lys Ser Asn Arg Asn Lys Val Asp Ser Met Val Ser Thr
1445 1450 1455
Val Asp Tyr Glu Asp Tyr Gln Ser Val Thr Arg Phe Leu Asp Leu Ile
1460 1465 1470
Pro Gln Asp Thr Leu Ala Val Ala Ser Phe Arg Ser Lys Ala Tyr Thr
1475 1480 1485
Arg Ala Val Met His Phe Glu Ser Phe Ile Thr Glu Lys Lys Gln Asn
1490 1495 1500
Ile Gln Glu His Leu Gly Phe Leu Gln Lys Leu Tyr Ala Ala Met His
1505 1510 1515 1520
Glu Pro Asp Gly Val Ala Gly Val Ser Ala Ile Arg Lys Ala Glu Pro
1525 1530 1535
Ser Leu Lys Glu Gln Ile Leu Glu His Glu Ser Leu Gly Leu Leu Arg
1540 1545 1550
Asp Ala Thr Ala Cys Tyr Asp Arg Ala Ile Gln Leu Glu Pro Asp Gln
1555 1560 1565
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Ile Ile His Tyr His Gly Val Val Lys Ser Met Leu Gly Leu Gly Gln
1570 1575 1580
Leu Ser Thr Val Ile Thr Gln Val Asn Gly Val His Ala Asn Arg Ser
1585 1590 1595 1600
Glu Trp Thr Asp Glu Leu Asn Thr Tyr Arg Val Glu Ala Ala Trp Lys
1605 1610 1615
Leu Ser Gln Trp Asp Leu Val Glu Asn Tyr Leu Ala Ala Asp Gly Lys
1620 1625 1630
Ser Thr Thr Trp Ser Val Arg Leu Gly Gln Leu Leu Leu Ser Ala Lys
1635 1640 1645
Lys Arg Asp Ile Thr Ala Phe Tyr Asp Ser Leu Lys Leu Val Arg Ala
1650 1655 1660
Glu Gln Ile Val Pro Leu Ser Ala Ala Ser Phe Glu Arg Gly Ser Tyr
1665 1670 1675 1680
Gin Arg Gly Tyr Glu Tyr Ile Val Arg Leu His Met Leu Cys Glu Leu
1685 1690 1695
Glu His Ser Ile Lys Pro Leu Phe Gln His Ser Pro Gly Asp Ser Ser
1700 1705 1710
Gln Glu Asp Ser Leu Asn Trp Val Ala Arg Leu Glu Met Thr Gln Asn
1715 1720 1725
Ser Tyr Arg Ala Lys Glu Pro Ile Leu Ala Leu Arg Arg Ala Leu Leu
1730 1735 1740
Ser Leu Asn Lys Arg Pro Asp Tyr Asn Glu Met Val Gly Glu Cys Trp
1745 1750 1755 1760
Leu Gln Ser Ala Arg Val Ala Arg Lys Ala Gly His His Gln Thr Ala
1765 1770 1775
Tyr Asn Ala Leu Leu Asn Ala Gly Glu Ser Arg Leu Ala Glu Leu Tyr
1780 1785 1790
Val Glu Arg Ala Lys Trp Leu Trp Ser Lys Gly Asp Val His Gln Ala
1795 1800 1805
Leu Ile Val Leu Gln Lys Gly Val Glu Leu Cys Phe Pro Glu Asn Glu
1810 1815 1820
Thr Pro Pro Glu Gly Lys Asn Met Leu Ile His Gly Arg Ala Met Leu
1825 1830 1835 1840
Leu Val Gly Arg Phe Met Glu Glu Thr Ala Asn Phe Glu Ser Asn Ala
1845 1850 1855
Ile Met Lys Lys Tyr Lys Asp Val Thr Ala Cys Leu Pro Glu Trp Glu
1860 1865 1870
Asp Gly His Phe Tyr Leu Ala Lys 'I,
.jr Tyr Asp Lys Leu Met Pro Met
1875 1880 1885
Val Thr Asp Asn Lys Met Glu Lys Gln Gly Asp Leu Ile Arg Tyr Ile
1890 1895 1900
Val Leu His Phe Gly Arg Ser Leu Gln Tyr Gly Asn Gln Phe Ile Tyr
1905 1910 1915 1920
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Gln Ser Met Pro Arg Met Leu Thr Leu Trp Leu Asp Tyr Gly Thr Lys
1925 1930 1935
Ala Tyr Glu Trp Glu Lys Ala Gly Arg Ser Asp Arg Val Gln Met Arg
1940 1945 1950
Asn Asp Leu Gly Lys Ile Asn Lys Val IlP Thr Glu His Thr Asn Tyr
1955 1960 1965
Leu Ala Pro Tyr Gln Phe Leu Thr Ala Phe Ser Gln Leu Ile Ser Arg
1970 1975 1980
Ile Cys His Ser His Asp Glu Val Phe Val Val Leu Met Glu Ile Ile
1985 1990 1995 2000
Ala Lys Val Phe Leu Ala Tyr Pro Gln Gln Ala Met Trp Met Met Thr
2005 2010 2015
Ala Val Ser Lys Ser Ser Tyr Pro Met Arg Val Asn Arg Cys Lys Glu
2020 2025 2030
Ile Leu Asn Lys Ala Ile His Met Lys Lys Ser Leu Glu Lys Phe Val
2035 2040 2045
Gly Asp Ala Thr Arg Leu Thr Asp Lys Leu Leu Glu Leu Cys Asn Lys
2050 2055 2060
Pro Val Asp Gly Ser Ser Ser Thr Leu Ser Met Ser Thr His Phe Lys
2065 2070 2075 2080
Met Leu Lys Lys Leu Val Glu Glu Ala Thr Phe Ser Glu Ile Leu Ile
2085 2090 2095
Pro Leu Gln Ser Val Met Ile Pro Thr Leu Pro Ser Ile Leu Gly Thr
2100 2105 2110
His Ala Asn His Ala Ser His Glu Pro Phe Pro Gly His Trp Ala Tyr
2115 2120 2125
Ile Ala Giy Phe Asp Asp Met Val Glu Ile Leu Ala Ser Leu Gln Lys
2130 2135 2140
Pro Lys Lys Ile Ser Leu Lys Gly Ser Asp Gly Lys Phe Tyr Ile Met
2145 2150 2155 2160
Met Cys Lys Pro Lys Asp Asp Leu Arg Lys Asp Cys Arg Leu Met Glu
2165 2170 2175
Phe Asn Ser Leu Ile Asn Lys Cys Leu Arg Lys Asp Ala Glu Ser Arg
2180 2185 2190
Arg Arg Glu Leu His Ile Arg Thr Tyr Ala Val Ile Pro Leu Asn Asp
2195 2200 2205
Glu Cys Gly Ile Ile Glu Trp Val Asn Asn Thr Ala Gly Leu Arg Pro
2210 2215 2220
Ile Leu Thr Lys Leu Tyr Lys Glu Lys Gly Val Tyr Met Thr Gly Lys
2225 2230 2235 2240
Glu Leu Arg Gln Cys Met Leu Pro Lys Ser Ala Ala Leu Ser Glu Lys
2245 2250 2255
Leu Lys Val Phe Arg Glu Phe Leu Leu Pro Arg His Pro Pro Ile Phe
2260 2265 2270
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His Glu Trp Phe Leu Arg Thr Phe Pro Asp Pro Thr Ser Trp Tyr Ser
2275 2280 2285
Ser Arg Ser Ala Tyr Cys Arg Ser Thr Ala Val Met Ser Met Val Gly
2290 2295 2300
Tyr Ile Leu Gly Leu Gly Asp Arg His Gly Glu Asn Ile Leu Phe Asp
2305 2310 2315 2320
Ser Leu Thr Gly Glu Cys Val His Val Asp Phe Asn Cys Leu Phe Asn
2325 2330 2335
Lys Gly Glu Thr Phe Glu Val Pro Glu Ile Val Pro Phe Arg Leu Thr
2340 2345 2350
His Asn Met Val Asn Gly Met Gly Pro Met Gly Thr Glu Gly Leu Phe
2355 2360 2365
Arg Arg Ala Cys Glu Val Thr Met Arg Leu Met Arg Asp Gln Arg Glu
2370 2375 2380
Pro Leu Met Ser Val Leu Lys Thr Phe Leu His Asp Pro Leu Val Glu
2385 2390 2395 2400
Trp Ser Lys Pro Val Lys Gly His Ser Lys Ala Pro Leu Asn Glu Thr
2405 2410 2415
Gly Glu Val Val Asn Glu Lys Ala Lys Thr His Val Leu Asp Ile Glu
2420 2425 2430
Gln Arg Leu Gln Gly Val Ile Lys Thr Arg Asn Arg Val Thr Gly Leu
2435 2440 2445
Pro Leu Ser Ile Glu Gly His Val His Tyr Leu Ile Gln Glu Ala Thr
2450 2455 2460
Asp Glu Asn Leu Leu Cys Gln Met Tyr Leu Gly Trp Thr Pro Tyr Met
2465 2470 2475 2480
(2) INFORMATION FOR.SEQ ID NO:34:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 9385 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: cDNA
(v) FRAGMENT TYPE: linear
(ix) FEATURE:
(A) NAME/KEY: CDS
(B) LOCATION: 190..9357
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:
GCGAGAGGAG TCGGGATCTG CGCTGCAGCC ACCGCCGCGG TTGATACTAC TTTGACCTTC 60
CGAGTGCAGT GAGGCATACA TCACAATTTG GAATTATGCA TTGGTTTATC AATTTACTT G 120
TTTATTGTCA CCCTGCTGCC CAGATATGAC TTCATGAGGA CAGTGATGTG TGTTCTGAAA 180
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TTGTGAACC ATG AGT CTA GTA CTT AAT GAT CTG CTT ATC TGC TGC CGT 228
Met Ser Leu Val Leu Asn Asp Leu Leu Ile Cys Cys Arg
1 5 10
CAA CTA GAA CAT GAT AGA GCT ACA GAA CGA AAG AAA GAA GTT GAG AAA 276
Gln Leu Glu His Asp Arg Ala Thr Glu Arg Lys Lys Glu Val Glu Lys
15 20 25
TTT AAG CGC CTG ATT CGA GAT CCT GAA ACA ATT AAA CAT CTA GAT CGG 324
Phe Lys Arg Leu Ile Arg Asp Pro Glu Thr Ile Lys His Leu Asp Arg
30 35 40 45
CAT TCA GAT TCC AAA CAA GGA AAA TAT TTG AAT TGG GAT GCT GTT TTT 372
His Ser Asp Ser Lys Gln Gly Lys Tyr Leu Asn Trp Asp Ala Val Phe
50 55 60
AGA TTT TTA CAG AAA TAT ATT CAG AAA GAA ACA GAA TGT CTG AGA ATA 420
Arg Phe Leu Gln Lys Tyr Ile Gln Lys Glu Thr Glu Cys Leu Arg Ile
65 70 75
GCA AAA CCA AAT GTA TCA GCC TCA ACA CAA GCC TCC AGG CAG AAA AAG 468
Ala Lys Pro Asn Val Ser Ala Ser Thr Gln Ala Ser Arg Gln Lys Lys
80 85 90
