Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02412306 2002-11-22
DESCRIPTION
Human Sodium Channels 8CN12A and SCNBA
Technical Field
The present invention relates to a novel human nervous system sodium
channel a subunit SCN 12A and its splicing variant SCN 12A-s, to a novel human
sodium channel SCNBA, to human genes encoding these molecules, and to cDNAs of
these genes.
Background Art
Membrane voltage-gated sodium channels are membrane protein
molecules existing in the cell membrane of excitable cells such as neurons and
muscle cells. Generating an action potential, excitable cells attain their
functions.
For neurons, for example, the action potential generated in them is propagated
by
axons, and neurons thereby attain their function, information transmission.
Sodium channels are protein molecules that participate in the initiation and
propagation of action potential along with potassium channels.
The membrane voltage-gated sodium channel is composed of plural
subunits, of which the a subunit has the essential function of the channel.
The
existence of plural a subunit genes in mammals has heretofore been clarified.
In
human, at least 9 genes, SCN1A (2q24), SCN2A (2q23-q24.3), SCN3A (2q24-q31),
SCN4A (17q23.1-q25.3), SCNSA (3p21-24), SCN6A (2q21-q23), SCNBA (12q13.1),
SCN9A (2q24), and SCN 10A (3p22-q24) have been clarified (human chromosome
location is parenthesized). At present, however, not all these genes have been
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CA 02412306 2002-11-22
cloned in complete forms. For some of them, only partial sequences have been
reported; and for some others, human homologous genes have been identified
from
mouse or rat homologous sequences. In particular, the full-length cDNA of
SCNBA
has not as yet been identified, and all the protein which the gene encodes is
not
completely known.
Recently, in human and animals, some diseases caused by the mutation of
these genes have been identified, and it has been clarified that the sodium
channel a
subunits are not only physiologically important molecules but also their
mutation
causes diseases. For example, it has been clarified that the mutation of SCN4A
causes familial hyperkalemic periodic paralysis and the mutation of SCNSA
causes
long QT syndrome type 3. In addition, it is known that mouse mutant motor
endplate disease (med) is caused by the mutation of SCNBA, though the
corresponding disease in human is not known.
As mentioned above, it is extremely important to clarify the
molecular-biological substance and the function of membrane voltage-gated
sodium
channels for understanding the physiological mechanism in human and for
identifying the direct causes of various diseases. Moreover, inferring from
their
physiological function, the substances that act on sodium channels could be
medicines (e.g., narcotics, sedatives, muscle relaxants) for controlling the
function of
the cells that express the substances, and the substances are important for
the
target of novel medicine development.
Through genetic cloning for the purpose of identifying all sodium channels
that are expressed in human nervous system, the inventors of this application
have
found that AA446997 registered as the partial sequence of SCNBA in the EST
(Expressed Sequence Tags) data base is not the partial sequence of SCNBA and,
in
addition, it differs from the sequence of any other known sodium channel gene.
With that, the inventors have succeeded in cloning the full-length cDNA that
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CA 02412306 2002-11-22
includes the sequence AA446997, and named the cDNA-encoding novel sodium
channel SCN 12A.
In addition, the inventors have succeeded in cloning the full-length cDNA of
human SCNBA, of which only the partial sequence was identified, and in
clarifying
the whole amino acid sequence of SCNBA which encodes the cDNA.
Disclosure of the laueafioa
One object of this application is to concretely provide the novel sodium
channel SCN 12A which the inventors have found, and its gene and cDNA. Another
object of this application is to provide the sodium channel SCNBA which the
inventors have entirely clarified, and its gene and cDNA. Still another object
of this
application is to provide the antibodies to SCN12A and SCNBA.
This application is for the invention to solve the problems noted above,
providing a purified human sodium channel SCN12A having the amino acid
sequence of SEQ ID NO. 2, and a purified human sodium channel SCN12A-s having
the amino acid sequence of SEQ ID NO. 4.
This application also provides a purified human sodium channel SCNBA
having the amino acid sequence of SEQ ID NO. 6.
This application further provides a human gene encoding the
above-mentioned SCN12A and SCN12A-s, which exists in human chromosome No.
3 short arm (3p23-p21.3); and a human gene encoding the above-mentioned SCNBA,
which exists in human chromosome No. 12 long arrn (12q13).
This application still further provides polynucleotides having the base
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CA 02412306 2002-11-22
sequence of SEQ ID NO. 1 and having the base sequence of SEQ ID NO. 3,
respectively, which are cDNAs of the above-mentioned human SCN 12A gene.
This application still further provides a polynucleotide having the base
sequence of SEQ ID NO. 5, which is a cDNA of the above-mentioned human SCNBA
gene.
This application still further provides antibodies against the
above-mentioned SCN12A or SCN12A-S, and to SCNBA.
Brief Description of the Drawings
Fig. 1 is a schematic view showing the primer set used in PCR amplification
of SCN12A, and showing the EST sequence and lmown sequences that are the bases
for synthesis of the primers.
Fig. 2 is a schematic view of a full-length cDNA clone of SCN 12A.
Fig. 3 is a schematic view showing the relationship between the structures
of cDNAs of SCN 12A and SCN 12A-s, and the clones obtained through RT-PCR and
RACE.
Fig. 4 shows the result of chromosomal location of SCN12A in FISH. The
metaphase plate shows a hybridization signal of SCN12A on the human
chromosome 3p23-p21.3 (arrow). The schematic view of the human chromosome
No. 3 shows the localization of SCN 12A (bar on the right side).
Fig. 5 shows the result of SCN 12A expression in various organs in
Northern blot analysis. The upper side is the result in various adult tissues;
and
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CA 02412306 2002-11-22
the lower side is the result in various central nervous system tissues.
Fig. 6 shows the result of in-situ hybridization of SCN 12A in rat organs.
DIG-labeled RNA probes specific to SCN 12A were used. A is hippocampus; B is
olfactory bulb; C is lower magnification of cerebellum; D is higher
magnification of
cerebellum; E is lower magnification of spinal cord; F is higher magnification
of
spinal cord; G is spleen; and H is placenta.
Fig. 7 shows the result of RT-PCR of SCN12A in established human cell
lines. The cell lines are glioblastoma U215, neuroblastoma LAN-5 and SHSY-5Y.
Whole brain, white matter, cerebellum, spinal cord and DRG (dorsal root
ganglion)
were also tested.
Fig. 8 is a schematic view showing the primer set used in PCR amplification
of SCNBA, and showing the Down sequences that are the bases for synthesis of
the
primers.
Fig. 9 is a schematic view showing the relationship between the structure
of SCNBA cDNA, and the clones obtained through RT-PCR and RACE.
Fig. 10 is a schematic view of a full-length cDNA clone of SCNBA.
Best Mode for Carryiag Out The Iaveation
The sodium channels SCN 12A and SCN 12A-s of the invention are different
transcripts that are expressed by the same gene. SCN12A comprises 1791 amino
acids of SEQ 117 NO. 2; and SCN12A-s comprises 1444 amino acids of SEQ ID NO.
4
(the two will be hereinafter simply referred to as "SCN12A").
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The sodium channel SCNBA of the invention is a transcript that is
expressed by the cDNA having the base sequence of SEQ ID NO. 1, and it
comprises
1980 amino acids of SEQ ID NO. 1.
SCN12A and SCNBA of the invention can be obtained in lmown methods,
for example, according to a method of isolating them from human organs (e.g.,
brain,
spleen, small intestine, placenta and spinal cord, as confirmed in the
Examples
mentioned hereinunder), a method of preparing peptides through chemical
synthesis
based on the amino acid sequences which this application provides, or a method
of
producing them through recombinant DNA technology using the polynucleotides
which this application provides. In case where the proteins are produced
according
to recombinant DNA technology, an RNA is prepared through in-vitro
transcription
from a vector having the polynucleotide (SEQ ID NO. l, 3 or 4) of the
invention, and
the protein SCN12A or SCNBA is obtained through in-vitro translation using the
RNA as a template. When the polynucleotide translation region is recombined
with
a suitable expression vector in a Imown manner and Escherichia coli, Bacillus
subtilis, yeast, or animal or plant cells are transformed with the recombinant
vector,
then the protein can be mass-expressed in the resulting transformants.
In case where SCN12A or SCNBA of the invention is produced through
in-vitro translation, the following process is employable: The translation
region of
the polynucleotide of the invention is recombined with a vector having an RNA
polymerase promoter, and the recombinant vector is added to an in-vitro
translation
system such as rabbit reticulocyte lysate or wheat germ extract that contains
the
RNA polymerase for the promoter. The RNA polymerase promoter includes, for
example, T7, T3, and SP6. The vector that contains the RNA polymerase promoter
includes, for example, pKAl, pCDMB, pT3/T7 18, pT7/3 19, and pBluescript II.
In case where SCN 12A or SCNBA of the invention is expressed in
microorganisms such as Escherichia coli, the following process is employable:
The
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CA 02412306 2002-11-22
translation region of the polynucleotide of the invention is recombined with
an
expression vector that has an origin, a promoter, a ribosome-binding site, a
DNA-cloning site and a terminator replicable in microorganisms to construct a
recombinant expression vector, host cells are transformed with the recombinant
expression vector, and the transformant cells are cultured. In this process,
when an
initiation codon and a termination codon are added to the polynucleotide
before and
after the desired translation region thereof, a protein fragment having the
desired
region can be obtained. If desired, a fused protein with any other protein can
be
expressed. The fused protein may be cleaved with a suitable protease to give
SCN12A alone. The expression vector for Escherichia coli includes, for
example,
pUCs, pBluescript II, pET expression systems, and pGEM expression systems.
In case where SCN12A or SCNBA of the invention is expressed in
eucaryotic cells, the translation region of the polynucleotide of the
invention is
recombined with an expression vector for eucaryotic cells that has a promoter,
a
splicing region and a poly(A)-addition site, and the recombinant expression
vector is
introduced into eucaryotic cells. The expression vector includes, for example,
pKAl,
pCDMB, pSVK3, pMSG, pSVL, p8K-CMV, pBK-RSV, EBV vector, pRS, and pYES2.
For eucaryotic cells, generally employed are cultured mammalian cells such as
monkey kidney cells COS7, Chinese hamster ovary cells CHO, as well as budded
yeast, divided yeast, silkworm cells, Xenopus laevis egg cells, but these are
not
limitative. The expression vector may be introduced into eucaryotic cells in
any
known method of, for example, electmporation, calcium phosphate method,
liposome method or DEAF dextran method.
After proteins have been expressed in procaryotic cells or eucaryotic cells
according to the method mentioned above, the intended protein is isolated and
purified from the cell culture, for which known separation techniques may be
combined. The separation techniques are, for example, processing with a
denaturing agent such as urea or with a surfactant, ultrasonic processing,
enzyme
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digestion, salting out, solvent precipitation, dialysis, centrifugation,
ultrafiltration, gel
permeation, SDS-PAGE, isoelectric focusing, ion-exchange chromatography,
hydrophobic chromatography, affinity chromatography, and reversed-phase
chromatography.
SCN12A of the invention includes all peptide fragments (with at least 5
amino acid residues) containing any and every partial sequence of the amino
acid
sequence of SEQ ID NO. 2 or 4. SCNBA of the invention includes all peptide
fragments with at least 5 amino acid residues of the amino acid sequence of
SEQ ID
NO. 6. These peptide fragments may be used for antigens for producing
antibodies.
SCN12A and SCNBA of the invention include fused proteins with any other
proteins.
One gene of the invention encodes the above-mentioned SCN 12A, existing
in human chromosome No. 3 short arm (3p23-p21.3). Another gene of the
invention encodes the above-mentioned SCNBA, existing in human chromosome No.
12 long arm (12q13.3). These genes can be isolated from lmown genome
libraries,
for which, for example, the respective polynucleotides or their partial
sequences of
the invention may be used as probes.
2o The polynucleotides (cDNAs) of the invention may be cloned, for example,
from human cell-derived cDNAs. For synthesizing the cDNAs, a poly-A+RNA
extracted from human cells is used for the template. For the synthesis, for
example,
employed are an Okayama-Berg method (Mol. Cell. Biol., 2:161-170, 1982); a
Gubler-Hoffman method (J. Gene 25:263-269, 1983); and a capping method (Gene
150:243-250, 1994). Commercially-available human cDNA libraries may also be
employed. For cloning the cDNAs of the invention from cDNA libraries,
employable
is the following process: An oligonucleotide is synthesized, based on a
certain
partial base sequence of the cDNA of the invention, and this is used as a
prnbe in
lmown colony or plaque hybridization for screening. Alternatively, the cDNAs
of the
invention may also be prepared through RT-PCR, starting from an mRNA isolated
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frnm human cells and using a primer oligonucleotide synthesized through
hybridization at both ends of the intended cDNA fragment.