ATG CAG GAA ATC AGT AGT TTG GTC AAA TAC TTC ATC AAA TGT GCA AAC 516
Met Gln Glu Ile Ser Ser Leu Val Lys Tyr Phe Ile Lys Cys Ala Asn
95 100 105
AGA AGA GCA CCT AGG CTA AAA TGT CAA GAA CTC TTA AAT TAT ATC ATG 564
Arg Arg Ala Pro Arg Leu Lys Cys Gln Glu Leu Leu Asn Tyr Ile Met
110 115 120 125
GAT ACA GTG AAA GAT TCA TCT AAT GGT GCT ATT TAC GGA GCT GAT TGT 612
Asp Thr Val Lys Asp Ser Ser Asn Gly Ala Ile Tyr Gly Ala Asp Cys
130 135 140
AGC AAC ATA CTA CTC AAA GAC ATT CTT TCT GTG AGA AAA TAC TGG TGT 660
Ser Asn Ile Leu Leu Lys Asp Ile Leu Ser Val Arg Lys Tyr Trp Cys
145 150 155
GAA ATA TCT CAG CAA CAG TGG TTA GAA TTG TTC TCT GTG TAC TTC AGG 708
Glu Ile Ser Gln Gln Gln Trp Leu Glu Leu Phe Ser Val Tyr Phe Arg
160 165 170
CTC TAT CTG AAA CCT TCA CAA GAT GTT CAT AGA GTT TTA GTG GCT AGA 756
Leu Tyr Leu Lys Pro Ser Gln Asp Val His Arg Val Leu Val Ala Arg
175 180 185
ATA ATT CAT GCT GTT ACC AAA GGA TGC TGT TCT CAG ACT GAC GGA TTA 804
Ile Ile His Ala Val Thr Lys Gly Cys Cys Ser Gln Thr Asp Gly Leu
190 195 200 205
AAT TCC AAA TTT TTG GAC TTT TTT TCC AAG GCT ATT CAG TGT GCG AGA 852
Asn Ser Lys Phe Leu Asp Phe Phe Ser Lys Ala Ile Gln Cys Ala Arg
210 215 220
CAA GAA AAG AGC TCT TCA GGT CTA AAT CAT ATC TTA GCA GCT CTT ACT 900
Gln Glu Lys Ser Ser Ser Gly Leu Asn His Ile Leu Ala Ala Leu Thr
225 230 235
ATC TTC CTC AAG ACT TTG GCT GTC AAC TTT CGA ATT CGA GTG TGT GAA 948
Ile Phe Leu Lys Thr Leu Ala Val Asn Phe Arg Ile Arg Val Cys Glu
240 245 250
TTA GGA GAT GAA ATT CTT CCC ACT TTG CTT TAT ATT TGG ACT CAA CAT 996
Leu Gly Asp Glu Ile Leu Pro Thr Leu Leu Tyr Ile Trp Thr Gln His
255 260 265
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AGG CTT AAT GAT TCT TTA AAA GAA GTC ATT ATT GAA TTA TTT CAA CTG 1044
Arg Leu Asn Asp Ser Leu Lys Glu Val Ile Ile Glu Leu Phe Gln Leu
270 275 280 285
CAA ATT TAT ATC CAT CAT CCG AAA GGA GCC AAA ACC CAA GAA AAA GGT 1092
Gln Ile Tyr Ile His His Pro Lys Gly Ala Lys Thr Gln Glu Lys Gly
290 295 300
GCT TAT GAA TCA ACA AAA TGG AGA AGT ATT TTA TAC AAC TTA TAT GAT 1140
Ala Tyr Glu Ser Thr Lys Trp Arg Ser Ile Leu Tyr Asn Leu Tyr Asp
305 310 315
CTG CTA GTG AAT GAG ATA AGT CAT ATA GGA AGT AGA GGA AAG TAT TCT 1188
Leu Leu Val Asn Glu Ile Ser His Ile Gly Ser Arg Gly Lys Tyr Ser
320 325 330
TCA GGA TTT CGT AAT ATT GCC GTC AAA GAA AAT TTG ATT GAA TTG ATG 1236
Ser Gly Phe Arg Asn Ile Ala Val Lys Glu Asn Leu Ile Glu Leu Met
335 340 345
GCA GAT ATC TGT CAC CAG GTT TTT AAT GAA GAT ACC AGA TCC TTG GAG 1284
Ala Asp Ile Cys His Gln Val Phe Asn Glu Asp Thr Arg Ser Leu Glu
350 355 360 365
ATT TCT CAA TCT TAC ACT ACT ACA CAA AGA GAA TCT AGT GAT TAC AGT 1332
Ile Ser Gln Ser Tyr Thr Thr Thr Gln Arg Glu Ser Ser Asp Tyr Ser
370 375 380
GTC CCT TGC AAA AGG AAG AAA ATA GAA CTA GGC TGG GAA GTA ATA AAA 1380
Val Pro Cys Lys Arg Lys Lys Ile Glu Leu Gly Trp Glu Val Ile Lys
385 390 395
GAT CAC CTT CAG AAG TCA CAG AAT GAT TTT GAT CTT GTG CCT TGG CTA 1428
Asp His Leu Gln Lys Ser Gln Asn Asp Phe Asp Leu Val Pro Trp Leu
400 405 410
CAG ATT GCA ACC CAA TTA ATA TCA AAG TAT CCT GCA AGT TTA CCT AAC 1476
Gln Ile Ala Thr Gln Leu Ile Ser Lys Tyr Pro Ala Ser Leu Pro Asn
415 420 425
TGT GAG CTG TCT CCA TTA CTG ATG ATA CTA TCT CAG CTT CTA CCC CAA 1524
Cys Glu Leu Ser Pro Leu Leu Met Ile Leu Ser Gln Leu Leu Pro Gln
430 435 440 445
CAG CGA CAT GGG GAA CGT ACA CCA TAT GTG TTA CGA TGC CTT ACG GAA 1572
Gln Arg His Gly Glu Arg Thr Pro Tyr Val Leu Arg Cys Leu Thr Glu
450 455 460
GTT GCA TTG TGT CAA GAC AAG AGG TCA AAC CTA GAA AGC TCA CAA AAG 1620
Val Ala Leu Cys Gln Asp Lys Arg Ser Asn Leu Glu Ser Ser Gln Lys
465 470 475
TCA GAT TTA TTA AAA CTC TGG AAT AAA ATT TGG TGT ATT ACC TTT CGT 1668
Ser Asp Leu Leu Lys Leu Trp Asn Lys Ile Trp Cys Ile Thr Phe Arg
480 485 490
GGT ATA AGT TCT GAG CAA ATA CAA GCT GAA AAC TTT GGC TTA CTT GGA 1716
Gly Ile Ser Ser Glu Gin Ile Gln Ala Glu Asn Phe Gly Leu Leu Gly
495 500 505
GCC ATA ATT CAG GGT AGT TTA GTT GAG GTT GAC AGA GAA TTC TGG AAG 1764
Ala Ile Ile Gln Gly Ser Leu Val Glu Val Asp Arg Glu Phe Trp Lys
510 515 520 525
TTA TTT ACT GGG TCA GCC TGC AGA CCT TCA TGT CCT GCA GTA TGC TGT 1812
Leu Phe Thr Gly Ser Ala Cys Arg Pro Ser Cys Pro Ala Val Cys Cys
530 535 540
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TTG ACT TTG GCA CTG ACC ACC AGT ATA GTT CCA GGA GCG GTA AAA ATG 1860
Leu Thr Leu Ala Leu Thr Thr Ser Ile Val Pro Gly Ala Val Lys Met
545 550 555
GGA ATA GAG CAA AAT ATG TGT GAA GTA AAT AGA AGC TTT TCT TTA AAG 1908
Gly Ile Glu Gln Asn Met Cys Glu Val Asn Arg Ser Phe Ser Leu Lys
560 565 570
GAA TCA ATA ATG AAA TGG CTC TTA TTC TAT CAG TTA GAG GGT GAC TTA 1956
Glu Ser Ile Met Lys Trp Leu Leu Phe Tyr Gln Leu Glu Gly Asp Leu
575 580 585
GAA AAT AGC ACA GAA GTG CCT CCA ATT CTT CAC AGT AAT TTT CCT CAT 2004
Glu Asn Ser Thr Glu Val Pro Pro Ile Leu His Ser Asn Phe Pro His
590 595 600 605
CTT GTA CTG GAG AAA ATT CTT GTG AGT CTC ACT ATG AAA AAC TGT AAA 2052
Leu Val Leu Glu Lys Ile Leu Val Ser Leu Thr Met Lys Asn Cys Lys
610 615 620
GCT GCA ATG AAT TTT TTC CAA AGC GTG CCA GAA TGT GAA CAC CAC CAA 2100
Ala Ala Met Asn Phe Phe Gln Ser Val Pro Glu Cys Glu His His Gln
625 630 635
AAA GAT AAA GAA GAA CTT TCA TTC TCA GAA GTA GAA GAA CTA TTT CTT 2148
Lys Asp Lys Glu Glu Leu Ser Phe Ser Glu Val Glu Glu Leu Phe Leu
640 645 650
CAG ACA ACT TTT GAC AAG ATG GAC TTT TTA ACC ATT GTG AGA GAA TGT 2196
Gln Thr Thr Phe Asp Lys Met Asp Phe Leu Thr Ile Val Arg Glu Cys
655 660 665
GGT ATA GAA AAG CAC CAG TCC AGT ATT GGC TTC TCT GTC CAC CAG AAT 2244
Gly Ile Glu Lys His Gln Ser Ser Ile Gly Phe Ser Val His Gln Asn
670 675 680 685
CTC AAG GAA TCA CTG GAT CGC TGT CTT CTG GGA TTA TCA GAA CAG CTT 2292
Leu Lys Glu Ser Leu Asp Arg Cys Leu Leu Gly Leu Ser Glu Gin Leu
690 695 700
CTG AAT AAT TAC TCA TCT GAG ATT ACA AAT TCA GAA ACT CTT GTC CGG 2340
Leu Asn Asn Tyr Ser Ser Glu Ile Thr Asn Ser Glu Thr Leu Val Arg
705 710 715
TGT TCA CGT CTT TTG GTG GGT GTC CTT GGC TGC TAC TGT TAC ATG GGT 2388
Cys Ser Arg Leu Leu Val Gly Val Leu Gly Cys Tyr Cys Tyr Met Gly
720 725 730
GTA ATA GCT GAA GAG GAA GCA TAT AAG TCA GAA TTA TTC CAG AAA GCC 2436
Val Ile Ala Glu Glu Glu Ala Tyr Lys Ser Glu Leu Phe Gln Lys Ala
735 740 745
AAC TCT CTA ATG CAA TGT GCA GGA GAA AGT ATC ACT CTG TTT AAA AAT 2484
Asn Ser Leu Met Gln Cys Ala Gly Glu Ser Ile Thr Leu Phe Lys Asn
750 755 760 765
AAG ACA AAT GAG GAA TTC AGA ATT GGT TCC TTG AGA AAT ATG ATG CAG 2532
Lys Thr Asn Glu Glu Phe Arg Ile Gly Ser Leu Arg Asn Met Met Gln
770 775 780
CTA TGT ACA CGT TGC TTG AGC AAC TGT ACC AAG AAG AGT CCA AAT AAG 2580
Leu Cys Thr Arg Cys Leu Ser Asn Cys Thr Lys Lys Ser Pro Asn Lys
785 790 795
ATT GCA TCT GGC TTT TTC CTG CGA TTG TTA ACA TCA AAG CTA ATG AAT 2628
Ile Ala Ser Gly Phe Phe Leu Arg Leu Leu Thr Ser Lys Leu Met Asn
800 805 810
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GAC ATT GCA GAT ATT TGT AAA AGT TTA GCA TCC TTC ATC AAA AAG CCA 2676
Asp Ile Ala Asp Ile Cys Lys Ser Leu Ala Ser Phe Ile Lys Lys Pro
815 820 825
TTT GAC CGT GGA GAA GTA GAA TCA ATG GAA GAT GAT ACT AAT GGA AAT 2724
Phe Asp Arg Gly Glu Val Glu Ser Met Glu Asp Asp Thr Asn Gly Asn
830 835 840 845
CTA ATG GAG GTG GAG GAT CAG TCA TCC ATG AAT CTA TTT AAC GAT TAC 2772
Leu Met Glu Val Glu Asp Gln Ser Ser Met Asn Leu Phe Asn Asp Tyr
850 855 860
CCT GAT AGT AGT GTT AGT GAT GCA AAC GAA CCT GGA GAG AGC CAA AGT 2820
Pro Asp Ser Ser Val Ser Asp Ala Asn Glu Pro Gly Glu Ser Gln Ser
865 870 875
ACC ATA GGT GCC ATT AAT CCT TTA GCT GAA GAA TAT CTG TCA AAG CAA 2868
Thr Ile Gly Ala Ile Asn Pro Leu Ala Glu Glu Tyr Leu Ser Lys Gln
880 885 890
GAT CTA CTT TTC TTA GAC ATG CTC AAG TTC TTG TGT TTG TGT GTA ACT 2916
Asp Leu Leu Phe Leu Asp Met Leu Lys Phe Leu Cys Leu Cys Val Thr
895 900 905
ACT GCT CAG ACC AAT ACT GTG TCC TTT AGG GCA GCT GAT ATT CGG AGG 2964
Thr Ala Gln Thr Asn Thr Val Ser Phe Arg Ala Ala Asp Ile Arg Arg
910 915 920 925
AAA TTG TTA ATG TTA ATT GAT TCT AGC ACG CTA GAA CCT ACC AAA TCC 3012
Lys Leu Leu Met Leu Ile Asp Ser Ser Thr Leu Glu Pro Thr Lys Ser
930 935 940
CTC CAC CTG CAT ATG TAT CTA ATG CTT TTA AAG GAG CTT CCT GGA GAA 3060
Leu His Leu His Met Tyr Leu Met Leu Leu Lys Glu Leu Pro Gly Glu
945 950 955
GAG TAC CCC TTG CCA ATG GAA GAT GTT CTT GAA CTT CTG AAA CCA CTA 3108
Glu Tyr Pro Leu Pro Met Glu Asp Val Leu Glu Leu Leu Lys Pro Leu
960 965 970
TCC AAT GTG TGT TCT TTG TAT CGT CGT GAC CAA GAT GTT TGT AAA ACT 3156
Ser Asn Val Cys Ser Leu Tyr Arg Arg Asp Gln Asp Val Cys Lys Thr
975 980 985
ATT TTA AAC CAT GTC CTT CAT GTA GTG AAA AAC CTA GGT CAA AGC AAT 3204
Ile Leu Asn His Val Leu His Val Val Lys Asn Leu Gly Gln Ser Asn
990 995 1000 1005
ATG GAC TCT GAG AAC ACA AGG GAT GCT CAA GGA CAG TTT CTT ACA GTA 3252
Met Asp Ser Glu Asn Thr Arg Asp Ala Gln Gly Gln Phe Leu Thr Val
1010 1015 1020
ATT GGA GCA TTT TGG CAT CTA ACA AAG GAG AGG AAA TAT ATA TI'C TCT 3300
Ile Gly Ala Phe Trp His Leu Thr Lys Glu Arg Lys Tyr Ile Phe Ser
1025 1030 1035
GTA AGA ATG GCC CTA GTA AAT TGC CTT AAA ACT TTG CTT GAG GCT GAT 3348
Val Arg Met Ala Leu Val Asn Cys Leu Lys Thr Leu Leu Glu Ala Asp
1040 1045 1050
CCT TAT TCA AAA TGG GCC ATT CTT AAT GTA ATG GGA AAA GAC TTT CCT 3396
Pro Tyr Ser Lys Trp Ala Ile Leu Asn Val Met Gly Lys Asp Phe Pro
1055 1060 1065
GTA AAT GAA GTA TTT ACA CAA TTT CTT GCT GAC AAT CAT CAC CAA GTT 3444
Val Asn Glu Val Phe Thr Gln Phe Leu Ala Asp Asn His His Gln Val
1070 1075 1080 1085
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CGC ATG TTG GCT GCA GAG TCA ATC AAT AGA TTG TTC CAG GAC ACG AAG 3492
Arg Met Leu Ala Ala Glu Ser Ile Asn Arg Leu Phe Gln Asp Thr Lys
1090 1095 1100
GGA GAT TCT TCC AGG TTA CTG AAA GCA CTT CCT TTG AAG CTT CAG CAA 3540
Gly Asp Ser Ser Arg Leu Leu Lys Ala Leu Pro Leu Lys Leu Gln Gln
1105 1110 1115
ACA GCT TTT GAA AAT GCA TAC TTG AAA GCT CAG GAA GGA ATG AGA GAA 3588
Thr Ala Phe Glu Asn Ala Tyr Leu Lys Ala Gln Glu Gly Met Arg Glu
1120 1125 1130
ATG TCC CAT AGT GCT GAG AAC CCT GAA ACT TTG GAT GAA ATT TAT AAT 3636
Met Ser His Ser Ala Glu Asn Pro Glu Thr Leu Asp Glu Ile Tyr Asn
1135 1140 1145
AGA AAA TCT GTT TTA CTG ACG TTG ATA GCT GTG GTT TTA TCC TGT AGC 3684
Arg Lys Ser Val Leu Leu Thr Leu Ile Ala Val Val Leu Ser Cys Ser
1150 1155 1160 1165
CCT ATC TGC GAA AAA CAG GCT TTG TTT GCC CTG TGT AAA TCT GTG AAA 3732
Pro Ile Cys Glu Lys Gln Ala Leu Phe Ala Leu Cys Lys Ser Val Lys
1170 1175 1180
GAG AAT GGA TTA GAA CCT CAC CTT GTG AAA AAG GTT TTA GAG AAA GTT 3780
Glu Asn Gly Leu Glu Pro His Leu Val Lys Lys Val Leu Glu Lys Val
1185 1190 1195
TCT GAA ACT TTT GGA TAT AGA CGT TTA GAA GAC TTT ATG GCA TCT CAT 3828
Ser Glu Thr Phe Gly Tyr Arg Arg Leu Glu Asp Phe Met Ala Ser His
1200 1205 1210
TTA GAT TAT CTG GTT TTG GAA TGG CTA AAT CTT CAA GAT ACT GAA TAC 3876
Leu Asp Tyr Leu Val Leu Glu Trp Leu Asn Leu Gln Asp Thr Glu Tyr
1215 1220 1225
AAC TTA TCT TCT TTT CCT TZT ATT TTA TTA AAC TAC ACA AAT ATT GAG 3924
Asn Leu Ser Ser Phe Pro Phe Ile Leu Leu Asn Tyr Thr Asn Ile Glu
1230 1235 1240 1245
GAT TTC TAT AGA TCT TGT TAT AAG GTT TTG ATT CCA CAT CTG GTG ATT 3972
Asp Phe Tyr Arg Ser Cys Tyr Lys Val Leu Ile Pro His Leu Val Ile
1250 1255 1260
AGA AGT CAT TZT GAT GAG GTG AAG TCC ATT GCT AAT CAG ATT CAA GAG 4020
Arg Ser His Phe Asp Glu Val Lys Ser Ile Ala Asn Gln Ile Gln Glu
1265 1270 1275
GAC TGG AAA AGT CTT CTA ACA GAC TGC TTT CCA AAG ATT CTT GTA AAT 4068
Asp Trp Lys Ser Leu Leu Thr Asp Cys Phe Pro Lys Ile Leu Val Asn
1280 1285 1290
ATT CZT CCT TAT TIT GCC TAT GAG GGT ACC AGA GAC AGT GGG ATG GCA 4116
Ile Leu Pro Tyr Phe Ala Tyr Glu Gly Thr Arg Asp Ser Gly Met Ala
1295 1300 1305
CAG CAA AGA GAG ACT GCT ACC AAG GTC TAT GAT ATG CTT AAA AGT GAA 4164
Gln Gln Arg Glu Thr Ala Thr Lys Val Tyr Asp Met Leu Lys Ser Glu
1310 1315 1320 1325
AAC TTA TTG GGA AAA CAG ATT GAT CAC TTA TTC ATT AGT AAT TTA CCA 4212
Asn Leu Leu Gly Lys Gln Ile Asp His Leu Phe Ile Ser Asn Leu Pro
1330 1335 1340
GAG ATT GTG GTG GAG TTA TTG ATG ACG TTA CAT GAG CCA GCA AAT TCT 4260
Glu Ile Val Val Glu Leu Leu Met Thr Leu His Glu Pro Ala Asn Ser
1345 1350 1355
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AGT GCC AGT CAG AGC ACT GAC CTC TGT GAC TTT TCA GGG GAT TTG GAT 4308
Ser Ala Ser Gln Ser Thr Asp Leu Cys Asp Phe Ser Gly Asp Leu Asp
1360 1365 1370
CCT GCT CCT AAT CCA CCT CAT TTT CCA TCG CAT GTG ATT AAA GCA ACA 4356
Pro Ala Pro Asn Pro Pro His Phe Pro Ser His Val Ile Lys Ala Thr
1375 1380 1385
TTT GCC TAT ATC AGC AAT TGT CAT AAA ACC AAG TTA AAA AGC ATT TTA 4404
Phe Ala Tyr Ile Ser Asn Cys His Lys Thr Lys Leu Lys Ser Ile Leu
1390 1395 1400 1405
GAA ATT CTT TCC AAA AGC CCT GAT TCC TAT CAG AAA ATT CTT CTT GCC 4452
Glu Ile Leu Ser Lys Ser Pro Asp Ser Tyr Gln Lys Ile Leu Leu Ala
1410 1415 1420
ATA TGT GAG CAA GCA GCT GAA ACA AAT AAT GTT TAT AAG AAG CAC AGA 4500
Ile Cys Glu Gln Ala Ala Glu Thr Asn Asn Val Tyr Lys Lys His Arg
1425 1430 1435
AZT CTT AAA ATA TAT CAC CTG TTT GTT AGT TTA TTA CTG AAA GAT ATA 4548
Ile Leu Lys Ile Tyr His Leu Phe Val Ser Leu Leu Leu Lys Asp Ile
1440 1445 1450
AAA AGT GGC TTA GGA GGA GCT TGG GCC TTT GTT CTT CGA GAC GTT ATT 4596
Lys Ser Gly Leu Gly Gly Ala Trp Ala Phe Val Leu Arg Asp Val Ile
1455 1460 1465
TAT ACT TTG ATT CAC TAT ATC AAC CAA AGG CCT TCT TGT ATC ATG GAT 4644
Tyr Thr Leu Ile His Tyr Ile Asn Gln Arg Pro Ser Cys Ile Met Asp
1470 1475 1480 1485
GTG TCA TTA CGT AGC TTC TCC CTT TGT TGT GAC TTA TTA AGT CAG GTT 4692
Val Ser Leu Arg Ser Phe Ser Leu Cys Cys Asp Leu Leu Ser Gln Val
1490 1495 1500
TGC CAG ACA GCC GTG ACT TAC TGT AAG GAT GCT CTA GAA AAC CAT CTT 4740
Cys Gln Thr Ala Val Thr Tyr Cys Lys Asp Ala Leu Glu Asn His Leu
1505 1510 1515
CAT GTT ATT GTT GGT ACA CTT ATA CCC CTT GTG TAT GAG CAG GTG GAG 4788
His Val Ile Val Gly Thr Leu Ile Pro Leu Val Tyr Glu Gln Val Glu
1520 1525 1530