In general, polymorphism owing to individual difference is frequently seen
in human genes. Therefore, cDNAs modified from those of SEQ ID NO. l, 3 or 5
by
adding one or more nucleotides thereto, by deleting them, and/or by
substituting
them with any other nucleotides are within the scope of the polynucleotides of
the
invention. Similarly, SCN12A and SCNBA with addition of one or more amino
acids
thereto, deletion thereof from it, and/or substitution thereof with any other
amino
acids that will be caused by the base modification as above are also within
the scope
of the invention, so far as they have the activity of SCN12A having the amino
acid
sequence of SEQ ID NO. 2 or 4, or have the activity of SCNBA having the amino
acid
sequence of SEQ ID NO. 6.
F~zrther, the polynucleotides of the invention include all DNA fragments (of
at least 10 bp) containing any and every partial sequence of the base sequence
of
SEQ ID NO. 1, 3 or 5. In addition, they include such DNA fragments comprising
sense chains and antisense chains. These DNA fragments are useful for probes
for
genetic diagnosis.
Using SCN12A or SCN8A itself or its partial peptide as an antigen, the
antibodies of the invention can be obtained in any known method, and they may
be
polyclonal antibodies or monoclonal antibodies.
The following Examples are to demonstrate the process of producing
SCN12A and SCNBA of the invention and to show the properties of the proteins
produced.
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Examples
( 1 ) Purification of mRNA from human brain in autopsy:
2 g of a brain specimen from a non-neuropathy patient was completely
disrupted in a homogenizer along with a TRIZOL reagent (by Gibco-BRL), and
incubated at 30°C for 15 minutes. Next, 4 ml of chloroform was added to
it, stirred,
and then incubated at 30°C for 30 minutes. This was centrifuged at
12,000 x g for
minutes to separate an aqueous layer, and a total RNA was extracted from it
through ethanol precipitation. Using an mRNA purification kit, Dynabeads (by
10 DYNAL), a poly-+RNA (mRNA) fraction was purified from the total RNA.
(2) RT-PCR:
Using a reverse transcriptase, Superscript II (by Gibco BRL), the mRNA
purified in (1) as a template, and random primers, a single-stranded DNA was
15 synthesized. Using the single-stranded DNA as a template, a partial
sequence 1832
by of SCN12A was obtained through nested PCR. The primers used in PCR were
designed based on the sequences of EST AA446997 and known sodium channel a
subunits (human H and rat R) with high homology and good sequence retention,
as
in Fig. 1. Concretely, the following primers were used: Est-fl
(oligonucleotide of
SEQ ID NO. 7), Est-f2 (oligonucleotide of SEQ ID NO. 8), Na-rl
(oligonucleotide of
SEQ ID NO. 9), and Na-r2 (oligonucleotide of SEQ ID NO. 10).
Using the single-stranded DNA as a template, a partial sequence of a
sodium channel containing known sodium channel a subunits was obtained
through nested PCR, for which the primers used were oligonucleotides that had
been
designed based on the sequences of known sodium channel a subunits (human H
and rat R) with high homology and good sequence retention, as in Fig. 8. The
clone
of one of them, 1806 bp, has extremely high homology to the sequence that
corresponds to Scn8a cloned in rat, or that is, its base sequence homology is
91
and its amino acid sequence homology is 98 %. This confirnis that the clone is
a
partial sequence of human SCNBA cDNA.
CA 02412306 2002-11-22
(3) RACE:
Based on the base sequence of the RT-PCR product of SCN 12A obtained in
the above (2), primers were synthesized. Using Marathon-ready cDNA (by
Clontech)
serving as a template, 5'-side and 3'-side adapter-having cDNAs were obtained
through 5'-RACE and 3'-RACE. The primer used for 5'-RACE is Race-5
(oligonucleotide of SEQ ID NO. 11); and the primers used for 3'-RACE are Race-
3a
(oligonucleotide of SEQ ID NO. 12) and Race-3b (oligonucleotide of SEQ ID NO.
13).
The adapter primers used are AP1 (oligonucleotide of SEQ ID NO. 14) and AP2
(oligonucleotide of SEQ ID NO. 15).
For SCNBA, 5'-side and 3'-side cDNAs were obtained through 5'-RACE and
3'-RACE in the same manner as above. The 5'-side terminal of the cDNA was
constructed through PCR, for which the primers used had been designed based on
the 5'-terminal cDNA sequence of rat. The details of the cDNA fragments thus
obtained are shown in Fig. 9.
(4) Subcloning:
The cDNA fragments of SCN 12A obtained through RT-PCR and RACE were
subcloned into a plasmid vector pBluescript IISK(+).
Also, the cDNA fragments of SCNBA were subcloned into a plasmid vector
pBluescript IISK(+).
(5) Sequencing:
The plasmids of above (4) were propagated and purified, and they were
sequenced according to a diterminator and diprimer method. The reaction
products
were analyzed, using a fluorescence sequencer, 377A (Perldn Elmer/ABI).
(6) Northern Blot Analysis:
RNA blot membranes (by Clontech) prepared from poly-A+RNAs of various
human organs were subjected to Northern blotting, using the SCN12A cDNA
11
CA 02412306 2002-11-22
fragments as probes. The probe was labeled with [a-32P)dCTP. The hybridization
results were analyzed with a Storm 830 image analyzer (by Molecular Dynamics).
(7) In-situ Hybridization Analysis:
Rat organs were in-situ hybridized, using the SCN12A cDNA clones as
probes, and the expression sites were investigated in detail.
(8) Identification of Chromosome Location:
Using the SCN 12A cDNA clones as probes, the chromosome location was
identified through fluorescence in-situ hybridization (FISH).
(9) Formation of Full-length cDNA Expression Clones:
Using a human spleen poly-A+RNA (by Clontech) as a template, full-length
ORF-containing SCN 12A and SCN 12A-s were obtained through RT-PCR, and these
were subcloned into a plasmid vector pSP64TRT (modified from Promega's
pSP64Poly(A))) (Fig. 2). For the PCR primers for SCN12A, used were
oligonucleotides of SEQ ID NO. 16 and NO. 17; and for the PCR primers for
SCN12A-s, used were oligonucleotides of SEQ ID NO. 16 and NO. 18.
Using the mRNA purified in the above (1) as a template, a full-length
ORF-containing cDNA of SCNBA was obtained through RT-PCR, and this was
subcloned into a plasmid vector pSP64TR (Fig. 10).
( 10) Conclusion and Discussion:
RACE for cDNA cloning of SCN 12A gave two different cDNA fragments on
the 3'-side. The difference on the 3'-side will be alternative splicing. Of
the two
cDNAs reconstructed from these fragments, the longer one is SCN 12A cDNA, and
the shorter one is SCN12A-s cDNA (Fig. 3). SCN12A cDNA has a full length of
6528
by with ORF of 5373 bp, and encodes a protein of 1791 amino acid residues.
SCN12A-s cDNA has a full length of 5728 by with ORF of 4332 bp, and encodes a
protein of 1444 amino acid residues. In both proteins, identified are four
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CA 02412306 2002-11-22
transmembrane domains common to sodium channel a subunits.
Table 1 shows the homology to known sodium channel a subunits, the
chromosome location, the expression sites and the relation to diseases. The
homology of SCN 12A to known a subunits falls about 37 and 73 %, and SCN 12A
is
not so homologous to known a subunits. This suggests that the function of
SCN12A will differ from the function of known a subunits.
SCN12A has an amino acid residue of serine in the transmembrane
domain, SS2 segment, like known tetrodotoxin resistant (1TX-R) sodium
channels,
ScnlOa/PN3/SNS and NaN/SNS2, and it will be a TTX-R sodium channel.
The chromosome location of the SCN12A gene is mapped to human
chromosome No. 3 short arm (3p23-p21.3) (Fig. 4). The site is near the known a
subunit SCNSA (3p21-24), and this suggests the possibility of a sodium channel
a
subunit gene cluster existing in 3p21-p23.
13
CA 02412306 2002-11-22
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CA 02412306 2002-11-22
As in Fig. 5 that shows the result of Northern blot analysis, the mRNA size
of SCN 12A is about 7.0 kb, and SCN 12A was expressed in brain, spleen, small
intestine, placenta and spinal cord. Its expression in the other tissues in
Northern
blotting is lower than the detection sensitivity. As in Table l, the
expression sites of
known sodium channel a subunits are nervous tissues such as brain, spinal
cord,
dorsal root ganglion, and muscular tissues such as skeletal muscle, cardiac
muscle,
and uterus. As opposed to these, SCN 12A is expressed in brain, spinal cord,
spleen,
small intestine and placenta, but little in skeletal muscle, cardiac muscle
and uterus.
This confirms that the expression pattern of SCN12A differs from that of known
a
subunits.
In-situ hybridization with rat was carried out for investigating the
expression sites in more detail. SCN12A was expressed strongly in the
olfactory
bulb, the granular layer of cerebellar cortex, the dentate Virus of
hippocampus, the
central canal ependyrnocytes of spinal cord, the centroblasts of spleen, and
the
nutrient germ layer of placenta (Fig. 6). In RT-PCR with established human
cell
lines, SCN12A was expressed in both neurons and glia cells in nervous system,
but
no RT-PCR band was seen in dorsal root ganglion (DRG) owing to the human
material. In nested RT-PCR, however, SCN12A was expressed even in dorsal root
ganglion (Fig. 7).
On the other hand, cDNA of SCNBA has an amino acid sequence of SEQ ID
NO. 1, and its full length is 7053 by with ORF of 5940. This encodes a protein
of
1980 amino acid residues. In SCNBA, identified are four transmembrane domains
common to sodium channel a subunits.
Table 2 shows the homology of SCNBA to known sodium channel a
subunit gene cDNAs. The homology to mouse and rat homologous genes are 86
and 94 %, respectively. Of known a subunits, the homology to SCN 1A, SCN2A and
SCN3A is relatively high.
CA 02412306 2002-11-22
Table 2
Hunan Rat
SCI~IASCN2ASCN3A SCN4ASCNSA SCN6A SCN9A SCN8ASCNlOA
(SCN7A)
SCN8A75 76 73 61 61 45 70 94 55
Industrial Applicability
As described in detail hereinabove, this application provides novel sodium
channel a subunits and their cDNAs. The invention significantly contributes
towards clarification of excitable cells-related physiological mechanisms,
identification of the causes of various human diseases, and development of
novel
medicines.
16
CA 02412306 2002-11-22
iiss
SEQUENCE LISTING
<110> Jepan Science and Technofosy Corporation
<120> Hunan SodiuA Channel SCN12A and SCNBA
<130> NP0016T
<1d0> PCT/JP00104629
<141> 2000-OT-11
<150> JP2000-152085
<151~ 200006-23
13 <160> 18
<1T0> Patentin Ver. 2. 1
<210> 1
CZ11> 6528
<212> DNA
<213> Naw sap l ens
<220>
25 <221> COS
<222> t2~) . . t55T51
<300> '
<301> Soen-Vons Jeons et at. . .
30 <302> I dent i f i ca t I on of a Nova I Nu~an Ilo I ta8e-Ga t ed Sod i uo
Channe i a Subun i t Gene.
SCN12A
<303~ 8 i ocheo. 8 i ophys. Res.~ Co~un.
<304> Z6t
<305> 1
36 <306> 26t-2T0
<30T> 1000 .