GTT CAG AAA CAG GTA TTG GAC TTG TTG AAA TAC TTA GTG ATA GAT AAC 4836
Val Gln Lys Gln Val Leu Asp Leu Leu Lys Tyr Leu Val Ile Asp Asn
1535 1540 1545
AAG GAT AAT GAA AAC CTC TAT ATC ACG ATT AAG CTT TTA GAT CCT TTT 4884
Lys Asp Asn Glu Asn Leu Tyr Ile Thr Ile Lys Leu Leu Asp Pro Phe
1550 1555 1560 1565
CCT GAC CAT GTT GTT TTT AAG GAT TTG CGT ATT ACT CAG CAA AAA ATC 4932
Pro Asp His Val Val Phe Lys Asp Leu Arg Ile Thr Gln Gln Lys Ile
1570 1575 1580
AAA TAC AGT AGA GGA CCC TTT TCA CTC TTG GAG GAA ATT AAC CAT TTT 4980
Lys Tyr Ser Arg Gly Pro Phe Ser Leu Leu Glu Glu Ile Asn His Phe
1585 1590 1595
CTC TCA GTA AGT GTT TAT GAT GCA CTT CCA TTG ACA AGA CTT GAA GGA 5028
Leu Ser Val Ser Val Tyr Asp Ala Leu Pro Leu Thr Arg Leu Glu Gly
1600 1605 1610
CTA AAG GAT CTT CGA AGA CAA CTG GAA CTA CAT AAA GAT CAG ATG GTG 5076
Leu Lys Asp Leu Arg Arg Gln Leu Glu Leu His Lys Asp Gln Met Val
1615 1620 1625
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GAC ATT ATG AGA GCT TCT CAG GAT AAT CCG CAA GAT GGG ATT ATG GTG 5124
Asp Ile Met Arg Ala Ser Gln Asp Asn Pro Gln Asp Gly Ile Met Val
1630 1635 1640 1645
AAA CTA GTT GTC AAT TTG TTG CAG TTA TCC AAG ATG GCA ATA AAC CAC 5172
Lys Leu Val Val Asn Leu Leu Gln Leu Ser Lys Met Ala Ile Asn His
1650 1655 1660
ACT GGT GAA AAA GAA GTT CTA GAG GCT GTT GGA AGC TGC TTG GGA GAA 5220
Thr Gly Glu Lys Glu Val Leu Glu Ala Val Gly Ser Cys Leu Gly Glu
1665 1670 1675
GTG GGT CCT ATA GAT TTC TCT ACC ATA GCT ATA CAA CAT AGT AAA GAT 5268
Val Gly Pro Ile Asp Phe Ser Thr Ile Ala Ile Gln His Ser Lys Asp
1680 1685 1690
GCA TCT TAT ACC AAG GCC CTT AAG TTA TTT GAA GAT AAA GAA CTT CAG 5316
Ala Ser Tyr Thr Lys Ala Leu Lys Leu Phe Glu Asp Lys Glu Leu Gln
1695 1700 1705
TGG ACC TTC ATA ATG CTG ACC TAC CTG AAT AAC ACA CTG GTA GAA GAT 5364
Trp Thr Phe Ile Met Leu Thr Tyr Leu Asn Asn Thr Leu Val Glu Asp
1710 1715 1720 1725
TGT GTC AAA GTT CGA TCA GCA GCT GTT ACC TGT TTG AAA AAC ATT TTA 5412
Cys Val Lys Val Arg Ser Ala Ala Val Thr Cys Leu Lys Asn Ile Leu
1730 1735 1740
GCC ACA AAG ACT GGA CAT AGT TTC TGG GAG ATT TAT AAG ATG ACA ACA 5460
Ala Thr Lys Thr Gly His Ser Phe Trp Glu Ile Tyr Lys Met Thr Thr
1745 1750 1755
GAT CCA ATG CTG GCC TAT CTA CAG CCT TTT AGA ACA TCA AGA AAA AAG 5508
Asp Pro Met Leu Ala Tyr Leu Gln Pro Phe Arg Thr Ser Arg Lys Lys
1760 1765 1770
TTT TTA GAA GTA CCC AGA TTT GAC AAA GAA AAC CCT TTT GAA GGC CTG 5556
Phe Leu Glu Val Pro Arg Phe Asp Lys Glu Asn Pro Phe Glu Gly Leu
1775 1780 1785
GAT GAT ATA AAT CTG TGG ATT CCT CTA AGT GAA AAT CAT GAC ATT TGG 5604
Asp Asp Ile Asn Leu Trp Ile Pro Leu Ser Glu Asn His Asp Ile Trp
1790 1795 1800 1805
ATA AAG ACA CTG ACT TGT GCT TTT TTG GAC AGT GGA GGC ACA AAA TGT 5652
Ile Lys Thr Leu Thr Cys Ala Phe Leu Asp Ser Gly Gly Thr Lys Cys
1810 1815 1820
GAA ATT CTT CAA TTA TTA AAG CCA ATG TGT GAA GTG AAA ACT GAC TTT 5700
Glu Ile Leu Gln Leu Leu Lys Pro Met Cys Glu Val Lys Thr Asp Phe
1825 1830 1835
TGT CAG ACT GTA CTT CCA TAC TTG ATT CAT GAT ATT TTA CTC CAA GAT 5748
Cys Gln Thr Val Leu Pro Tyr Leu Ile His Asp Ile Leu Leu Gln Asp
1840 1845 1850
ACA AAT GAA TCA TGG AGA AAT CTG CTT TCT ACA CAT GTT CAG GGA TTT 5796
Thr Asn Glu Ser Trp Arg Asn Leu Leu Ser Thr His Val Gln Gly Phe
1855 1860 1865
TTC ACC AGC TGT CTT CGA CAC TTC TCG CAA ACG AGC CGA TCC ACA ACC 5844
Phe Thr Ser Cys Leu Arg His Phe Ser Gln Thr Ser Arg Ser Thr Thr
1870 1875 1880 1885
CCT GCA AAC TTG GAT TCA GAG TCA GAG CAC TTT TTC CGA TGC TGT TTG 5892
Pro Ala Asn Leu Asp Ser Glu Ser Glu His Phe Phe Arg Cys Cys Leu
1890 1895 1900
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GAT AAA AAA TCA CAA AGA ACA ATG CTT GCT GTT GTG GAC TAC ATG AGA 5940
Asp Lys Lys Ser Gln Arg Thr Met Leu Ala Val Val Asp Tyr Met Arg
1905 1910 1915
AGA CAA AAG AGA CCT TCT TCA GGA ACA ATT TTT AAT GAT GCT TTC TGG 5988
Arg Gln Lys Arg Pro Ser Ser Gly Thr Ile Phe Asn Asp Ala Phe Trp
1920 1925 1930
CTG GAT TTA AAT TAT CTA GAA GTT GCC AAG GTA GCT CAG TCT TGT GCT 6036
Leu Asp Leu Asn Tyr Leu Glu Val Ala Lys Val Ala Gln Ser Cys Ala
1935 1940 1945
GCT CAC TTT ACA GCT TTA CTC TAT GCA GAA ATC TAT GCA GAT AAG AAA 6084
Ala His Phe Thr Ala Leu Leu Tyr Ala Glu Ile Tyr Ala Asp Lys Lys
1950 1955 1960 1965
AGT ATG GAT GAT CAA GAG AAA AGA AGT CTT GCA TTT GAA GAA GGA AGC 6132
Ser Met Asp Asp Gin Glu Lys Arg Ser Leu Ala Phe Glu Glu Gly Ser
1970 1975 1980
CAG AGT ACA ACT ATT TCT AGC TTG AGT GAA AAA AGT AAA GAA GAA ACT 6180
Gln Ser Thr Thr Ile Ser Ser Leu Ser Glu Lys Ser Lys Glu Glu Thr
1985 1990 1995
GGA ATA AGT TTA CAG GAT CTT CTC TTA GAA ATC TAC AGA AGT ATA GGG 6228
Gly Ile Ser Leu Gln Asp Leu Leu Leu Glu Ile Tyr Arg Ser Ile Gly
2000 2005 2010
GAG CCA GAT AGT TTG TAT GGC TGT GGT GGA GGG AAG ATG TTA CAA CCC 6276
Glu Pro Asp Ser Leu Tyr Gly Cys Gly Gly Gly Lys Met Leu Gln Pro
2015 2020 2025
ATT ACT AGA CTA CGA ACA TAT GAA CAC GAA GCA ATG TGG GGC AAA GCC 6324
Ile Thr Arg Leu Arg Thr Tyr Glu His Glu Ala Met Trp Gly Lys Ala
2030 2035 2040 2045
CTA GTA ACA TAT GAC CTC GAA ACA GCA ATC CCC TCA TCA ACA CGC CAG 6372
Leu Val Thr Tyr Asp Leu Glu Thr Ala Ile Pro Ser Ser Thr Arg Gln
2050 2055 2060
GCA GGA ATC ATT CAG GCC TTG CAG AAT TTG GGA CTC TGC CAT ATT CTT 6420
Ala Gly Ile Ile Gln Ala Leu Gln Asn Leu Gly Leu Cys His Ile Leu
2065 2070 2075
TCC GTC TAT TTA AAA GGA TTG GAT TAT GAA AAT AAA GAC TGG TGT CCT 6468
Ser Val Tyr Leu Lys Gly Leu Asp Tyr Glu Asn Lys Asp Trp Cys Pro
2080 2085 2090
GAA CTA GAA GAA CTT CAT TAC CAA GCA GCA TGG AGG AAT ATG CAG TGG 6516
Glu Leu Glu Glu Leu His Tyr Gln Ala Ala Trp Arg Asn Met Gln Trp
2095 2100 2105
GAC CAT TGC ACT TCC GTC AGC AAA GAA GTA GAA GGA ACC AGT TAC CAT 6564
Asp His Cys Thr Ser Val Ser Lys Glu Val Glu Gly Thr Ser Tyr His
2110 2115 2120 2125
GAA TCA TTG TAC AAT GCT CTA CAA TCT CTA AGA GAC AGA GAA TTC TCT 6612
Glu Ser Leu Tyr Asn Ala Leu Gln Ser Leu Arg Asp Arg Glu Phe Ser
2130 2135 2140
ACA TTT TAT GAA AGT CTC AAA TAT GCC AGA GTA AAA GAA GTG GAA GAG 6660
Thr Phe Tyr Glu Ser Leu Lys Tyr Ala Arg Val Lys Glu Val Glu Glu
2145 2150 2155
ATG TGT AAG CGC AGC CTT GAG TCT GTG TAT TCG CTC TAT CCC ACA CTT 6708
Met Cys Lys Arg Ser Leu Glu Ser Val Tyr Ser Leu Tyr Pro Thr Leu
2160 2165 2170
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AGC AGG TTG CAG GCC ATT GGA GAG CTG GAA AGC ATT GGG GAG CTT TTC 6756
Ser Arg Leu Gln Ala Ile Gly Glu Leu Glu Ser Ile Gly Glu Leu Phe
2175 2180 2185
TCA AGA TCA GTC ACA CAT AGA CAA CTC TCT GAA GTA TAT ATT AAG TGG 6804
Ser Arg Ser Val Thr His Arg Gln Leu Ser Glu Val Tyr Ile Lys Trp
2190 2195 2200 2205
CAG AAA CAC TCC CAG CTT CTC AAG GAC AGT GAT TTT AGT TTT CAG GAG 6852
Gln Lys His Ser Gln Leu Leu Lys Asp Ser Asp Phe Ser Phe Gln Glu
2210 2215 2220
CCT ATC ATG GCT CTA CGC ACA GTC ATT TTG GAG ATC CTG ATG GAA AAG 6900
Pro Ile Met Ala Leu Arg Thr Val Ile Leu Glu Ile Leu Met Glu Lys
2225 2230 2235
GAA ATG GAC AAC TCA CAA AGA GAA TGT ATT AAG GAC ATT CTC ACC AAA 6948
Glu Met Asp Asn Ser Gln Arg Glu Cys Ile Lys Asp Ile Leu Thr Lys
2240 2245 2250
CAC CTT GTA GAA CTC TCT ATA CTG GCC AGA ACT TTC AAG AAC ACT CAG 6996
His Leu Val Glu Leu Ser Ile Leu Ala Arg Thr Phe Lys Asn Thr Gln
2255 2260 2265
CTC CCT GAA AGG GCA ATA TTT CAA ATT AAA CAG TAC AAT TCA GTT AGC 7044
Leu Pro Glu Arg Ala Ile Phe Gin Ile Lys Gln Tyr Asn Ser Val Ser
2270 2275 2280 2285
TGT GGA GTC TCT GAG TGG CAG CTG GAA GAA GCA CAA GTA TTC TGG GCA 7092
Cys Gly Val Ser Glu Trp Gln Leu Glu Glu Ala Gln Val Phe Trp Ala
2290 2295 2300
AAA AAG GAG CAG AGT CTT GCC CTG AGT ATT CTC AAG CAA ATG ATC AAG 7140
Lys Lys Glu Gln Ser Leu Ala Leu Ser Ile Leu Lys Gln Met Ile Lys
2305 2310 2315
AAG TTG GAT GCC AGC TGT GCA GCG AAC AAT CCC AGC CTA AAA CTT ACA 7188
Lys Leu Asp Ala Ser Cys Ala Ala Asn Asn Pro Ser Leu Lys Leu Thr
2320 2325 2330
TAC ACA GAA TGT CTG AGG GTT TGT GGC AAC TGG TTA GCA GAA ACG TGC 7236
Tyr Thr Glu Cys Leu Arg Val Cys Gly Asn Trp Leu Ala Glu Thr Cys
2335 2340 2345
TTA GAA AAT CCT GCG GTC ATC ATG CAG ACC TAT CTA GAA AAG GCA GTA 7284
Leu Glu Asn Pro Ala Val Ile Met Gln Thr Tyr Leu Glu Lys Ala Val
2350 2355 2360 2365
GAA GTT GCT GGA AAT TAT GAT GGA GAA AGT AGT GAT GAG CTA AGA AAT 7332
Glu Val Ala Gly Asn Tyr Asp Gly Glu Ser Ser Asp Glu Leu Arg Asn
2370 2375 2380
GGA AAA ATG AAG GCA TTT CTC TCA TTA GCC CGG TTT TCA GAT ACT CAA 7380
Gly Lys Met Lys Ala Phe Leu Ser Leu Ala Arg Phe Ser Asp Thr Gln
2385 2390 2395
TAC CAA AGA ATT GAA AAC TAC ATG AAA TCA TCG GAA ZTP GAA AAC AAG 7428
Tyr Gln Arg Ile Glu Asn Tyr Met Lys Ser Ser Glu Phe Glu Asn Lys
2400 2405 2410
CAA GCT CTC CTG AAA AGA GCC AAA GAG GAA GTA GGT CTC CTT AGG GAA 7476
Gln Ala Leu Leu Lys Arg Ala Lys Glu Glu Val Gly Leu Leu Arg Glu
2415 2420 2425
CAT AAA ATT CAG ACA AAC AGA TAC ACA GTA AAG GTT CAG CGA GAG CTG 7524
His Lys Ile Gln Thr Asn Arg Tyr Thr Val Lys Val Gln Arg Glu Leu
2430 2435 2440 2445
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GAG TTG GAT GAA TTA GCC CTG CGT GCA CTG AAA GAG GAT CGT AAA CGC 7572
Glu Leu Asp Glu Leu Ala Leu Arg Ala Leu Lys Glu Asp Arg Lys Arg
2450 2455 2460
TTC TTA TGT AAA GCA GTT GAA AAT TAT ATC AAC TGC TTA TTA AGT GGA 7620
Phe Leu Cys Lys Ala Val Glu Asn Tyr Ile Asn Cys Leu Leu Ser Gly
2465 2470 2475
GAA GAA CAT GAT ATG TGG GTA TTC CGG CTT TGT TCC CTC TGG CTT GAA 7668
Glu Glu His Asp Met Trp Val Phe Arg Leu Cys Ser Leu Trp Leu Glu
2480 2485 2490
AAT TCT GGA GTT TCT GAA GTC AAT GGC ATG ATG AAG AGA GAC GGA ATG 7716
Asn Ser Gly Val Ser Glu Val Asn Gly Met Met Lys Arg Asp Gly Met
2495 2500 2505
AAG ATT CCA ACA TAT AAA TTT TTG CCT CTT ATG TAC CAA TTG GCT GCT 7764
Lys Ile Pro Thr Tyr Lys Phe Leu Pro Leu Met Tyr Gln Leu Ala Ala
2510 2515 2520 2525
AGA ATG GGG ACC AAG ATG ATG GGA GGC CTA GGA TTT CAT GAA GTC CTC 7812
Arg Met Gly Thr Lys Met Met Gly Gly Leu Gly Phe His Glu Val Leu
2530 2535 2540
AAT AAT CTA ATC TCT AGA ATT TCA ATG GAT CAC CCC CAT CAC ACT TTG 7860
Asn Asn Leu Ile Ser Arg Ile Ser Met Asp His Pro His His Thr Leu
2545 2550 2555
TTT ATT ATA CTG GCC TTA GCA AAT GCA AAC AGA GAT GAA TTT CTG ACT 7908
Phe Ile Ile Leu Ala Leu Ala Asn Ala Asn Arg Asp Glu Phe Leu Thr
2560 2565 2570
AAA CCA GAG GTA GCC AGA AGA AGC AGA ATA ACT AAA AAT GTG CCT AAA 7956
Lys Pro Glu Val Ala Arg Arg Ser Arg Ile Thr Lys Asn Val Pro Lys
2575 2580 2585
CAA AGC TCT CAG CTT GAT GAG GAT CGA ACA GAG GCT GCA AAT AGA ATA 8004
Gln Ser Ser Gln Leu Asp Glu Asp Arg Thr Glu Ala Ala Asn Arg Ile
2590 2595 2600 2605
ATA TGT ACT ATC AGA AGT AGG AGA CCT CAG ATG GTC AGA AGT GTT GAG 8052
Ile Cys Thr Ile Arg Ser Arg Arg Pro Gln Met Val Arg Ser Val Glu
2610 2615 2620
GCA CTT TGT GAT GCT TAT ATT ATA TTA GCA AAC TTA GAT GCC ACT CAG 8100
Ala Leu Cys Asp Ala Tyr Ile Ile Leu Ala Asn Leu Asp Ala Thr Gln
2625 2630 2635
TGG AAG ACT CAG AGA AAA GGC ATA AAT ATT CCA GCA GAC CAG CCA ATT 8148
Trp Lys Thr Gln Arg Lys Gly Ile Asn Ile Pro Ala Asp Gln Pro Ile
2640 2645 2650
ACT AAA CTT AAG AAT TTA GAA GAT GTT GTT GTC CCT ACT ATG GAA ATT 8196
Thr Lys Leu Lys Asn Leu Glu Asp Val Val Val Pro Thr Met Glu Ile
2655 2660 2665
AAG GTG GAC CAC ACA GGA GAA TAT GGA AAT CTG GTG ACT ATA CAG TCA 8244
Lys Val Asp His Thr Gly Glu Tyr Gly Asn Leu Val Thr Ile Gln Ser
2670 2675 2680 2685
TTT AAA GCA GAA TTT CGC TTA GCA GGA GGT GTA AAT TTA CCA AAA ATA 8292
Phe Lys Ala Glu Phe Arg Leu Ala Gly Gly Val Asn Leu Pro Lys Ile
2690 2695 2700
ATA GAT TGT GTA GGT TCC GAT GGC AAG GAG AGG AGA CAG CTT GTT AAG 8340
Ile Asp Cys Val Gly Ser Asp Gly Lys Glu Arg Arg Gln Leu Val Lys
2705 2710 2715
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GGC CGT GAT GAC CTG AGA CAA GAT GCT GTC ATG CAA CAG GTC TTC CAG 8388
Gly Arg Asp Asp Leu Arg Gln Asp Ala Val Met Gln Gln Val Phe Gln
2720 2725 2730
ATG TGT AAT ACA TTA CTG CAG AGA AAC ACG GAA ACT AGG AAG AGG AAA 8436
Met Cys Asn Thr Leu Leu Gln Arg Asn Thr Glu Thr Arg Lys Arg Lys
2735 2740 2745
TTA ACT ATC TGT ACT TAT AAG GTG GTT CCC CTC TCT CAG CGA AGT GGT 8484
Leu Thr Ile Cys Thr Tyr Lys Val Val Pro Leu Ser Gln Arg Ser Gly
2750 2755 2760 2765
GTT CTT GAA TGG TGC ACA GGA ACT GTC CCC ATT GGT GAA TTT CTT GTT 8532
Val Leu Glu Trp Cys Thr Gly Thr Val Pro Ile Gly Glu Phe Leu Val
2770 2775 2780
AAC AAT GAA GAT GGT GCT CAT AAA AGA TAC AGG CCA AAT GAT TTC AGT 8580
Asn Asn Glu Asp Gly Ala His Lys Arg Tyr Arg Pro Asn Asp Phe Ser
2785 2790 2795
GCC TTT CAG TGC CAA AAG AAA ATG ATG GAG GTG CAA AAA AAG TCT TTT 8628
Ala Phe Gln Cys Gln Lys Lys Met Met Glu Val Gln Lys Lys Ser Phe
2800 2805 2810
GAA GAG AAA TAT GAA GTC TTC ATG GAT GTT TGC CAA AAT TTT CAA CCA 8676
Glu Glu Lys Tyr Glu Val Phe Met Asp Val Cys Gln Asn Phe Gln Pro
2815 2820 2825
GTT TTC CGT TAC TTC TGC ATG GAA AAA TTC TTG GAT CCA GCT ATT TGG 8724
Val Phe Arg Tyr Phe Cys Met Glu Lys Phe Leu Asp Pro Ala Ile Trp
2830 2835 2840 2845
TTT GAG AAG CGA TTG GCT TAT ACG CGC AGT GTA GCT ACT TCT TCT ATT 8772
Phe Glu Lys Arg Leu Ala Tyr Thr Arg Ser Val Ala Thr Ser Ser Ile
2850 2855 2860
GTT GGT TAC ATA CTT GGA CTT GGT GAT AGA CAT GTA CAG AAT ATC TTG 8820
Val Gly Tyr Ile Leu Gly Leu Gly Asp Arg His Val Gln Asn Ile Leu
2865 2870 2875
ATA AAT GAG CAG TCA GCA GAA CTT GTA CAT ATA GAT CTA GGT GTT GCT 8868
Ile Asn Glu Gln Ser Ala Glu Leu Val His Ile Asp Leu Gly Val Ala
2880 2885 2890
TTT GAA CAG GGC AAA ATC CTT CCT ACT CCT GAG ACA GTT CCT TTT AGA 8916
Phe Glu Gln Gly Lys Ile Leu Pro Thr Pro Glu Thr Val Pro Phe Arg
2895 2900 2905
CTC ACC AGA GAT ATT GTG GAT GGC ATG GGC ATT ACG GGT GTT GAA GGT 8964
Leu Thr Arg Asp Ile Val Asp Gly Met Gly Ile Thr Gly Val Glu Gly
2910 2915 2920 2925
GTC TTC AGA AGA TGC TGT GAG AAA ACC ATG GAA GTG ATG AGA AAC TCT 9012
Val Phe Arg Arg Cys Cys Glu Lys Thr Met Glu Val Met Arg Asn Ser
2930 2935 2940
CAG GAA ACT CTG TTA ACC ATT GTA GAG GTC CTT CTA TAT GAT CCA CTC 9060
Gln Glu Thr Leu Leu Thr Ile Val Glu Val Leu Leu Tyr Asp Pro Leu