<308> GenBank AF109T3T _
<309> 2000-01-15
<400> 1
tcctsctata cccacagt8s tgstcatctc ttctsatctt cacasccaat cagctcccaa 60
itcccctsac ctcagctcas cttttgtaga tccttat8ac accatccttt aagactsgae i20
46 tccta'~ca ssctgtttta ttcccgcctc ctgattcctt tctgagsatc titBBcttgt 180
CA 02412306 2002-11-22
z/ss
ctctstccts asgstgaag atg tat Sac asa tgc tac cca sta atc ttt cca 232
fief Asp A:v Ars Cys Tyr Pro Val Ile Phe Pro
1 b 10
Eat gas cgg aat ttc csc ccc ttc act tcc sac tct cts sct sca att 280
Asp Glu Ars Asn Phe Arg Pro Phe Thr Ser Asp Ser Leu Ala Ala (1e
20 25
t0 gag ais cst att gcc atc caa aas sas aaa aas aas tct aaa sac cas 328 ,
Glu Lys Ars Ile Ale Ile Gln Lys Glu Lys Lys Lys Ser Lys Asp Gln
30 35 40
aca sga saa sta ccc cag cct css cct cas ctt sac cta aas gcc tcc 3T6
15 Thr Gly Glu Yal Pro Gln Pro Ars Pro Gln Leu Aso Leu Lrs Ala Ser
~5 50 55
ass aas ttg ccc aag ctc tat ssc ac att cct cgt sas ctc ata gga 424
Art Ly: Leu Pro Lys Leu Tyr Gly Asp Ile Pro Arg Glu Leu Ile Gly
60 65 TO T5
aas cot cts saa gac ttg gac cca ttc tac csa aat cat aas aca ttt 472
Lys Pro Leu Glu Aso Leu Aso Pro Phe Tyr Ars Asn His Lys Thr Phe
80 85 90
ats stg tta aac asa aas ags acs atc tac csc ttc ast scc aas cat 520
Met Yal Leu Aan Ars Lya Arg Thr Ile Tyr Ars Phe Ser Ala Lys His
95 100 105
3D scc tts ttc att ttt sss cct ttc sat tca atc asa ast tta gcc att 568
Ala Leu Phe Ile Phe Gly Pro Phe Asn Ser Ile Ars Ser Leu Ala Ile
110 115 120 ~'~'
,_
asa stc tca stc cat tca tts ttc asc ats ttc att atc sac acc stt 616
35 Ars Val Ser Ya1 His Ser Leu Phe Ser Met Phe Ile ile Gly Thr Yal
125 130 135
atc atc aac tsc sts ttc ats sct aca ssg cct get aaa aac agc aac 664
Ile Ile Asn Cys Yal Phe Met Ala Thr Gly Pro Ala Lys Asn Ser Asn -_
40 140 145 150 155
ast aat aat act sac att sca sag tst gtc ttc act sss att tat att T1Z
Ser Asn Asn thr Aso 11e Ala Glu Cys Yal Phe Thr Gly Ile Tyr Ile
160 165 1T0
1. y
CA 02412306 2002-11-22
3I5 5
ttt ~aa Act tts att aaa ata ttA sca aAa sst ttc att cts eat sas 760
Phe r;lu Ala Leu Ile Lys lie Leu Ala Ars Gly Phe Ile Leu Asp Glu
175 1ao 185
ttt tct ttc ctt csa sat cca tAS aac tss.cts Aac tcc att stc att 808
Phe Ser Phe Leu ArA Asp Pro Trp Asn Trp Leu Aso Ser Ile Ya! 1!e
190 195 200
gsa ata scA att sts tea tat att eca ssa ate sec atc aaa cta tts 856
Gly Ile Ala Ile Yal Ser Tyr tle Pro Gly Ile Thr Ile Lys Leu Leu
205 210 215
ccc ets c't acc ttc est sts ttc aga sct ttt aaa gca att tca Ata 904
Pro Leu Ars Thr Phe Ars Yal Phe Ars Ala Leu Lys Ala ile Ser Yal
220 225 230 235
stt tca cst cts aas Atc atc stA Ass Acc ttA cta cgc tct stA aas 952
Yal Ser Ars Leu Lys Yal Its Yal Gly Ale Leu Leu ArA Ser Vai Lys
240 245 250
aas cts stc aac gtA att atc ctc acc ttc ttt tsc ctc asc atc ttt 1000
Lys Ltu Yai Asn Val Ile ile Leu Thr Phe Phe Cys leu Ser tie Phe
255 260 285
scc ctA sta Ast cas caA ctc ttc atg ssa ast ctA aac cts aaa tsc 1048
Aia Leu Val Gly Gln Gln Leu Phe list Gly Ser Leu Asn Leu Lys Cya ' ' ''
-t
270 275 280
atc tee spc sac tst aaa aat atc ast aae ccs saa rtct tat aac eat love
3D ile Ser Art Aso Cya Lya Asn lie Ser Asn Pro GIa Ala Tyr Asp Hia
2a5 290 295
tsc ttt Aaa aas aaa Aaa aat tca cct saa ttc aaa ate tst gsc atc 1144
Cys Phe Glu Lys Lys Glu Asn Ser Pro Glu Phe lrs tlet Cys Cty ile
W 300 305 310 315
tss atA tst aac aAt acc tst tcc ata caa tat saa tst aas cac acc 1192
Tro bet Gly Asn Ser Ala Cys Ser Ile Gln Tyr Glu Cys Lys His Thr
320 325 330
aaa att sat cct sac tat aat tat acA aat ttt gac aac ttt sec tss 1240
LYS Ile Asn Pro Asv tyr Asn Tyr Thr Asn Phe Asp Asn Phe Giy Trv
335 340 345
46 tct ttt ctt scc ate ttc cg8 cts ats acc caa sat tcc tgg sas aa8 1288
CA 02412306 2002-11-22
4iss
Ser Phe Leu Ala bet Phe Ark i.eu iltt Thr Gin A:o Ser Trp Glu Lys
350 355 360
ctt tat caa cas atc ct; cst act act s~ ctc tac tca gtc ttt ttc 1336
Leu Tyr Gln Gln Thr Leu Ars Thr Thr Giy leu Tyr Ser Val Phe Phe
365 370 375
ttc att sts xtc att ttc ctg ggc tcc ttc tac cts att aac tta acc 1384
Phe Ile Y,I Val Ile Phe Leu Gly Ser Phe Tyr Leu Ile Asn Leu Thr
380 385 390 395
cts sct stt stt acc ats sca tat aag sas cas aac aas aat sta sct 1432
Lw Ala Val Val Thr Wet Ala Tyr Glu Glu Gln Asn Lrs Asn Val Ala
400 40S 410
16
~ca ttts ata sag gcc aag gaa aas atg ttt cag saa gcc cag cas cts 1480
Ala Glu Ile Glu Ata lys Glu Lys bet Phe Gln Clu Ala Gln Gln Leu
415 420 425
tta aas ses saa aa~ sas sct ctg stt scc ats ssa att sac aga ast 1528
Leu Lys Glu Glu Lys Glu Ala Leu Yal Ala bet Gly Ile Aso Arg Ser
430 435 440
tca ctt act tcc ctt saa aca tca tat ttt acc cca aaa aas asa aas 1576
?5 Ser Leu Thr Ser Leu Glu Thr Ser Tyr Phe Thr Pro Lys Lys Ars Lys '
445 450 d55
ctc ttt sst art aas aaa a~ aas tcc ttc ttt ttg aga gab tct gss 162d
Leu Phe Gly Asn Lys Lys Ars Lys Ser Pha Phe Leu Ars Glu Ser Cly .
460 465 410 ~ 415
aaa su cascctcctssstcasattctsatsaagattsccaaaaaaas 1672
Lys AsvGlnProProGlySerAsvSerAavGluAspCysGlnLysLys w
480 485 490
eca cagCtcttagagtaaaecaaacgattstcecasaatctateatts t720
Pro GinLeuLeuGluGinThrLyaArsLeuSerGlnAsnLeuSerLeu
495 500 505 .. ~ . :
4D sac cattttsat'ascat~a satcctctccaaasscagasagcacts 1168
Aso Hi:PheAavGluHisGlyAsvProLeuGlnAr$GlnArgAlaLeu
510 515 520 '
agt sccstcascatcctcaccetcaccatsaassaacaasaaaaatca 1816
46 Ser AleY,ISerIleLeuThrIleThrfiletlysGluGlnGluLysSer
1~C~IVED Tfr~- ~""' ~'
.. : ":.
CA 02412306 2002-11-22
3155
S25 530 535
eaa reg ect ttt ctc cct tgc gw taa aac ett gca tce aag tae ctc 1864
Gln Glu Pro Cys Leu Pro Cys Gly Glu Asn Leu Ala Ser Lys Tyr Leu
540 545 550 555
gtt t~ aac ttt ttc ccc cas tgg ctg ttc ttt aas aat gtc ctg asa 1912
V,I Trp Asn Cys Cys Pro Gin trp Leu CYs V'I Lys Lys Val Leu Arg
560 565 5T0
act atg att act tac cct ttt act gat ctg gcc atc acc atc tgc atc 1960
Thr Val filet Thr Asp Pro Phe Thr Glu Leu Ala Ile Thr ile CYS Ile
515 580 585
atc atC aiC act ttc ttC ttt tCC att tat cat caC sag att tat tcc 200a
Ile Ile Asn Thr Val Phe Leu Ala filet Glu His His LYS Ikt Glu Ala
5s0 555 600
sat ttt tat aat ata ttt aat ata tst aat ttt stt ttc act agc att 2056
SD Ser Phe Glu Lys Ikt Leu Asn (1e Gly Asn Leu Val Phe Thr Ser Ile
605 610 615
ttt ata tca taa ats tsc cta aaa atc att tcg ctc sat ccc tac cac 2104
Phe Ile Ala Glu filet Cys Leu lys Ile Ile Ala Leu Asp Pro Tyr His
620 625 630 635
tac ttt ctc csa ttc tss aac att ttt sac agc att ttt tct ctt ctg 2152 .:..,
Tyr Phe Art Art Gly Trp Asn Ile Phe Asa Ser lie Val Ala Leu Leu
840 s45 sso
agt ttt tca tat tta atg aac tst tta ctt caa aag ata asc tsg cca 2200
Ser Phe AI~ Asp Vai Ikt Asn C1s Val Leu Gin Lys Art Ser Trv Pro
655 660 665
36 ttc ttt cgt tcc ttc att tts ctc agt ttc ttc sat tta tcc aaa tcc 2248
Phe leu Art Ser Phe Ars Vat Leu Arg Ya! Phe Lys Leu Ala Lys Ser
6T0 675 680
ttt cct act tts aac aca cta att aag ata atc stc sac tct ttc tta 2296
40 Trv Pro Thr Leu Asn Thr Leu Ile Lys Ile file Giy Asn Ser V'I Gly
685 690 695
gcc ctt tta aac ctt act tts ttc ct$ stc att stt atc ttt att ttc 2344
Ala Leu Gly Asn Leu Thr Val Val Leu Yal Ile Val lie Phe IIe Phe
s5 T00 T05 T10 T15
CA 02412306 2002-11-22
' 6/53
tca sta gtt egc ats cas ctt ttt ssc cst agc ttc sat tcc caa aas 2392
Ser Yal Val Gly Wet Gln Leu Phe Gly Art Ser Phe Asn Ser Gtn ~ys
120 725 130
agt cca aaa ctc tgt aac ccg aca sgC ccs aca stc tca tat tta css 2440
Ser Pro lya leu Cys Aan Pro Thr Gly Pro Thr Val Ser Cys Leu Arg
135 140 745
cac to cac atg ggs sat ttc tsg cac tcc ttc cta sts sta ttc csc 2488
His Trp Hit bet Gly A:v Phe Trp His Ser Phe Leu V,I Val Phe Ars
750 155 760
-,:. tr9:
~ :..3..; ;: y r ti
atc ctc tsc sss saa tes atc saa aat ats tas saa tst ats caa gaa 2536
Ile Leu Cys Gly Glu Tro Ile Glu Asn Ilet Trp Glu Cys get Gin Glu
165 TTO TT5
scs aat sca tca tca tca ttg tst stt att gtc ttc ata tts atc acs 2584
Ala Asn Ala Ser Ser Ser leu Cys Val Ile Va1 Phe Ile L~u Ila Thr
180 785 190 195
a
sts ata gsa aaa ctt stg gts ctc sac ctc ttc att gcc tta ctg ctc 2632
Val Ile Giy Lya Leu Val Val Leu Asn heu Phe Ile Ala Leu Leu Leu
aoa ea5 e10
aat tcc ttt asc aat sas saa asa sat sga aac tta gaa gsa sas scc 2680 _=~='~~.