2945 2950 2955
TTT GAC TGG ACC ATG AAT CCT TTG AAA GCT TTG TAT TTA CAG CAG AGG 9108
Phe Asp Trp Thr Met Asn Pro Leu Lys Ala Leu Tyr Leu Gln Gln Arg
2960 2965 2970
CCG GAA GAT GAA ACT GAG CTT CAC CCT ACT CTG AAT GCA GAT GAC CAA 9156
Pro Glu Asp Glu Thr Glu Leu His Pro Thr Leu Asn Ala Asp Asp Gln
2975 2980 2985
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GAA TGC AAA CGA AAT CTC AGT GAT ATT GAC CAG AGT TTC GAC AAA GTA 9204
Glu Cys Lys Arg Asn Leu Ser Asp Ile Asp Gln Ser Phe Asp Lys Val
2990 2995 3000 3005
GCT GAA CGT GTC TTA ATG AGA CTA CAA GAG AAA CTG AAA GGA GTG GAA 9252
Ala Glu Arg Val Leu Met Arg Leu Gln Glu Lys Leu Lys Gly Val Glu
3010 3015 3020
GAA GGC ACT GTG CTC AGT GTT GGT GGA CAG GTG AAT TTG CTC ATA CAG 9300
Glu Gly Thr Val Leu Ser Val Gly Gly Gln Val Asn Leu Leu Ile Gln
3025 3030 3035
CAG GCC ATA GAC CCC AAA AAT CTC AGC CGA CTT TTC CCA GGA TGG AAA 9348
Gln Ala Ile Asp Pro Lys Asn Leu Ser Arg Leu Phe Pro Gly Trp Lys
3040 3045 3050
GCT TGG GTG TGATCTTCAG TATATGAATT ACCCTTTC 9385
Ala Trp Val
3055
(2) INFORMATION FOR SEQ ID NO:35:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 3056 amino acids
(B) TYPE: amino acid
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: protein
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:35:
Met Ser Leu Val Leu Asn Asp Leu Leu Ile Cys Cys Arg Gln Leu Glu
1 5 10 15
His Asp Arg Ala Thr Glu Arg Lys Lys Glu Val Glu Lys Phe Lys Arg
20 25 30
Leu Ile Arg Asp Pro Glu Thr Ile Lys His Leu Asp Arg His Ser Asp
35 40 45
Ser Lys Gln Gly Lys Tyr Leu Asn Trp Asp Ala Val Phe Arg Phe Leu
50 55 60
Gln Lys Tyr Ile Gln Lys Glu Thr Glu Cys Leu Arg Ile Ala Lys Pro
65 70 75 80
Asn Val Ser Ala Ser Thr Gln Ala Ser Arg Gln Lys Lys Met Gln Glu
85 90 95
Ile Ser Ser Leu Val Lys Tyr Phe Ile Lys Cys Ala Asn Arg Arg Ala
100 105 110
Pro Arg Leu Lys Cys Gln Glu Leu Leu Asn Tyr Ile Met Asp Thr Val
115 120 125
Lys Asp Ser Ser Asn Gly Ala Ile Tyr Gly Ala Asp Cys Ser Asn Ile
130 135 140
Leu Leu Lys Asp Ile Leu Ser Val Arg Lys Tyr Trp Cys Glu Ile Ser
145 150 155 160
Gln Gln Gln Trp Leu Glu Leu Phe Ser Val Tyr Phe Arg Leu Tyr Leu
165 170 175
Lys Pro Ser Gln Asp Val His Arg Val Leu Val Ala Arg Ile Ile His
180 185 190
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Ala Val Thr Lys Gly Cys Cys Ser Gln Thr Asp Gly Leu Asn Ser Lys
195 200 205
Phe Leu Asp Phe Phe Ser Lys Ala Ile Gln Cys Ala Arg Gln Glu Lys
210 215 220
Ser Ser Ser Gly Leu Asn His Ile Leu Ala Ala Leu Thr Ile Phe Leu
225 230 235 240
Lys Thr Leu Ala Val Asn Phe Arg Ile Arg Val Cys Glu Leu Gly Asp
245 250 255
Glu Ile Leu Pro Thr Leu Leu Tyr Ile Trp Thr Gln His Arg Leu Asn
260 265 270
Asp Ser Leu Lys Glu Val Ile Ile Glu Leu Phe Gln Leu Gln Ile Tyr
275 280 285
Ile His His Pro Lys Gly Ala Lys Thr Gln Glu Lys Gly Ala Tyr Glu
290 295 300
Ser Thr Lys Trp Arg Ser Ile Leu Tyr Asn Leu Tyr Asp Leu Leu Val
305 310 315 320
Asn Glu Ile Ser His Ile Gly Ser Arg Gly Lys Tyr Ser Ser Gly Phe
325 330 335
Arg Asn Ile Ala Val Lys Glu Asn Leu Ile Glu Leu Met Ala Asp Ile
340 345 350
Cys His Gln Val Phe Asn Glu Asp Thr Arg Ser Leu Glu Ile Ser Gln
355 360 365
Ser Tyr Thr Thr Thr Gln Arg Glu Ser Ser Asp Tyr Ser Val Pro Cys
370 375 380
Lys Arg Lys Lys Ile Glu Leu Gly Trp Glu Val Ile Lys Asp His Leu
385 390 395 400
Gln Lys Ser Gln Asn Asp Phe Asp Leu Val Pro Trp Leu Gln Ile Ala
405 410 415
Thr Gin Leu Ile Ser Lys Tyr Pro Ala Ser Leu Pro Asn Cys Glu Leu
420 425 430
Ser Pro Leu Leu Met Ile Leu Ser Gln Leu Leu Pro Gln Gln Arg His
435 440 445
Gly Glu Arg Thr Pro Tyr Val Leu Arg Cys Leu Thr Glu Val Ala Leu
450 455 460
Cys Gln Asp Lys Arg Ser Asn Leu Glu Ser Ser Gln Lys Ser Asp Leu
465 470 475 480
Leu Lys Leu Trp Asn Lys Ile Trp Cys Ile Thr Phe Arg Gly Ile Ser
485 490 495
Ser Glu Gln Ile Gln Ala Glu Asn Phe Gly Leu Leu Gly Ala Ile Ile
500 505 510
Gln Gly Ser Leu Val Glu Val Asp Arg Glu Phe Trp Lys Leu Phe Thr
515 520 525
Gly Ser Ala Cys Arg Pro Ser Cys Pro Ala Val Cys Cys Leu Thr Leu
530 535 540
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Ala Leu Thr Thr Ser Ile Val Pro Gly Ala Val Lys Met Gly Ile Glu
545 550 555 560
Gln Asn Met Cys Glu Val Asn Arg Ser Phe Ser Leu Lys Glu Ser Ile
565 570 575
Met Lys Trp Leu Leu Phe Tyr Gin Leu Glu Gly Asp Leu Glu Asn Ser
580 585 590
Thr Glu Val Pro Pro Ile Leu His Ser Asn Phe Pro His Leu Val Leu
595 600 605
Glu Lys Ile Leu Val Ser Leu Thr Met Lys Asn Cys Lys Ala Ala Met
610 615 620
Asn Phe Phe Gln Ser Val Pro Glu Cys Glu His His Gln Lys Asp Lys
625 630 635 640
Glu Glu Leu Ser Phe Ser Glu Val Glu Glu Leu Phe Leu Gln Thr Thr
645 650 655
Phe Asp Lys Met Asp Phe Leu Thr Ile Val Arg Glu Cys Gly Ile Glu
660 665 670
Lys His Gln Ser Ser Ile Gly Phe Ser Val His Gln Asn Leu Lys Glu
675 680 685
Ser Leu Asp Arg Cys Leu Leu Gly Leu Ser Glu Gln Leu Leu Asn Asn
690 695 700
Tyr Ser Ser Glu Ile Thr Asn Ser Glu Thr Leu Val Arg Cys Ser Arg
705 710 715 720
Leu Leu Val Gly Val Leu Gly Cys Tyr Cys Tyr Met Gly Val Ile Ala
725 730 735
Glu Glu Glu Ala Tyr Lys Ser Glu Leu Phe Gln Lys Ala Asn Ser Leu
740 745 750
Met Gln Cys Ala Gly Glu Ser Ile Thr Leu Phe Lys Asn Lys Thr Asn
755 760 765
Glu Glu Phe Arg Ile Gly Ser Leu Arg Asn Met Met Gln Leu Cys Thr
770 775 780
Arg Cys Leu Ser Asn Cys Thr Lys Lys Ser Pro Asn Lys Ile Ala Ser
785 790 795 800
Gly Phe Phe Leu Arg Leu Leu Thr Ser Lys Leu Met Asn Asp Ile Ala
805 810 815
Asp Ile Cys Lys Ser Leu Ala Ser Phe Ile Lys Lys Pro Phe Asp Arg
820 825 830
Gly Glu Val Glu Ser Met Glu Asp Asp Thr Asn Gly Asn Leu Met Glu
835 840 845
Val Glu Asp Gln Ser Ser Met Asn Leu Phe Asn Asp Tyr Pro Asp Ser
850 855 860
Ser Val Ser Asp Ala Asn Glu Pro Gly Glu Ser Gln Ser Thr Ile Gly
865 870 875 880
Ala Ile Asn Pro Leu Ala Glu Giu Tyr Leu Ser Lys Gln Asp Leu Leu
885 890 895
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Phe Leu Asp Met Leu Lys Phe Leu Cys Leu Cys Val Thr Thr Ala Gln
900 9U5 910
Thr Asn Thr Val Ser Phe Arg Ala Ala Asp Ile Arg Arg Lys Leu Leu
915 920 925
Met Leu Ile Asp Ser Ser Thr Leu Glu Pro Thr Lys Ser Leu His Leu
930 935 940
His Met Tyr Leu Met Leu Leu Lys Glu Leu Pro Gly Glu Glu Tyr Pro
945 950 955 960
Leu Pro Met Glu Asp Val Leu Glu Leu Leu Lys Pro Leu Ser Asn Val
965 970 975
Cys Ser Leu Tyr Arg Arg Asp Gln Asp Val Cys Lys Thr Ile Leu Asn
980 985 990
His Val Leu His Val Val Lys Asn Leu Gly Gln Ser Asn Met Asp Ser
995 1000 1005
Glu Asn Thr Arg Asp Ala Gln Gly Gln Phe Leu Thr Val Ile Gly Ala
1010 1015 1020
Phe Trp His Leu Thr Lys Glu Arg Lys Tyr Ile Phe Ser Val Arg Met
1025 1030 1035 1040
Ala Leu Val Asn Cys Leu Lys Thr Leu Leu Glu Ala Asp Pro Tyr Ser
1045 1050 1055
Lys Trp Ala Ile Leu Asn Val Met Gly Lys Asp Phe Pro Val Asn Glu
1060 1065 1070
Val Phe Thr Gln Phe Leu Ala Asp Asn His His Gln Val Arg Met Leu
1075 1080 1085
Ala Ala Glu Ser Ile Asn Arg Leu Phe Gln Asp Thr Lys Gly Asp Ser