Asn Ser Phe ser Asn Glu Glu Art Aan Gly Asn Leu Glu Gly Glu Ala
815 820 825
ass aaa act aaa stc cag tta gca cts sat cga ttc csc css tct ttt 2728
Arg lys Thr Lys Yal G.lu Leu Ala Leu Aso Ars Phe Arg Ars Ala Phe
830 835 8A0
tgt ttt sts aga cat act ctt sas cat ttc tst cac aas tss tsc a~ 2716 ~
35 Cys Phe Yal Arg His Thr Leu Glu HI: Phe Cys His Lys Trv Cys Are
845 850 855
aas caa aac tta cca cas caa aaa sag sts sca ssa ssc tst sct sca 2824
lys Gln Asn leu Pro Gln Gln Lys Giu Vat Afa Giy Giy Cys Ala Ala
,0 8so ass s7o a7s - _'
caa ssc aaa sac atc att ccc cts stc ats sas ats aaa ass ssc tca 2812
Gin Ser Lys Aso ile 11c Pro Leu Val filet Glu lrlet Lys Arg Gly Ser ' ;
880 885 890
~,h
CA 02412306 2002-11-22
ms s
tat :cc cat tat tas ctt sst ata cta acc tct tta cca aat acc cti 2920
Glu Thr Gln Glu Glu Leu Gly Ile Leu Thr Ser Val Pro Lys Thr Leu
895 900 905
atc ttc att cat gat tts act to tts sca cca ctt scs sas tas taa 2968
Giy ltal Art His Aao Trv Thr Trv Leu Ala Pro Leu AIa Glu Glu Glu
910 915 920
sat sac att saa ttt tct sst aaa sat aat tca cas cgc atc aca caa 3016
AsD Asv Val Glu Phe Ser G1r Glu AsD Aan Ala Gln Arg Ile Thr Gln
925 930 935
cct sas cct saa caa cas scc tat sas ctc Cat cat saa aac aas aas 306d
Pro Glu Pro Glu Gln Gln Ala Tyr Gtu Lau His Gin Giu Asn Lys Lys
9d0 945 950 955
ccc ats asc cas asa stt caa ast sta taa att sac atg ttc tct gaa 3112
Pro Thr Ser Gin Ars Val Gln Ser Yal Glu Ile Asv llet Phe Ser Glu
960 965 9T0
sat tds cct cat cts acc ata caa tat ccc cga aas aas tct tat stt 3160
Aso Glu Pro Hia Leu Thr Ile Gln Aso Pro Art Lya Lya Ser Aso Yal
9T5 980 985
?5 acc ast ata cta tca saa tst asc acc att tat ctt cae sat ~c ttt 3208
Thr Ser Ile Leu Ser Glu Crs Ser Thr Ile A:D Leu 61n Aso Glr Phe
990 995 1000
asa t'g tta cct sat ats stt ccc.aaa aaa caa cca ~'S aaa tst tte 3256
30 GIy ~Trv Leu Pro Glu Ikt Val Pro Lys Ly= Gln Pro Gtu Arg Crs Leu
loos . lalo . loll
ccc aaa sac ttt aat tac tac ttt cca tac tst atc stt Sac aas asa 3304
Pro lys Gly Phe Gly Cys Crs Phe Pro Cys Cys Ser Val Asv Lrs Arg
1020 1025 1030 1035
~0
.
aaa cct ccc taa stc att tas tst aac cta cst aaa acc tsc tac caa 3352
Lys Pro Pro Trp Val Ile Trv Trv Asn Leu Ars Lys Thr Crs Tyr Gln
1040 1045 1050
ata sts aaa cac asc tss ttt tag asc ttt att atc ttt stt att ctg 3400
!1e Yal Ly= Hi: Ser Trv Phe Glu Ser Phe Ile Ile Phe Yal Ile leu .
1055 1060 1055
cts asc ast sst sca ctt ata ttt saa sat att cac ctt sag aac caa 3448
r,
CA 02412306 2002-11-22
aiss
Leu her Ser Gly Ala Leu IIe Phe Glu A:v Val Hia Leu Glu Asn Gln
1010 1075 1080
ccc aaa atc caa gaa tta cta aat tst act gac att att ttt acs cat 3496
Pro Ly= Ile Gin Glu Leu Leu Asn.Crs Thr Asp Ile Ile Phe Thr His
1085 1090 1095
att ttt atc cts sas ats sta cta aaa tss sta scc ttc gga ttt gsa 3544
Ile Phe Ile Leu Glu Ilet Yal Leu LYS "fro Yat Ala Phe Gly Phe Gly
1100 1105 1110 1115
aag tat ttc acc est scc tsg tsc tsc ctt sat ttc atc att stg att 3592
Ly: Trr Phe Thr Ser Ala Trp Crs Cys Leu Asp Phe Ile Ile Yal Ile
1120 1126 1130
stc tct its arc acc ctc att sac tta ats saa ttg aas tcc ttc css 3640
Y,i Ser Val Thr Thr Leu Ile Asn Leu Itet Glu leu Lys Ser Phe Arg
1185 1140 1145
act cta csa sca ctg agg cct ctt cgt scs cts tcc cas ttt aaa ~a 3688
Thr Leu Ars Ala Leu Ars Pro Leu Ars Ala Leu Ser Gin Phe Glu GIy
1150 1155 1160
atg aes sts tts stc aat sct ctc ata sst acc ata cct scc att ctg 3736
?a I~let Lrs Val Yal Yal Asn Ala Leu Ile GIY Aia Ile Pro Ala Ile Leu
1115 ~ 1110 1175
aat stt tts ctt stc tsc ctc att ttc tgs ctc sta ttt tgt att cts ,3784
Aan Yal Leu Leu Val Cys Leu Ile Phe Trp Leu Val Phe Crs Ile Leu
3D 1180 ~ 1185 ~ 1190 1195
ausa sta tac ttc ttt tct ssa aaa ttt ~s aaa tgc att aat 8ga acs 3832 ,
Gly Val Trr Phe Phe Ser Gly Lys Phe Gly Lys Cya Ile Asn Gly Thr
1200 1205 1210
gac tca gtt ata aat tat acc atc att aca aat aaa ast caa tgt gaa 3880 , ~,,
Asp Ser Val ile Asn Tyr Thr ile Ile Thr Asn Lys Ser Gln Cys Glu
1215 1220 1225
~s
40 agt ssC aat ttc tct tgs atc sac cag aaa stc aac ttt gac aat sts 3928
Ser Gly Asn Phe Ser Trp lle Asn Gin Lys Val Asn Phe Asp Asn Yal
1230 1235 1240
gga aat get tac ctc sct cts cte caa stg gca aca ttt aas ssc tgs 3976
46 Gly Asn Ala Tyr Leu Ala Leu leu Gin Yal Ala Thr Phe Lys Gly Trp ,
a
CA 02412306 2002-11-22
9~ss
1245 1250 1255
ats pt att ata tat sca sct stt pt tcc ua sas aaa saa caa cat 4024
Wet Asv (1e Ile Tyr Ala Ala Yai Aso Ser Thr Glu Lys Glu Gtn Gin
1260 1265 1270 1275
cca sas ttt 'a~ asc aat tca ctc sst tac att tac ttc sta stc ttt 4072
Pro Glu Phe Glu Ser Asn Ser Leu Gly Tyr Ile Trr Phe Yal Yal Phe
1280 1285 1290 .
atc atc ttt ssc tca ttc ttc act cts aat ctc ttc att src stt atc 4120
Ile IIe~Phs Giy Ser Phe Phe Thr Leu ~n Leu Phe Ile Gly Val Ile
1295 1300 1305
~5 att sac aac ttc aac caa cas cas aaa aas tta gst ggc caa pc att 4168
Ile Aso Asn Phe Asn Gin Gln Gin lys Lys Leu Gly Giy Gln Aso lle
1310 1315 1320
ttt ats aca pa saa cas aas aaa tac tat aat gca atg aaa aaa tta 4216
ai Phe Wet Thr Glu Glu Gin Lys Lys Tyr Tyr Asn Ala Ikt lrs Lys ~eu
13x5 1330 1335
r
ssa tcc aaa aaa cct caa aaa ccc att cca css cct cts sac aaa tst 4264
Gly Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Leu Asn Lys Cys
25 1340 ~ 1345 1350 1355
caa sgt ctc stg ttc gac ata stc acs asc cas atc ttt sac atc atc 4312
Gln Giy Leu Val Phe Asp Ile Val Thr Ser Gln Ile Phe Asv Ile Ile
1360 1365 t310
3D
stc ata agt ctc att atc cta aac ats att asc ats ats get gaa tca 4360
Ile Ila Ser Leu 11e fle Leu Aan Wet ile Ser Ihet Ilet Ala Glu Ser
i375 1380 1385
3~ tac aac caa ccc aaa scc ats aaa tcc atc ctt gar cat ctc aac tss 4408
Tyr Asn Gln Pro Lys Ala llet Lys Ser ile Leu Asv His Leu Asn Tro
13a0 1395 1400
xtc ttt sts stc atc ttt acs tta saa tst ctc atc aaa ~tc ttt get 4456
40 Val Phe Yal Yal tle Phe Thr Leu Glu Cys Leu Ile Lys lie Phe Ala
1405 1410 1415
tts ass caa tac tac ttc acc aat asc tsg aat tta ttt gac tgt atg 4504
Leu Ars Gin Tyr Tyr Phe Thr Asn Gly Tro Asn Leu Phe Aso Cys Val r~,=~'~'
1420 1425 1430 1435
CA 02412306 2002-11-22
ioiss
gic gtg ctt ctt tec att gtt ttt aca atg att tet acc ttg gas aat 4552
Val Val 4eu Leu Ser ile Val Ser Thr Wet Ile Ser Thr Leu Glu Asn
14d0 1445 1450
;_
cag fag cu att cct ttc cct cct act ctc ttc asa att gtc csc tts 4600
Gln flu Hls ile Pro Phe Pro Pro Thr Leu Phe Arg Ile Yal Arg leu
1455 1460 1465
1o tet Cgg att ttc cta atc ctt att ctt ste cst ict sca csa gta atc 4648
Ala Arg Ile Giy Arg ile Leu Arg Leu YaI Ars Ala Ala Ars Gly Ile
14T0 1475 i480
agg act ete ete ttt get etg atg att te~c ett ect tet cts tte aae 4696
Arg Thr Leu leu Phe Ala Leu Het Ikt Ser l.eu Pro Ser t.eu Phe Asn
1485 1490 1495
att stt ctt cta ctc ttt cts att ats ttt atc tat tcc att ctt sst 4744
Ile GIy Leu Leu leu Phe Leu Ile Wet Phe Ile Tyr Ala Ile Leu Gly
1500 1505 1510 1575
ats aac tss ttt tcc aaa sts aat cca sas tct ssa atc sat sac ata 4792
I~et Asn Trp Phe Ser l.rs Yal Asn Pro Glu Ser Gly Ile Asp Aso Itt
1520 1525 1530
~J a
ttc aac ttc aas act ttt scc asc asc atg ctc 1st ctc ttc cas ate 4840 ~~'~'~
Phe Asn Phe ly: Thr Phe Ala Ser Ser Ikt Leu Cys Leu Phe Gln Ile
1535 1540 1545
3D agc aca tca sca sit tts sat tcc~ctt~ctc agc ccc ats cts csa tca 4888
Ser 'Thr Ser Ala Gly Tro Asp Ser Leu Leu Ser Pro Vet Leu Arg Ser
1550 1555 1560
aaa gaa tca tgt aac tct tcc tca gat aac ttc cac ctc cct ssc ata 4936
3s Lys Glu Ser Crs Asn Ser Ser Ser Glu A:n Crs His Leu Pro Gly 11e
1565 1570 1575
get aea tce tae ttt ste ,8t tac att atc etc tcc ttt ctc att stt 4984
Ala Thr Ser Tyr Phe Y'I Ser Tyr Ile Ile Ile Ser Phe Leu Ile Yal
1580 1585 1590 1595
ttc aae att tac att sct stg att tta sag aac ttc aat aca gcc act 5032 "~~
Yal Asn Wet Tyr Ile Ala Yal Ile Leu Glu Asn Phe Asn Thr Ala Thr
1600 1605 1610
,. :,
CA 02412306 2002-11-22
' i mss
tae Sea ast sas sac cct ttg sst saa Bet sac ttt sac ata ttt tat 5080
Giu Glu Ser Glu Aso Pro Leu Gly Glu Aap Asp Phe Asp Ile Phe Tyr
1615 1620 1625
see sts tis saa aas ttt sac cca saa sca acs caa ttt atc aaa tat 5128
Giu Val Trp Glu Lys Phe Asv Pro Glu Ala Thr Gin Phe Ile Lys Tyr
1630 1635 1640
tCt sec ctt tct sac ttt set sat sec tts cct gas cct ttS cst stc 5176
Ser Ala Leu Ser Asp Phe Ala Asv Ala Leu Pro Glu Pro Leu Are Yal
1645 1650 ~ 1655 '
sca aas cca sat aaa tat caa ttt cta sta ats sac tts ccc ats sts 5224
Ala Lys Pro Asn Lys Tyr Gln Phe Leu Yai bet Aap Leu Pro filet Val
1660 1665 1670 1675
ast sea sat crsc ctc cac tsc ats sat att ctt ttc scc ttc acc ect 5272
Ser Glu Aao Ars Leu His Cys filet Asv ile Leu Phe Ala Phe Thr Ala
1680 1685 1690
ass sta ctc fst gsc tct sat Bsc cta rat ast a18 aaa sca ats ats 5320
Ars Yat Leu Gly Gly Ser Asp Gly Leu Asp Ser Itet Lys Ala wet Ilet
1685 1700 1105
sea sas aas ttc ats saa scc aat cct ctc sag ass tts tat eaa ccc 5368
Giu Gtu Lys Phe >wlet Glu AIa Asn Pro Leu Lys Lys leu Tyr Glu Pro
1710 1715 1720
ata stc acc acc acc aas asa aas saa iag saa ass sst act act att 5416
Ile Yal~ Thr Thr Thr Lys Ars Lys Giu Glu Glu Ars Gly Ala Ala Ile
17Z5 1730 1735
att caa eas scc ttt csa aas tac ats ats aas stg acc aas sst sac 546~
lie Gln l.ys Ala Phe Ars Lys Tyr Wet I~et Lys Val Thr Lrs Gty Asp
36 1740 1745 1750 1155
caa 1st pc caa sat sac tts saa aac sss cct tat tca cca ctc cas 5512 .
Gln G1~ Asp Gln Asn Asp Leu Glu Asn Gty Pro His Ser Pro Leu Gin
1760 1765 1770
~0
act ctt tsc aat s8a gac tts tct agc ttt sss sts gcc aag egc aag 5560
Thr Lw Cys Asn GIy Asp Leu Ser Ser Phe Gly Yal Ala Lys Gty Lys
1775 1780 1785
46 stc cac 1st sac tsa sccctcacct ccacscctac ctcatagctt cacascctts 5615
CA 02412306 2002-11-22
~ 2rss
Yal His
Cys Asv
1790
ccctcascctctsasctccasssstcascascttaststatcaacasssastspttcac5615
caaattasccattccattttcttttctssctsaataaatsatatttcaatttcattttaa5735 .
atsatacttacasasatataasataassctaCttsaCaaCCa~CSStaCtattttaataa5795
10ssaassa'aClcca~alssaCtstaaaassacattccaattttassattssaitxsttc5855
aasccsacs castssctcattccts~tccca~cactttgasatsccaassca~stss5915
,,;
attacsasstcaasasatcsasaccatcctssccaaccatsatsaaactccstctctact5975
aaaatac,aaaattasctssscatssttgcstscscctstastcccasctactt~ass6035
ctsas~cassasx~tcscttaaacctsisasacssatsttscastsascCaasatcstit6095 .
a1cactscactccascctsstsacasastsasactctstttcaaaaaasaaaasaaaasaaa6155
crtssttcaaattatatctaaacaaaaaasaataasaaacaaaatacacattaa~tatttt6215
aastt~tattttctatstttctasatacatcatttttstttsatattttcctsatscaas6215
2r
tat~tsstttatcacatstasctcttttscat8ctaaatsaaaattcaasacttsccaat6335
aaatsaatascttattscasacattttttsccaacsttaattattttssstttstttaaa8395
30acctaEasiCacaatcttsacttstcaattactaccctttcacaasctaccatctcasat6455
atatatatatatataaattcaataaasctttctstttststtccataaaaaaaaaaaaaa6515
aeaasaaa~aaaaa 6528
<210> 2
<211> 1791
<212> PRT
rt.
~0 <213> Noso sapiens
<400> 2
filet Asp Asv Ars Cys Tyr Pro Yal tle Phe Pro Asv Glu Ars Asn Phe
1 5 10 15 _
~6 Ars Pro Phe Thr Ser Asv Ser Leu Ala Ala lle Glu lys Ar8 Ile Aia ..
CA 02412306 2002-11-22
~ 3~s s
20 25 30
ileOlnLys GluLysLys lysSerLysAspGlnThrGlyGluYalPro
35 40 45'
GlnProArt ProGinLeu AsaLeuLysAlaSerArsLysLeuProLrs
GO 55 60
Leul~rrGly AapIlePro ArgGluLeuIleGlyLysProLeuGluAsp
85 TO T5 80
LeuAtpPro PheTyrAr' AsnHisLysThrPheMetYalLeuAsnArg
as 90 95
t0 LysArgThr IfeTyrArs PheSerAlaLysHisAlaLeuPheilePhe
100 105 110
GlyProPhe AsnSerIle ArgSerLeuAlalieAreYaiSerYalHis "~:
115 120 125
SerLeuPhe SerIktPhe IleIleGlyThrValIlelieAsnCysYal
,s 1ao 135 140
PheWetAla ThrGlyPro AlaLrsAanSerAsnSerAsnAsnThrAsp
145 150 i55 160
lleAfaGlu CysV,IPhe ThrGlyIleTyrilePheGluAlaLeuIle w
_ 165 1T0 175
LysIleLeu AiaArsGiy PheIleLeuAspGluPheSerPheLeuArs
180 185 190
AspProTrp AsnTrpLeu AspSerlieVaiIteGiyIleAlalieVai
195 200 205
SerTyrIle ProGlyIle ThrIleLysLeuLeuProLeuArsThrPhe
25 210 215 220 - ' ;
~._
ArgYalPhe AreAlaLeu LysAia(1eSerYalValSerArgLeuLys
225 230 235 240
ValileVai GIyAlaLeu LeuAr,eSerYalLysLysLeuValAsnYal
245 250 255
IteIleLeu ThrPhePhe CysLeuSerIlePheAIa~LeuValGlyGin
Z60 265 . 270
~
GlnLeuPhe IktGiySer LeuAsnLeuLy:CysllaSerArkAspCys
2T5 280 285
LysAsnIle SerAsnPro GluAlaTyrAsaHisCyaPheGluLysLys
290 295 300
GluAsnSer ProGluPhe LyawetCrsGlyIleTrpIktGlyAsnSer
305 310 315 320
AlaCysSer IleGlnTyr GluCysLysHisThrLysIleAsnProAsp
325 330 335-''
4D TyrAsnTyr ThrAsnPhe AspAsnPheGlyTrvSerPheLeuAlafilet
340 345 350
PheAr8Leu I~etThrGin AsPSerTraGlulysLeuTyrGinGlnThr
355 3so ass
LeuArgThr ThrGlyLeu TyrSerVaiPhePhePhelieValYalIle
46 3T0 3T5 380
al
y
CA 02412306 2002-11-22
14/35
Phe Leu Gly Ser Phe Tyr Leu Ile Asn leu Thr Leu Ala Yal Val Thr
885 ~ 390 395 400
trkt Illa Tyr Glu Glu Gln Asn Lys A:n Y'1 Ala Ala Glu Ile Glu Ala
405 410 415
Lys Glu Lys filet Phe Gin Glu Ala Gln Gln Leu Leu Lys Glu Glu Lya
4Z0 425 430
Glu Ala Leu V,I Ala Ikt Gly Ile Asp Arg Ser Ser Leu Thr Ser Leu
435 440 445
Glu Thr Ser Tyr Phe Thr Pro Lya Lys Arg Lys Leu Phe Giy Asn Lys
t0 450 455 460
Lys Arg Lys Ser Phe Phe teu Ars Glu Ser Gly Lys Aso Gfn Pro Pro
485 470 4T5 480
Gfy Sar Aap Ser Asp Glu Asp Cys Gln Lys lys Pro Gin Leu Leu Glu
485 490 495
Gln Thr Lys Arg Leu Ser Gin Asn Leu Ser Leu Aso His Phe Aso Glu
500 505 510
His Gly Asp Pro Leu Gin Arg Gln Arg Ala Leu Ser A!a Yal Ser Ile
515 520 525
Leu Thr Ile Thr Wet Lys Glu Gln Glu Lys Ser Gln Glu Pro Cya Leu
530 535 540 -,.
Pro Cys Gly Glu Asn Leu Ala Ser Lys Tyr Leu Yal Trp Asn Cys Cys
545 550 555 560
Pro Gln Trp Leu Cys Val Lys Lys Yal Leu Arg Thr Val Wet Thr Asp
565 5T0 5T5
Pro Phe thr Glu Leu Ala Ile Thr Ile Cys Ile Ile Ile Asn Thr Val
580 585 590 .. :.
Phe leu Ala wet Glu His Hit Lys Wet Glu Ala Ser Phe Giu Lys Akt
596 600 605
Leu Atn Ile Gly Asn Leu Val Phe Thr Ser ite Pha Ilo Ala Glu Wot
3D 610 615 620
Cys Lau Lys Ile Ile Ala Leu Asp Pro Tyr His Tyr Phe Arg Arg Giy
625 630 635 ~ 6
Trp Asn Ile Phe Asp Ser Ilo V'I Ala Lou Leu Ser Phe Ala Asp Val
645 650 655
3x5 wet Asn Cys V,I Leu Gin Lys Aig Ser Tro Pro Phe Leu Art Ser Phe
660 665 6T0
Ars V,I Leu Ars Val Phe Lys Leu Ala Lrs Ser Trp Pro Thr Leu Asn
675 seo sas
thr Leu Ile Lys ile Ile Gly Asn Ser Yal Gly Ala Leu Gly Asn Leu ;
40 690 695 700
Thr Val Val Leu Yal Ile Vat Ile Phe Ile Phe Ser Yal Yal Gty wet
T05 710 T15 T20 w:
Y.c
Gln Leu Phe Gly Arg Ser Phe Asn Ser Gln lys Ser Pro Lys Leu Cys
T25 130 T35
46 Asn Pro Thr Gly Pro Thr Vat Ser Cys Leu Arg His Trp Hls Ilet GJy
. ,.
__ ___ _. CA 02412306 2002-11-22
~s~ss
. ;:~ ,
:.
T40 T45 T50
A:p Phe Trp His Ser Phe Leu Val Val Phe Arg Ile Leu Cys Gly Glu
T55 T60 T65
Trp Ile Glu Asn Ilet Trp Glu Cys filet Gln Glu Ala Asn Ala Ser Ser
7T0 TT5 T80
Sar Leu Cys Val ile Val Phe Ile Leu Ile Thr Va1 Ile Gly Lys Leu
T85 T90 795 800
Yal Val Leu Asn Leu Phe Ile Ali Leu Leu Leu Asn Ser Phe Ser Asn
805 810 81S
Glu Glu Arg Asn Gly Asn Leu Glu Gly Glu Ala Ars Lys Thr Lya Val
820 825 830
Gln Leu Ala Leu Aso Arg Phe Ar' Arg Ale Phe Cya Phe Y~l-Arg Hi:
835 840 845
Thr Leu Giu His Phe Cy: His Lys Tro Cys Arg Lys Gln Asn Leu Pro
850 855 860
Gln Gln Lys Glu Y'I Ala Gly Gly Cys Ala Ala Gln Ser Lys Asp Ile
885 87D 8T5 880
Ile Pro Leu Yal Akt Glu filet Lys Arg Gly Ser Glu Thr Gin Glu Giu
885 890 895
aJ Leu Gly (1e Leu Thr Ser Yal Pra Lys Thr leu Glr Val Are Hi: Asv
900 905 910
Trp Thr Trp Leu Ala Pro Leu Ala Glu Glu Glu Asv Asp Y,I Glu Phe
915 920 925
Ser Gly Glu Asv Asn Ala Gin Art Ile Thr Gln Pro Giu Pro Glu Gin
2s 930 935 940
Gin Ala Tyr Giu Leu His Gln Glu Asn Lys Lys Pro Thr Ser Gln Arg
945 950 955 960
Val Gln Ser Val Glu Ile Asv filet Phe Ser Glu Asp Glu Pro His Leu
965 970 9T5
30 Thr lie Gln Asp Pro Arg Lys Lys Ser Asp Yal Thr Ser ile Leu Ser
980 985 990 ;
Glu Cys Ser Thr tie Asp Leu Gln Asp Gly Phe Gly Trp Leu Pro Glu
995 1000 1005
bet Yal Pro Lys Lys Gln Pro Giu Arg Cys Leu Pro Lys Gly Phs GIy
S>5 1010 1015 1020
Cys Cys Phe Pro Cys Cys Ser Yal Aso Lya Arg Lys Pro Pro Trp Vai
1025 1030 1085 1040
Ile Tro Trp Asn Leu Ar8 Lys Thr Cys Tyr Gin Ile Yal Lys His Ser
1045 1050 1055 .. :-
40 Trp Phe Gtu Ser Phe Ile Ile Phe Val Ile Leu Leu Ser Ser Gly Ala
1060 1065 10T0
Leu 111 Phe Glu Asv Val His Leu Glu Asn Gln Pro Lys Ile Gln Giu
10T5 1080 1085 ,,
Leu Leu Asn Cys Thr Asa Ile lle Phe Thr His Ile Phe Ile Leu Glu ;
46 1090 1095 1100
i6iss
list1~,)Leu lyaTrpYalAlaPheGlyPhe GlyLysTyrPheThrSer
1105 1110 1115 1120
'
AlaT~rvCys CxsLeuAspPheIleIleYal IleV$ISerYelThrThr
1125 1130 1135
LeuIleAsn LeuIletGluleuLysSerPhe ArgThrleuArgAlaleu
1140 1145 1150
ArgPtoLeu ArgAlaleuSerGinPheGlu GixttetLysYalYalYal
1155 1160 1165 .
AanAiaLeu ileGlyAiallaProAI'(1e leuAsnYalLeuLeuYal
1170 1175 1180
Cysleuile Phe"froLeuYaiPheCxsIle LeuGlxYolTyrPhePhe
1185 1180 1195 1200
SerGlyLxs PheGixlysCxsliaAsnGly ThrAsoSerValileAsn
1205 1210 1215
TyrThrIle lleThrAsnLxsSerGlnCys GluSerGiyAsnPheSer
1220 1225 1230
TrplleA:n GlnLysYelAsnPheAspAsn YalGlyAsnAlaTyrLeu
1235 1240 1245
AlaLeuLeu GlnValAlaThrPhelysGly TrpfiletAspIleIleTyr
120 1255 1260
AlaAfaVal AsvSerThrGluLxsGluGln GlnProGluPheGluSer
1265 1270 1275 1280
AsnSerLeu GlxTyrIlcTxrPhcYalVai PheIleIlePheGlySer
1285 1290 1295
PhePheThr LeuAsnleuPheileGlyVal IleIleAspAsnPheAsn
1300 1305 1310
GlnGlnGln LxsLxsleuGlyGlyGinAso IlePhefiletThrGluGlu w
1315 1320 1325
G!nlxaLys TyrTyrAsnAlaIletLysLys LeuGixSerlrsLysPro
3D 1330 1335 .. ~ 1$40 ::,;
Glnly:Pro IleProArsProleuAanLys CysGlnGlxleuValPhe w
1345 1350 1353 1360
AspIleVal ThrSerGlnIlePheAsplle IleIleIleSerLeuIlc
1365 1370 1375.