1090 1095 1100
Ser Arg Leu Leu Lys Ala Leu Pro Leu Lys Leu Gln Gln Thr Ala Phe
1105 1110 1115 1120
Glu Asn Ala Tyr Leu Lys Ala Gln Glu Gly Met Arg Glu Met Ser His
1125 1130 1135
Ser Ala Glu Asn Pro Glu Thr Leu Asp Glu Ile Tyr Asn Arg Lys Ser
1140 1145 1150
Val Leu Leu Thr Leu Ile Ala Val Val Leu Ser Cys Ser Pro Ile Cys
1155 1160 1165
Glu Lys Gln Ala Leu Phe Ala Leu Cys Lys Ser Val Lys Glu Asn Giy
1170 1175 1180
Leu Glu Pro His Leu Val Lys Lys Val Leu Glu Lys Val Ser Glu Thr
1185 1190 1195 1200
Phe Gly Tyr Arg Arg Leu Glu Asp Phe Met Ala Ser His Leu Asp Tyr
1205 1210 1215
Leu Val Leu Glu Trp Leu Asn Leu Gln Asp Thr Glu Tyr Asn Leu Ser
1220 1225 1230
Ser Phe Pro Phe Ile Leu Leu Asn Tyr Thr Asn Ile Glu Asp Phe Tyr
1235 1240 1245
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Arg Ser Cys Tyr Lys Val Leu Ile Pro His Leu Val Ile Arg Ser His
1250 1255 1260
Phe Asp Glu Val Lys Ser Ile Ala Asn Gln Ile Gln Glu Asp Trp Lys
1265 1270 1275 1280
Ser Leu Leu Thr Asp Cys Phe Pro Lys Ile Leu Val Asn Ile Leu Pro
1285 1290 1295
Tyr Phe Ala Tyr Glu Gly Thr Arg Asp Ser Gly Met Ala Gln Gln Arg
1300 1305 1310
Glu Thr Ala Thr Lys Val Tyr Asp Met Leu Lys Ser Glu Asn Leu Leu
1315 1320 1325
Gly Lys Gln Ile Asp His Leu Phe Ile Ser Asn Leu Pro Glu Ile Val
1330 1335 1340
Val Glu Leu Leu Met Thr Leu His Glu Pro Ala Asn Ser Ser Ala Ser
1345 1350 1355 1360
Gln Ser Thr Asp Leu Cys Asp Phe Ser Gly Asp Leu Asp Pro Ala Pro
1365 1370 1375
Asn Pro Pro His Phe Pro Ser His Val Ile Lys Ala Thr Phe Ala Tyr
1380 1385 1390
Ile Ser Asn Cys His Lys Thr Lys Leu Lys Ser Ile Leu Glu Ile Leu
1395 1400 1405
Ser Lys Ser Pro Asp Ser Tyr Gln Lys Ile Leu Leu Ala Ile Cys Glu
1410 1415 1420
Gln Ala Ala Glu Thr Asn Asn Val Tyr Lys Lys His Arg Ile Leu Lys
1425 1430 1435 1440
Ile Tyr His Leu Phe Val Ser Leu Leu Leu Lys Asp Ile Lys Ser Gly
1445 1450 1455
Leu Gly Gly Ala Trp Ala Phe Val Leu Arg Asp Val Ile Tyr Thr Leu
1460 1465 1470
Ile His Tyr Ile Asn Gln Arg Pro Ser Cys Ile Met Asp Val Ser Leu
1475 1480 1485
Arg Ser Phe Ser Leu Cys Cys Asp Leu Leu Ser G2n Val Cys Gln Thr
1490 1495 1500
Ala Val Thr Tyr Cys Lys Asp Ala Leu Glu Asn His Leu His Val Ile
1505 1510 1515 1520
Val Gly Thr Leu Ile Pro Leu Val Tyr Glu Gln Val Glu Val Gln Lys
1525 1530 1535
Gin Val Leu Asp Leu Leu Lys Tyr Leu Val Ile Asp Asn Lys Asp Asn
1540 1545 1550
Glu Asn Leu Tyr Ile Thr Ile Lys Leu Leu Asp Pro Phe Pro Asp His
1555 1560 1565
Val Val Phe Lys Asp Leu Arg Ile Thr Gln Gln Lys Ile Lys Tyr Ser
1570 1575 1580
Arg Gly Pro Phe Ser Leu Leu Glu Glu Ile Asn His Phe Leu Ser Val
1585 1590 1595 1600
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Ser Val Tyr Asp Ala Leu Pro Leu Thr Arg Leu Glu Gly Leu Lys Asp
1605 1610 1615
Leu Arg Arg Gln Leu Glu Leu His Lys Asp Gln Met Val Asp Ile Met
1620 1625 1630
Arg Ala Ser Gln Asp Asn Pro Gln Asp Gly Ile Met Val Lys Leu Val
1635 1640 1645
Val Asn Leu Leu Gln Leu Ser Lys Met Ala Ile Asn His Thr Gly Glu
1650 1655 1660
Lys Glu Val Leu Glu Ala Val Gly Ser Cys Leu Gly Glu Val Gly Pro
1665 1670 1675 1680
Ile Asp Phe Ser Thr Ile Ala Ile Gln His Ser Lys Asp Ala Ser Tyr
1685 1690 1695
Thr Lys Ala Leu Lys Leu Phe Glu Asp Lys Glu Leu Gln Trp Thr Phe
1700 1705 1710
Ile Met Leu Thr Tyr Leu Asn Asn Thr Leu Val Glu Asp Cys Val Lys
1715 1720 1725
Val Arg Ser Ala Ala Val Thr Cys Leu Lys Asn Ile Leu Ala Thr Lys
1730 1735 1740
Thr Gly His Ser Phe Trp Glu Ile Tyr Lys Met Thr Thr Asp Pro Met
1745 1750 1755 1760
Leu Ala Tyr Leu Gin Pro Phe Arg Thr Ser Arg Lys Lys Phe Leu Glu
1765 1770 1775
Val Pro Arg Phe Asp Lys Glu Asn Pro Phe Glu Gly Leu Asp Asp Ile
1780 1785 1790
Asn Leu Trp Ile Pro Leu Ser Glu Asn His Asp Ile Trp Ile Lys Thr
1795 1800 1805
Leu Thr Cys Ala Phe Leu Asp Ser Gly Gly Thr Lys Cys Glu Ile Leu
1810 1815 1820
Gln Leu Leu Lys Pro Met Cys Glu Val Lys Thr Asp Phe Cys Gln Thr
1825 1830 1835 1840
Val Leu Pro Tyr Leu Ile His Asp Ile Leu Leu Gln Asp Thr Asn Glu
1845 1850 1855
Ser Trp Arg Asn Leu Leu Ser Thr His Val Gln Gly Phe Phe Thr Ser
1860 1865 1870
Cys Leu Arg His Phe Ser Gln Thr Ser Arg Ser Thr Thr Pro Ala Asn
1875 1880 1885
Leu Asp Ser Glu Ser Glu His Phe Phe Arg Cys Cys Leu Asp Lys Lys
1890 1895 1900
Ser Gln Arg Thr Met Leu Ala Val Val Asp Tyr Met Arg Arg Gln Lys
1905 1910 1915 1920
Arg Pro Ser Ser Gly Thr Ile Phe Asn Asp Ala Phe Trp Leu Asp Leu
1925 1930 1935
Asn Tyr Leu Glu Val Ala Lys Val Ala Gln Ser Cys Ala Ala His Phe
1940 1945 1950
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Thr Ala Leu Leu Tyr Ala Glu Ile Tyr Ala Asp Lys Lys Ser Met Asp
1955 1960 1965
Asp Gln Glu Lys Arg Ser Leu Ala Phe Glu Glu Gly Ser Gln Ser Thr
1970 1975 1980
Thr Ile Ser Ser Leu Ser Glu Lys Ser Lys Glu Glu Thr Gly Ile Ser
1985 1990 1995 2000
Leu Gln Asp Leu Leu Leu Glu Ile Tyr Arg Ser Ile Gly Glu Pro Asp
2005 2010 2015
Ser Leu Tyr Gly Cys Gly Gly Gly Lys Met Leu Gln Pro Ile Thr Arg
2020 2025 2030
Leu Arg Thr Tyr Glu His Glu Ala Met Trp Gly Lys Ala Leu Val Thr
2035 2040 2045
Tyr Asp Leu Glu Thr Ala Ile Pro Ser Ser Thr Arg Gln Ala Gly Ile
2050 2055 2060
Ile Gin Ala Leu Gln Asn Leu Gly Leu Cys His Ile Leu Ser Val Tyr
2065 2070 2075 2080
Leu Lys Gly Leu Asp Tyr Glu Asn Lys Asp Trp Cys Pro Glu Leu Glu
2085 2090 2095
Glu Leu His Tyr Gln Ala Ala Trp Arg Asn Met Gln Trp Asp His Cys
2100 2105 2110
Thr Ser Val Ser Lys Glu Val Glu Gly Thr Ser Tyr His Glu Ser Leu
2115 2120 2125
Tyr Asn Ala Leu Gln Ser Leu Arg Asp Arg Glu Phe Ser Thr Phe Tyr
2130 2135 2140
Glu Ser Leu Lys Tyr Ala Arg Val Lys Glu Val Glu Glu Met Cys Lys
2145 2150 2155 2160
Arg Ser Leu Glu Ser Val Tyr Ser Leu Tyr Pro Thr Leu Ser Arg Leu
2165 2170 2175
Gln Ala Ile Gly Glu Leu Glu Ser Ile Gly Glu Leu Phe Ser Arg Ser
2180 2185 2190
Val Thr His Arg Gln Leu Ser Giu Val Tyr Ile Lys Trp Gln Lys His
2195 2200 2205
Ser Gln Leu Leu Lys Asp Ser Asp Phe Ser Phe Gin Glu Pro Ile Met
2210 2215 2220
Ala Leu Arg Thr Val Ile Leu Glu Ile Leu Met Glu Lys Glu Met Asp
2225 2230 2235 2240
Asn Ser Gln Arg Glu Cys Ile Lys Asp Ile Leu Thr Lys His Leu Val
2245 2250 2255
Glu Leu Ser Ile Leu Ala Arg Thr Phe Lys Asn Thr Gln Leu Pro Glu
2260 2265 2270
Arg Ala Ile Phe Gln Ile Lys Gln Tyr Asn Ser Val Ser Cys Gly Val
2275 2280 2285
Ser Glu Trp Gln Leu Glu Glu Ala Gln Val Phe Trp Ala Lys Lys Glu
2290 2295 2300
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Gln Ser Leu Ala Leu Ser Ile Leu Lys Gln Met Ile Lys Lys Leu Asp
2305 2310 2315 2320
Ala Ser Cys Ala Ala Asn Asn Pro Ser Leu Lys Leu Thr Tyr Thr Glu
2325 2330 2335
Cys Leu Arg Val Cys Gly Asn Trp Leu Ala Glu Thr Cys Leu Glu Asn
2340 2345 2350
Pro Ala Val Ile Met Gln Thr Tyr Leu Glu Lys Ala Val Glu Val Ala
2355 2360 2365
Gly Asn Tyr Asp Gly Glu Ser Ser Asp Glu Leu Arg Asn Gly Lys Met
2370 2375 2380
Lys Ala Phe Leu Ser Leu Ala Arg Phe Ser Asp Thr Gln Tyr Gln Arg
2385 2390 2395 2400
Ile Glu Asn Tyr Met Lys Ser Ser Glu Phe Glu Asn Lys Gln Ala Leu
2405 2410 2415
Leu Lys Arg Ala Lys Glu Glu Val Gly Leu Leu Arg Glu His Lys Ile
2420 2425 2430
Gln Thr Asn Arg Tyr Thr Val Lys Val Gln Arg Glu Leu Glu Leu Asp
2435 2440 2445
Glu Leu Ala Leu Arg Ala Leu Lys Glu Asp Arg Lys Arg Phe Leu Cys
2450 2455 2460
Lys Ala Val Glu Asn Tyr Ile Asn Cys Leu Leu Ser Gly Glu Glu His
2465 2470 2475 2480
Asp Met Trp Val Phe Arg Leu Cys Ser Leu Trp Leu Glu Asn Ser Gly
2485 2490 2495
Val Ser Glu Val Asn Gly Met Met Lys Arg Asp Gly Met Lys Ile Pro
2500 2505 2510
Thr Tyr Lys Phe Leu Pro Leu Met Tyr Gln Leu Ala Ala Arg Met Gly
2515 2520 2525
Thr Lys Met Met Gly Gly Leu Gly Phe His Glu Val Leu Asn Asn Leu
2530 2535 2540
Ile Ser Arg Ile Ser Met Asp His Pro His His Thr Leu Phe Ile Ile
2545 2550 2555 2560
Leu Ala Leu Ala Asn Ala Asn Arg Asp Glu Phe Leu Thr Lys Pro Glu
2565 2570 2575
Val Ala Arg Arg Ser Arg Ile Thr Lys Asn Val Pro Lys Gln Ser Ser
2580 2585 2590
Gln Leu Asp Glu Asp Arg Thr Glu Ala Ala Asn Arg Ile Ile Cys Thr
2595 2600 2605
Ile Arg Ser Arg Arg Pro Gln Met Val Arg Ser Val Glu Ala Leu Cys
2610 2615 2620
Asp Ala Tyr Ile Ile Leu Ala Asn Leu Asp Ala Thr Gln Trp Lys Thr
2625 2630 2635 2640
Gin Arg Lys Gly Ile Asn Ile Pro Ala Asp Gin Pro Ile Thr Lys Leu
2645 2650 2655
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Lvs Asn Leu Glu Asp Val Val Val Pro Thr Met Glu Ile Lys Val Asp
2660 2665 2670
His Thr Gly Glu Tyr Gly Asn Leu Val Thr Ile Gln Ser Phe Lys Ala
2675 2680 2685
Glu Phe Arg Leu Ala Gly Gly Val Asn Leu Pro Lys Ile Ile Asp Cys
2690 2695 2700
Val Gly Ser Asp Gly Lys Glu Arg Arg Gln Leu Val Lys Gly Arg Asp
2705 2710 2715 2720
Asp Leu Arg Gln Asp Ala Val Met Gln Gln Val Phe Gln Met Cys Asn
2725 2730 2735
Thr Leu Leu Gln Arg Asn Thr Glu Thr Arg Lys Arg Lys Leu Thr Ile
2740 2745 2750
Cys Thr Tyr Lys Val Val Pro Leu Ser Gln Arg Ser Gly Val Leu Glu
2755 2760 2765
Trp Cys Thr Gly Thr Val Pro Ile Gly Glu Phe Leu Val Asn Asn Glu
2770 2775 2780
Asp Gly Ala His Lys Arg Tyr Arg Pro Asn Asp Phe Ser Ala Phe Gln
2785 2790 2795 2800
Cys Gln Lys Lys Met Met Glu Val Gln Lys Lys Ser Phe Glu Glu Lys
2805 2810 2815
Tyr Glu Val Phe Met Asp Val Cys Gln Asn Phe Gln Pro Val Phe Arg
2820 2825 2830
Tyr Phe Cys Met Glu Lys Phe Leu Asp Pro Ala Ile Trp Phe Glu Lys
2835 2840 2845
Arg Leu Ala Tyr Thr Arg Ser Val Ala Thr Ser Ser Ile Val Gly Tyr
2850 2855 2860
Ile Leu Gly Leu Gly Asp Arg His Val Gln Asn Ile Leu Ile Asn Glu
2865 2870 2875 2880
Gln Ser Ala Glu Leu Val His Ile Asp Leu Gly Val Ala Phe Glu Gln
2885 2890 2895
Gly Lys Ile Leu Pro Thr Pro Glu Thr Val Pro Phe Arg Leu Thr Arg
2900 2905 2910
Asp Ile Val Asp Gly Met Gly Ile Thr Gly Val Glu Giy Val Phe Arg
2915 2920 2925
Arg Cys Cys Glu Lys Thr Met Glu Val Met Arg Asn Ser Gln Glu Thr
2930 2935 2940
Leu Leu Thr Ile Val Glu Val Leu Leu Tyr Asp Pro Leu Phe Asp Trp
2945 2950 2955 2960
Thr Met Asn Pro Leu Lys Ala Leu Tyr Leu Gln Gln Arg Pro Giu Asp
2965 2970 2975
Glu Thr Glu Leu His Pro Thr Leu Asn Ala Asp Asp Gln Glu Cys Lys
2980 2985 2990
Arg Asn Leu Ser Asp Ile Asp Gln Ser Phe Asp Lys Val Ala Glu Arg
2995 3000 3005
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Val Leu Met Arg Leu Gln Glu Lys Leu Lys Gly Val Glu Glu Gly Thr
3010 3015 3020
Val Leu Ser Val Gly Gly Gln Val Asn Leu Leu Ile Gln Gln Ala Ile
3025 3030 3035 3040
Asp Pro Lys Asn Leu Ser Arg Leu Phe Pro Gly Trp Lys Ala Trp Val
3045 3050 3055
(2) INFORMATION FOR SEQ ID NO:36:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 19 amino acids
(B) TYPE: amino acid
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID N0:36:
Met Ser Gly Gly Ser Ser Cys Gln Thr Pro Ser Arg Ala Ile Pro Ala
1 5 10 15
Thr Arg Arg
(2) INFORMATION FOR SEQ ID NO:37:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:37:
Gly Asp Tyr Ser Thr Thr Pro Gly Gly Thr Leu Phe Ser Thr Thr Pro
1 5 10 15
Gly Gly Thr Arg Arg
(2) INFORMATION FOR SEQ ID NO:38:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 12 amino acids
(B) TYPE: amino acid
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:38:
Glu Cys Arg Asn Ser Pro Val Thr Lys Thr Arg Arg
1 5 10
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(2) INFORMATION FOR SEQ ID NO:39:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 12 amino acids
(B) TYPE: amino acid
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:39:
Gly Val Thr Ser Pro Ser Ser Asp Glu Pro Arg Arg
1 5 10
(2) INFORMATION FOR SEQ ID NO:40:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 10 amino acids
(B) TYPE: amino acid
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:40:
Met Glu Ala Ser Gln Ser His Leu Arg Arg
1 5 10
(2) INFORMATION FOR SEQ ID NO:41:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 12 amino acids
(B) TYPE: amino acid
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:41:
Arg Arg Asn Ser Pro Glu Asp Lys Arg Ala Gly Gly
1 5 10
(2) INFORMATION FOR SEQ ID NO:42:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 12 amino acids
(B) TYPE: amino acid
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:
Gly Glu Glu Ser Gln Phe Glu Met Asp Ile Arg Arg
1 5 10
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- 204 -
INDICATIONS RELATING TO A DEPOSITED MICROORGANISM
(PCF Rule 13Gis)
A. The indications made below relate to the microorganism referred to in the
description
on page 10 , lines 2-6
B. IDEiVTIFICATION OF DEPOSIT Further deposits are identified on an additional
sheet
Name of depositary institution
American Type Culture Collection
Address of depositary institution (including postal code and country)
12301 Parklawn Drive
Rockville, MD 20852
us
Date of deposit Accession Number s
7 Noventber 1996 HB 12233 and HB 12234
C. ADDITIONAL INDICATIONS (leave blank iJnot applicablr) This information is
continued on an additional sbeet ~
"In respect of those designations in which a European patent is sought,
a sample of the deposited microorganism will be made available until the
publication of the mention of the grant of the European patent or until the
date on which the application has been refused or withdrawn or is deemed to
be withdrawn, only by the issue of such a sample to an expert nominated by
the person requesting the sample (Rule 28(4) EPC)."
D. DESIGNATED STATES FOR WHICH INDICATIONS ARE MADE
(i/theindicationtarenot(orapduignatedStatu)
EP
E. SEPARATE FURNISHING OF INDICATIONS (leave blank if not applicablt)
The indications listed below wilt be submitted to the International Bureau
later (specify tkegaraaf naiureofthe indicatioRt e.g., 'Accersion
Number ofDeposit')
For receiving Office use only For International Bureau use only
f[XTbis sheet was received with tbe international application This sheet was
received by the international Bureau on:
Auth rFzed~ fj ~'1 ;~ Authorized ofGcer
{T~~ r
1 ~
Forrn PCT/RO/134 (July 1992)