36 IleLeuAsn AietIleSerfiletlletAlaGlu SerTxrAsnGinProlys
1380 1385 1390
AlaIletLxs SerlieLeuAsvHisLeuAsn TrpVa1PheYalYaiIle
1395 1400 1405 .
PheThrlcu GtuCysleuIlelxsiiePhe AlaLeuArsGlnTxrTyr
40 1410 1415 1420
PheThrAan GlyTrpAsnLeuPheAspCxs V'IYalYalLeuLeuSer
1425 1430 1435 1440
Ile Ser ThrltetIleSerThrLeuGlu A:nGinGtuHis-
Vat lie
Pro
1445 1450 1455
PhePraPro ThrLeuPheArgileValArg LeuAlaArgIleGlyArg
CA 02412306 2002-11-22
CA 02412306 2002-11-22
17/55
1460 1465 1470
lle Leu Ar5 Leu Val Are Ala Ala ArD Gly Ile Art Thr leu
Leu Phe
1475 1480 1485
Ala Leu Wet Wet Ser Leu Pro Ser Leu Phe Asn Ile Gly Leu
Leu Leu
1490 1495 1500
Phe Leu Ile I~t Phe Ile Tyr Ala Ile Leu Gly filet Asn Tro
Phe Ser
1505 1510 1515 1520
Lys Val Asn Pro Glu Ser Gly Ile Asp Asp Ile Phe Asn Phe
Lys Thr
1525 1530 1535
Phe Ala Ser Ser Wet leu Cys Leu Phe Gln Ile Ser Thr Ser
Ala Gly
1540 1545 1550 '
Tro Aso Ser Leu leu Ser Pro Wet Leu Arg Ser Lys Glu Ser
Cya Asn
1555 1560 1565
Ser Ser Ser G1u Asn Cys His leu Pro Gly Ile Aia Thr Ser
Tyr Phe
1570 1575 1580
Vai Ser Tyr ile Ile ile Ser Phe Leu Ile Y'I Yal Asn Wet
Tyr Ile
1585 1590 1595 1600
Ala Yal Ile Leu Glu Asn Phe Asn Thr Ala Thr Glu Glu Ser
Glu AsD
1605 1610 1615
Pro Leu Gly Glu Aso Aso Phe Aso Ile Phe Tyr Glu Val Tro
Glu Lys
1620 1625 1630
Phe Aav Pro Glu Ala Thr Gln Phe Ile Lys Tyr Ser Ala Leu
Ser Aso
1635 1640 1645
Pht Afa Asp Ala Leu Pro Glu Pro leu Ara Val Ala Lys Pro
Asn Lys
160 1655 1660
Tyr Gle Phe Leu Yal Wet Asa Leu Pro Wet Val Ser Glu Aav
Ar' Leu
1665 1670 1675 1680
Nis Cys Ilet A:o Ile Leu Phe Ala Phe Thr AIa Ar$ Val Leu
Gly Gly
1685 1690 16!<5
8flSer Aso Gly Leu Aso Ser Iriet Lys Ala Wet Wet Glu Glu Lys
Phe Wet
1700 1705 1710
Glu Ale Asn Pro Leu Lys Lys Leu Tyr Glu Pro Ile Yal Thr
Thr Thr
1715 1720 iTZS
Lys Art Lys Glu Glu Glu Ara Gly Aia Ala ile Ife Gln lys
Ala Phe
36 1730 ~ 1135 1740
Ars Lys tyr islet Wet Lys Val Thr Lys Giy Aso Gln Gly Aao
Gln Asn
1745 1750 1755 1160
Aso Leu Glu Aan Gly Pro Nis Ser Pro Lw Gln Thr Leu Cys :t r
Asn Gly
1765 1770 177 5
A:o Leu Ser Ser Phe Gly Yal Ala Lys Gly Lys Val His Cys
Asp
1780 1185 1790 .
:
,.
<210> 3
,.,~.-.~.
CA 02412306 2002-11-22
I
' ~Biss
C211 >. 5t28 .
<212> DIVA
0213>~Hoso Sapiens
<220)~
<221>~CDS
<222~ ~ t!00) . . (4534)
C300>~
t0 <301>~Saen-llon' Jeons et al.
0302) I dent i f i cat i on of a Nove I Husan Yo Subun 1~t GCnE.
I fate-Gated Sod i us Channe I a
SCN12A
<303) 8lochee. B i ovhys. Res. Come. .
<304) 28T
C305> 1
<306) ' 282-270
<30T) ' 2000
0308) GenBank AF150882
<309) 2000-01-15
<400~ '3
tcctsqtxta cccacasts4 tsetcatctc t,tctsatctt cacasccaat80
casctcccaa
sscccctiac ctcatctcas ctttt$tasa tccttatsac accatccttt120
aagactgsaa
tcctassica ssctstttta ttcccgcctc ctsasscctt tctsassatc180
tgtsscttst T
ctctstccts assstsaas ats sat sac asa tsc tac cca 232
sta atc ttt~cca
bet Asp Aao Art Cys Tyr Pro Yal Ila Phe Pro
30 1 5 10 r
at sat css aat ttc esc ecc ttc act tec sac tct 2d0
ets get sea aft
AsD GIb Ars Asn Phe Arg Pro Phe Thr Ser Asp Ser
Leu Ata Ala Ile
15 20 25
sas aaa css att scc atc caa aas gag aaa aas aas 328 .
tct aaa gac cas
Glu Ly: Ars Ile Aia Ite Gln Lys Glu Lys Lys Lys
Ser Lys Asp Gln
30 35 40
40 aca tsa taa sta ccc cag cct cgs cct cas ctt sac 3t6
cta aas scc tcc
Thr Gly Glu Val Pro Gln Pro Ars Pro Gln Leu AsD
Leu Lys Ala Ser
4S 50 55
ass aas tts ccc aas ctc tit ssc sac att cct cst 424
sas ctc ata ssa
45 Ars Lys Leu Pro Lys Leu Tyr Gly Aso Ile Pro Arg
Glu Leu..lle Gly
q(Y
w.
. w.,
rr
CA 02412306 2002-11-22
' 19/35
60 . 65 78 T5
aag cct cts saa sac tts sac cca ttc tac e'a aat cat aa~ acs ttt 4T2
Ly: Pro leu Glu Aso Leu Asv Pro Phe Tyr Ars Asn His Lys Thr Phe
80 85 90
ats sts tta aac asa sag ags aca atc tac csc ttc ast scc aag cat 520
flat Yal Leu Asn Ars Lys Ars Thr ile Tyr Ars Phe Ser Ala Lys His
95 100 105
1D
gcc ttg ttc aft ttt ssg cct ttc aat tca atc asa agt tta stc att 568
Ala Leu Phe Ile Phe Gly Pro Phe Asn Ser Ile Ars Ser Leu Ala Ile ~ ~ .
110 115 120 ;
'>b asa gtc tca stc cat tca tts ttc asc ats ttc aft atc ssc acc stt 616
Ars Val Ser Val His Ser Leu Phe Ser Ik t Phe Ile lie Gly Thr Val
1Z5 130 135
atC atc aac tsc sts ttc ata sct aca sss cct sct aaa aac asc aac 664
2D Ile Ile Asn Cya Val Phe Wet Ala Thr.Gly Pro Ala Lys Asn Sor Asn
140 145 150 155
ast aac aat act sac aft sca sas tst Stc ttc act gss att tat att T12
Ser Asn Asn Thr Asv Ile Aia Glu Cys Val Phe Thr Gir Ile Tyr 11e
25 160 165 170 .,
,,w~...~ ~-
ttt saa sct tts att aaa ata ttg sca asa s8t ttc att ctg sat gas T60
Phe Glu Ala Leu ile Lys ile Leu Ala Art Gly Phe Ile Leu Asv Glu ,
1T5 180 185
ttt tct ttc ctt cga sat cca tgs aac t~ ctg sac tcc att stc att 808
Phe Ser Phe Leu Ars Asp Pro Trp Asn Trp Leu Asp Ser Ile Yal ile
190 195 200
3~5 ssa ate 8cs att sts tca tat att cca tga atc acc atc aaa cta tts 856
Gly Ile Ala Ile Val Ser Tyr Ile Pro Gly (1e Thr Ile Lys leu Leu
205 210 215
y.
CCC Ct~ Cgt acc ttC cst gtg ttc asa sct tts aaa sca att tca eta 904
40 Pro Leu Arg Thr Phe Arg Val Phe Ars Ala Leu Lys Ala Ile Ser Val
220 ~ 225 230 235
gtt tca cst cts aa8 stc atc stg sss fcc tts cta cic tct gts aag 952 .
Val Ser Arg Leu Lys Vai Ile Val Gly Ala Leu Leu Ars Ser Yal lys
240 245 250
. ='>y' _,
CA 02412306 2002-11-22
' zoiss
aag dtg gtc aae gtt att atc cte ace ttc ttt tgc ctc agc atc ttt 1000 ,
Lys Leu Yai Asn Val Ile Ile Leu Thr Phe Phe Cys Leu Ser Ile Phe
255 260 265
6
gcc c'tt~ gta ggt cag cag ctc ttc atg ~a agt cts sac cta aaa tgc 1048
Ala Leu Y,I Gly Gin Gln Leu Fhe Wet Gfy Ser Leu Asn Leu Lya Cya
270 2T5 280
ate teg agg gac tgt aaa sat atc agt sac cc: saa get tat aac cat 1096
Ile Ser Arg Asv Cya Lys Asn Ile Ser Asn Pro Glu Ala Tyr Aso His
2e5 290 295
tgc ttt gaa aas aaa saa aat tca cct gaa ttc aaa at: tst sgc atc 1144
Cys Phe Glu Lys Lys Glu Asn Ser Pro Glu Phe Lys Ikt Cys Gly Ile
300 305 310 315
tag at: fit aac agt :cc tat tcc ata caa tat gaa tgt aag cat aCC 1192
Trv Wet Gly Asn Ser Ala Cys Ser Ile Gln Tyr Glu Cys Lys Hi: Thr
Zn 320 3Z5 330
aaa att aat cct gac tat aat tat acs aat ttt sac aac ttt sgc tss 1240
Lya Ile Asn Pro Asp Tyr Asn Tyr Thr Aan Phe Asv Asn Phe Gly Trv
335 340 345
tct ttt ctt scc at: ttc cgg cts atg acc caa gat tcc tsg gag aas 1288 , '
Ser Phe Leu Ata bet Phe Ara Leu llet Thr Gln AsD Ser Trs Glu Lys
350 355 360
3o ctt tilt caa cag acc ctg cst act act sgg ctc tac tca gtc ttc tic 1336
Leu T~r'Gin Gln Thr Leu Arg Thr Thr Giy Leu Tyr Ser Yo) Phe Phe
3~5 370 375
..
ttc att sts rtc att ttc cts sac tcc ttc tac ct' att aac tta acc 1384
3S Phe Ile Yal Yal Ile Phe Leu Gly Ser Phe Tyr Leu Ile Aan Leu Thr
380 385 390 395
ctg sct gtt stt ace at: :ca tat :as tag eaa aac aag aat ata get 1432
Leu Also Yal Yal Thr Ikt Ata Tyr Glu Glu Gin Asn Lya Asn Yal Ala ,
40 ; 400 405 410
:ca aag ata :a8 gcc aas gaa aag atg ttt cag gaa scc cag caa ctg 1480
Ala Glu Ile Glu Ala Lys Glu Lys filet Phe Gln Glu Ala Gln Gln Leu
415 420 425
. "
k
CA 02412306 2002-11-22
Zi/ss
tta a g.gas gaa aag gag get ctt stt Sec atg sta att gac aga agt 1528
Leu L~rs'Gtu Glu Lys Glu Aia leu Yal Ala tkt Gly Ile Asp Arg Ser
430 435 440
8 tca ctt act tcc ctt saa aca tca tat ttt acc cca aaa sag asa aag 1516
Ser Leu Thr Ser Leu Glu Thr Ser Tyr Phe Thr Pro Lya Lys Arg Lys
M5 450 455
ctc ttt gst sat aas aaa ass aag tcc ttc ttt tts asa sas tct ssg 1624 ,
14 leu Phe Gly Asn Lys Lys Arg Lya Ser Phe Phe leu Ars Glu Ser Gly
460 465 410 415
aaa sac us cct cct ggs tca sat tct pt gaa gat tsc caa aaa aag 1612 . 'yy
Lys Asp Gln Pro Pro Giy Ser Asp Ser Asp Glu Aso Crs Gln Lrs Lys
15 ~ 480 485 490
cca cps ctc cta sag caa acc aaa csa cts tcc cas aat cta tca cts 1120
Pro Gln Leu Leu Glu Gin Thr lys Ars Leu Ser GIn Asn Leu Ser Leu
495 500 505 - "
sac eac ttt sat gas cat ssa sat cct ctc eaa ags cas aga sca cts 1168 ,
Asp Hia Phe Aso Glu His Gly Asp Pro Leu Gtn Ars Gln Ars Ala Leu
510 515 520
?5 ast tcc gtc agc atc ctc acc atc acc atg aas saa caa saa aaa tca 1816 ,,
Ser Al~a Yaf Ser Ile Leu Thr lle Thr Itet Lys Glu Gln Glu Lya Ser ,
525 530 535
caa sat cct tgt ctc cct tsc $s8 as sic cts sca tcc aas tac ctc 1864
30 Gln GIu~Pro Cya Leu Pro Cys Gly Glu Asn Leu Ala Ser Lys Tyr Leu
540 ' S45 550 555
tts tss aac tst tsc ccc cas tss cts tsc stt ass ass stc cts asa 1912
Yai Trp Asn Cys Cys Pro Gln Trp Leu Cys Y,I Lys Lys Y'I leu Ars
560 565 510
act std its act sac cc: ttt act sas ctg scc atc acc atc tgc atc 1960
Thr Ya1 Wet Thr Asp Pro Phe Thr Glu Leu Ala Ile Thr Ile Crs ile
j 515 580 585
. 5~-:r
atc atc aac act gtc ttc ttg gcc atg gas cat cac aag ats gas scc 2008 _
Ile Ile Asn Thr Yal Phe Leu Ala Ilet Glu His His Lys rwet Glu Ala
590 595 600
d6 ast ttt sag aas ats tts sat ata ses aat tts stt ttc act asc att 2056 _~.r
1
W
CA 02412306 2002-11-22
I
ZZ/ss
Ser e. Leu Ile Gly A:s Leu Yal Ser
Glu Asn Phe Thr Ile
Lys
Wet
605' 610 615
ttt a~ta~ tsc aaa atc att ses ete tac 2104
sca eta set ccc cat
saa
ats
Phe I~e Cya Lys Ile Ile Ala leu Tyr
Ala Leu Aao Pro Nis
Glu
list
620 ~ 625 630 635
tac ttt tgg att ttt sac asc att ctt 2152
csc aac stt sct cts
csa
uc
Tyr Phe Tro Ile Phe Asp Ser Ile leu
Art Asn Val Ala Leu
Art
Gly
~ 645 650
640
ast ttt ats tst sta ctt caa aas tgg 2200
sca aac asa asc cca
sat
sta
Ser Pie flat Cya Val Leu Gle Lys Tro . ,
Ala Asn Ara Ser Pro
Aav
Val
6SS 660 665
'
ttc ttt ats ctc agg stc ttc aas aaa 2248
cst ttt !ta tcc tcc
tcc
ttc
Phe Leu Ars leu Ars Yal Phe Lys Lys
Ars Vai Leu Ala Ser
Ser
Phe
670 6T5 680
tgg cca act tts aac aca cta att aat ata atc ttc sac tct ttc ~a 2296
Tro Pro Thr Leu Asn Thr Leu Ile Lys Ile Ile Gty Asn Ser val Gly
885 690 695
tcc cttggaaac acttt8ttcctsttcatttttatctttattttc 2344
ctt
Aia LeuGlyAsn ThrValYalLeuValIleValIlePheIlePhe w
Leu
T00 T05 T10 T15
tca ttatttssc catctttttggccttascttcaattcccaaaas 2392
att
Ser YslValGIy GlnLeuPheGlyAraSerPheAsnSerGlnLrs
Wet
~ T20 ~ TtS ~ T30
aft caaau ctc aaccctaw ssccctacastctcatstttacss 2440
tst
Ser ProLysLeu AsnProThrGirProThrYaiSerCyaLeuArt
Cys
T35 T40 T45
cac tggcacatt at ttctgscaciccttcctasttstattccsc 2488
tss
His TrpHisstet AsoPheTroHisSerPheLeuY,IYalPheArt
Gly
T50 T55 T60
atc ctctgctss t~ atctaaaatat=tggsaatstatgcaasaa 2536
saa
ile LeuCysGly TroIleGluAsnWetTroGluCyaWetGlnGlu
Glu
T6;5 TTO TT5
scs sat sca tca tca tca ttg ttt stt att stc ttc ata ttt atc acs 2584
as Ala Asn Ala Ser Ser Ser Leu Cys Yai Ile Yal Phe Ile leu Ile Thr
CA 02412306 2002-11-22
I
29/sS
I
I
780 T85 790 T95
sts ata ssa aaa ctt sts sts ctc aac ctc ttc att scc tta cts ctc 2632
V'I Ile Gly Lys Leu Val Val Lw Asn Leu Phe Ile Ala Leu Leu Leu
810
aat ttc ttt asc aat sas aaa ass aat as aac tta saa ssa sas scc 2680
Asn S!r Phe Ser A:n Glu Giu Arg Asn Gly Asn Leu Glu Gly Glu Ala
a15 8zo 825
~o
ass aaa act aaa stc cas tta sca cts at csa ttc csc css Sct ttt 2T28
Ars Lys Thr Lys Val Gln Leu Ala Leu Asp Ars Phe Arg Ars Ala Phe
830 835 ~0 : r ~.
15 tat tit sts asa cac act ctt sas cat ttc tst cac sas tss tsc ass ?TT6
Cys Phe Yal Ars His Thr Leu Glu His Phe Cys His Lys Trv Cys Ars
8~5 . 850 855 ,
aas caa aac tta cca cas caa aaa sas sts sca ssa ssc 1st sct sca 2824
Lya Gln Asn Leu Pro Gln Gin Lya Glu Val Ala Gly Gly Cys Ala Ala
860 865 8T0 8T5
caa asc aaa sac atc att ccc cts stc ats sas ats aaa ass ssc tca Z8T2
Gln Ser Lys Asp ile Ile Pro Leu Val wkt Glu tlet Lys Ars Gly Ser
880 885 890
sas acc cas sas sas ctt set ata cta acc tct sta cca aas acc cts 2920
Glu Thr Gln Glu Glu Leu Gly Ile Leu Thr Ser Val Pro Lys Thr leu
895 900 905 °A
ssc stir ash cat sat tss act tss tts sca cca ctt scs as as as 2968
Clr Ya~l Ars His Aav Trv Thr Trv Leu Ala fro Leu Ala Glu Glu Glu
910 915 920
sat sae stt.saa ttt tct sst gaa sat aat sca cas cse atc aca caa 3016
Asp Asp Val Glu Phe 5er Giy Glu Asn Aan Ala Gin Ars Ile Thr Gln
9Z5 930 935
cct sas cct saa caa cas scc tat sas ctc cat cas aaa aac aas aas 3064
40 Pro Glu Pro Glu Gln Gln Ala Tyr Glu Leu His Gin Glu Asn Lys Lys ~~ '
940 , 945 950 955
9.r>.. :..
ccc act asc cas asa stt caa ast sts saa att sac ats ttc tct saa 3112 °v
Pro Thr Ser Gln Arg Val Gln Ser Val Glu Ile Asv filet Phe Ser Glu
960 965 970
CA 02412306 2002-11-22
', Z4/ss
i
set as cctcatctr atacarsatccccraaarsirtctratrtt3160
acc
Asv GluProHlsLeu IleGinAavProArrLysLysSerAsvVal
Thr
9T5 980 985
acc aftatactatca trtarcaccattsatcttcarratsrcttt3208
raa
Thr SerileLeuSer CysSerThrIleAsvLeuGlnAsvGlyPhe
Glu
990 885 1000
ssa t~ ttaecttar rttcccearsascaaccasasasatsttts3256
atr
Gly TrvleuProGlu V,IProLysLyaGinProGluArgCysLeu
filet
1 005 1010 1015
ccc aaassctttsst trctttccatrctstascstssacaasasa3304
tsc
Pro LysGlyPheGly CysPheProCYSCysSerYsiAsvLysArr
Cys
1020 1025 1030 1035
aas cet ccc tss stc att tas t~ aac ctr css aaa acc trc tac caa 3352
Lys Pro Pro Tw Yal ile Trv Trp Asn Leu Ars Lys Thr Cys Tyr Gin
2D 1040 1045 1050
ate str aaa cac arc tsr ttt rar arc ttt att atc ttt sts att cts 3400
Ile Val Lya His Ser Trp Phe Glu Ser Phe Ile lle Phe Yai Ile Leu
1055 1060 1065
ctr arcartsss ctsatetttraa rttcaccttsasaaccaa 3448 ;.
rca rat
Leu SerSer61yAlaLeuIlePheGlu YalHisLeuGluAsnGin ' .
Asp
1010 1015 1080
3D ccc aaaatccaaraattactaaattst sacattatttttacecat 3486
act
Pro lrsileGlnGluLeuLeuAsnCys AspIleI.lePheThrHis
Thr
10x5 1090 1095
att tttatcctrraratgstactaa" rtasccttc~a tttssa 3544
tss
36 11e PheIleleuGluWetYalLeulys Va1AlaPheGlyPheGly
Trv
1100 1105 1110 1115 '
!
~.e~
.: 't1
aas tatttcaccastscctsstsctsc satttcatcattstsatt 3592 -
ctt
lys TyrPheThrSerAlaTrvCysCys AsvPheIleIleValIla '_
Leu
40 1120 1125 1130 ~ ~'
;:
stc tctstseccaccctcattsactta saattraartccttccrr 3540 ~ . '
ats
Val SerValThrThrLeuIleAsnLeu GluLeuLysSerPheArs
Wet
1135 1140 1145
4g
i~ , ty
a i
25/55
,. ,
;;
:ct c~a cts sca ctt sss cct ctt cst tct ctt tcc cat ttt gaa gga 3685
Thr Lhu Ars Ala Leu Art Pro Leu Art Ala Leu Ser Gln Phe Glu Gly
1150 1155 1160 '
att aag its sts stc aat sct ctc ata sgt scc ata cct scc att ctg 3736
filet Lys Vai Val Yal Asn Ala Leu Ile GIy Ala Ile Pro Ala Ile Leu
1165 1110 1175
sat ttt tts ctt ttc tsc ctc att ttc tts ctc sta ttt tst att ctg 3184
Asn Yal Leu Leu Yal Cya Leu lle Phe Tro Leu Yal Phe Cys Ile Leu
1180 1185 1190 1195
ssa sta tac ttc ttt tct tsa aaa ttt ggg aaa ttc att sat gga aca 3832 r .:
Gly Val Tyr Phe Phe Ser Gly Lys Phc GIy Lya Cys Ile Asn Giy Thr
1200 1205 1210
tac tca ttt ata aat tat acc atc att aca aat aaa ast caa ttt gaa 3880
Aao Ser Vsl Ile Asn Tyr Thr Ile Ile Thr Asn Lys Ser Gin Cys Glu
1215 1220 1225
att ssc aat ttc tct tsg atc aac cas aaa ttc aac ttt sac aat stg 3928
Ser Giy Asn Phe Ser Tro Ile Asn Gln Lya Yal Aan Phe Aso Asn Val
1230 1235 120
sga aat sct tac ctc act ctg cts caa gts tca acs ttt asg sec tss 3916 ,
Gly Asn Ala Tyr Leu Ala Leu Leu Gin Yal Ala Thr Phe Lys Gly Trp ~1,:.
1245 1250 1255
ats sat att ata tat sca Rct ttt sat tcc aca eas aaa eaa caa cas 4024
bet Asp Ile Ile Tyr Ala Ala Val Asp Ser Thr Glu Lys Glu Gln Gin ..
1260 . 1265 1270 1275
cca set ttt sas ase aat tca cte tgt tae att tac ttc sta stc ttt 4012
Pro Glu Phe Glu Ser A:n Ser leu Gly Tyr Ile Tyr Phe Y,I Yal Phe
1280 1285 1290 ~.
atc atc ttt ssc tca ttc ttc act cts aat ctc ttc att ggc stt atc 4120
(1e II~ Phe Gly Ser Phe Phe Thr leu Asn leu Phe Ile Gly Vai Ile
. 1295 1300 1305 . ~ '"'
40 : .
att tac uc ttc aac caa cas cas aaa aat tta 18't ssc caa sac att 4168
Ile Aao Asn Phe Aan Gin Gin Gin Lys Lys Leu Gly Gly Gin Asp lle
1310 1315 1320 .
46 ttt ats aca taa saa cas aas aaa tac tat aat tca ats aaa aaa tta 4216
,,
CA 02412306 2002-11-22
CA 02412306 2002-11-22
a6rss
i
,.
Phe t'Thr Giu Glu Gln Lys Lys Tyr Tyr Asn Ata Vet Lys Lys Leu
13 5 1330 1335
i,
ssa tic aaa aas cct eas aaa ccc ott eea css cct cts sac aaa tst 4264
Gly Ser Lys Lys Pro Gln Lys Pro Ile Pro Ars Pro Leu Asn Lys Cys
1340 : 1345 1350 1355 '
caa stt ctc stg ttc sac ata gtc aca asc cas stc ttt sac atc atc 4312
Gln Gly Leu Yal Phe Asv Ile V,I Thr Ser Gln Ile Phe Aso Ile Ile
1360 1365 1370
atc a~a agt ctc att atc cta aac ats att asc ats ats sct saa tca 4360
Ile Ile Ser Leu Ile Ile Leu Asn flat Ile Ser Wet r~let Ala Glu Ser
' 1375 1380 1385
1S
tac arc caa ccc ass ~cc ats aaa tcc atc ctt sac cat ctc aac tss 4408
Tyr A=n Gin Pro lys Ala flat lys Ser !1e Leu Asv His Leu Asn Trv
1390 1395 1400
stc ttt sta stc atc ttt acg tta saa tst ctc atc ssa atc ttt sct 4456
Yal PHe Val Val Ile Phe Thr Leu Glu Cya Leu Ile Lys Ile Phe Ala
1405 1410 1415
tts aas caa tac tac ttc acc aat gsc tss aat tta ttt sac tst sts 4504
?5 Leu Ars Gln Tyr Tyr Phe Thr Asn Gly Trp Asn Leu Phe Aso Cys val '
1420 1425 1430 1435
stc st't ctt ctt tcc att stt ast aas tas aatcascast casasssact 4554
Yal Yal Leu Leu Ser Ile Vai Ser Lys
3n . 1440 ~ 1445 ,
ttaasaacca saastsastt tstaaatctt atcatttttt saastttstt caaactatcc 4614
acaaascap aaactssscc aastgtactt tctsaastsa tasscassss tactaatscc 4674
3r;
attctctact sssaasttsc tassasstas asastsattt ctsttccctt aactcactac 4734
acaact'asa tasasttcaa taatcatsca sctaatstat tcaatssaaa tasacaaaat 1794
4o taaeat~act casaastttt tstsstssta acctsattta ttcasataat tsagtcaaas 4x54 '
ttctaccttt cctscscaac tataasctct ateascattt tttastttta asgatttact 4914 ,
seccatsttt tttcetttst teaaaatccs eatssstsee asatcacaat tattstseee 4914
CA 02412306 2002-11-22
i __ _ i
27/55
.
_,
ctgt~cict gctgtgcccc ctttcaaccC ctatacaagg ccccatggcc cactcta at 34 . '"
s 50
tgggc~ttca augtatatc attcagacaa tcaaagcttt ttttctattc tatatcccat 5094
gttaacttaa accaugtgt gaactgtgct tstctcasat tctttgaccc cgcttaccaa 5154
CcegcctCat tctctaatCa gtatattttt CCtaatCaCa Cgcagggtta actaaaaggc 5214
ttataiaaga atacaaaaga aassugtta ttaccatact ccttcsttat aaaacacaca 52T4
tacac~catc aactttaaaa ttaaattctt catggctaag ccataagtsc ttactctgsg 5334
ttttt~aagt ctssttttaa ttaaactgtt aacttgacat tttataatta tgtaaaactg 5384
;= ;: .
i5 tccaggagcc cttctcatag ttcaaaacac aatgaasaca aagaaaacts attttccaaa 5454
tggaagcttt tttgcgatct cagaaagaat gcatcaaaca gatatattgs atcaasatat 5514
tttsgttcct aatsctacts cagcattsca satatttcas asaacaacaa caaatatgct b574
'~::
9
acasttcata gtgtgttcts gtttctaasc tatsatstta atgta8ataa agcttatnaa 5634
tagattcttc catsasttta casttaasta sacctttaat ttttattatt caattccaat 5694
2S cacaagtttt ggtaaattg acascasgaa aaaa 5728
,: .
<210> 4
<211> 1444
30 <212) ~PRT .
<213> .~H~o~no sap i en:
<400> 4
Ikt Asp Aso Arg Cy: Tyr Pro Yal Ile Phe Pro Asa Glu Ars Asn Phe
1 S 10 15
Ars P~,o Phe Thr Ser Asp Ser Leu Ala Ala Ile Glu lya Arg Ile Ala
i 20 25 30 .:.
Ile Gh Lys Glu Lys Lys Lys Ser Lys A:p Gln Thr Gly Glu Yal Pro
35 40 45
;. ,,
40 Gln P~,o Arg Pro Gln Leu Asp Leu Lys Ala Ser Ars Lys Leu Pro Lys
55 60 -
Leu Tyr Gly Asp Ila Pro Ars Glu Leu Ile Gly Lys Pro Leu Glu Aso
65 TO T5 80
Leu Aso Pro Phe Tyr Ars Asn His Lys Thr Phe tlet Yal Leu Asn Arg
85 90 95
CA 02412306 2002-11-22
Zaiss . '.
~,;
Lys a Thr Its Tyr Are Phe Ser AIa,Lys His Ala Leu Pha ile
A Phe
100
105
110
'
Gly
Pro~Phe
Asn
Ser
Ile
Arlc
Ser
Leu
Ala
Ile
Art
Vai
Ser
Yel
His
;115 '
120
125
~
6 Ser
Lw'Phe
Ser
aet
Phe
Ile
Ile
Gly
Thr
Val
Ile
Ile
Asn
Cys
Val
1~0 ;
135
140
Phe
W!t
AIs
Thr
Gly
Pro
Ala
Lys
Asn
Ser
Asn
Ser
Asn
Asn
Thr
Asv
145
'
150
155
160
Ile
Ala
Glu
Cys
Yal
Phe
Thr
Gly
Ile
Tyr
ile
Phe
Glu
Ala
Leu
Ile
165
170
175
Lys
Ile
Leu
Ala
Are
Gly
Phe
Ile
Leu
Asp
Glu
Phe
Ser
Phe
Leu
Arg
180
185
190
Asp , '>
Pro h
Tro
Aan
Trp
Leu
Asp
Ser
Ile
Val
Ile
GIr
Ile
A1s
Ile
Val
195
200
205
Ser
T1~
r
Ile
Pro
Gly
Ile
Thr
Ile
Lys
Leu
Leu
Pro
Leu
Ar=
Thr
Phe
210
215
220
Are
Val
Phe
Art
Ala
Leu
Lys
Ala
Ile
Set
Val
Val
Ser
Arg
Leu
Lys
225
~
230
235
240
Val
Ile
VaI
Gly
Ala
Leu
Leu
Ars
Ser
Val
Lys
lys
Leu
Val
Asn
Vai
245
250
255
Ile
Ile
Leu
Thr
Phe
Phe
Cys
leu
Ser
ite
Phe
Ala
Leu
Yai
Gly
Gln
.280
265
270
Gln
Leu
Phe
Wet
Gly
Ser
Leu
Asn
Leu
Lya
Cys
Ile
Ser
Ar8
Asv
Gys
2T5
280
285
Ly:
Aan
Ile
Ser
Asn
Pro
Glu
Ala
Tyr
Asp
His
Cys
Phe
Glu
Lys
Lys
290 . . . .~
295
300
Glu
Ann
Ser
Pro
Giu
Phe
Lys
Ilet
Cys
Gly
lie
Tro
Wet
Gly
Asn
Ser
305 '
.
310
315
320
Ala
Crs
Ser
Ile
Gin
Tyr
Glu
Cys
Lys
Nis
Thr
Lys
Ile
Asn
Pro
Aso
.
3ia'
325
380
335
Tyr
Ann
Tyr
Thr
Asn
Phe
Asv
Asn
Phe
Gly
Trv
Ser
Phe
Leu
Ata
Wet
340
345
350
Phe
Ara
Leu
Wet
Thr
Gln
Asv
Ser
Trv
Glu
Ly:
Leu
Tyr
Gln
Gln
Thr
355
360
365
Leu
A~~
Thr
Thr
Gly
Leu
Tyr
Ser
Yal
Phe
Phe
Phe
Ile
Val
Val
Ile
3r0
375
380
Phe
Leu
Gly
Ser
Phe
Tyr
Leu
Ile
Asn
Leu
Thr
Leu
Ala
Yii
Val
Thr
385 ,..
~
390
395
400
llkt .;
AI _
Tyr
Glu
Glu
Gln
Asn
Lys
Aan
Val
Ala
Ala
Glu
Ile
Glu
Ala
40 ~ .
405 ~
410 'y
415
Lrs a;.
Gli
Lys
Wet
Pht
Gln
Glu
Ala
Gin
Gin
Leu
Leu
Lys
Glu
Glu
Lys
,
420
425
430
Glu ,
Ali
Lw
Yal
Ala
Wet
GIy
Ile
Asv
Ara
Ser
Ser
Leu
Thr
Ser
Leu
~
435
440
445
46 Glu Thr 5er Tyr Phe Thr Pro Lya Lys Ars Lys Leu Phe Glr Asn Lys
i
z9iss
460 455 460
Lys Ary Lys Ser Phe Phe leu Ars Glu Ser Gly Lys Aso Gln Pro Pro
4ss ~ 4to 4T5 4ao
Gly Ser Asn Ser Aso Glu Asa Cys Gln Lys ly: Pro Gln Leu Leu Glu
~ 485 4!0 495
Gln T~r Lys Ars Leu Ser Gln Asn Leu Ser Leu Aso His Phe Asp Glu
500 505 510
His Giy Aao Pro Leu Gln Ars Gln Ars Ale Leu Ser Ala Val Ser Ile
515 520 625
Leu Thr Ile Thr flat Lys Glu Gin Glu lys Ser Gtn Gtu Pro Cys Leu
530 535 540
Pro Crs Gly Glu Aan Leu Ala Ser Lys Tyr Leu Yal tra Asn Cya Cys
646 550 555 560 ,
Pro Gfn Tro Leu Cys Val Lys Lys Val Leu Ars Thr Val rrkt Thr Aso
1b ' 585 5t0 575 .
Pro Phe Thr Glu Leu Ala ile Thr Ile Cys Ile tte Ile Asn Thr Val
580 585 590
Phe Leu AI, Wet Giu His His Lys Wet Glu Ala Ser Phe Glu Lys Wet
595 600 605
Leu A=n iie Gfy Asn Leu Val Phe Thr Ser Ile Phe Ile Ala Glu Wet
610 615 620
Cys Leu lys Ile Ile Ala Leu Asp Pro Tyr His Tyr Phe Ars Ars Gly
625 630 635 640
Tro Asn Ile Phe Asp Ser Ile Val Ala Leu Leu Ser Phe Ala Asv Val
~5 615 650 655
Wet Asn Cys Vei Leu Gin Lys Ar0 Ser Tro Pro Phe Leu Ars Ser Phe . '
860 685 670 ' '
Are Val Leu Arg Yal Phe Lys Leu Ala Lys Ser Trv Pro Thr Leu Asn
8T5 680 685
Thr Ldu~lle Lys Ile Ile Gly A:n Ser Vel Gly Ala leu Gly Asn Leu
690 695 700
Thr Vi) Vat Leu Yal Ife Vaf Ite Phe Ile Phe Ser Yal Val Gly Wet
t05 ; 710 t15 t20
!A.~
Gln Leu Phe Giy Arg Ser Phe Asn Ser Gln Lys Ser Pro Lys leu Cys
3b T25 t30 t35
Asn Pro Thr Gly Pro Thr Val Ser Cys leu Ars His Tro His Wet Gly
T40 T45 t50
Aso Phe Trv His Ser Phe Leu Val Vat Phe Are Ile Leu Cys Gly Glu
' t55 t60 t65 ,:4N°
X10 Tro I (je Glu Asn Ifet Trv Glu Cys Itet Gln Glu Ala Asn Ala Ser Ser w
Tt~ TT5 780
Ser Lair Cy: Val Ile Val Phe Ile Leu Ile Thr Vai IIe GIy Lys Leu
785 ~ T90 T95 800
Val Val Leu Asn Leu Phe Ile Ala leu Leu leu Asn Ser Phe Ser Asn
46 805 810 815 a
.w
CA 02412306 2002-11-22
3oiss
GluGluArg GlyAsnLeuGluGlyGlu AleArgLysThrLysVtl ,
Asn
820 825 830
GinLeuAlaLeuAsoArePheAreAreAle PheCysPheYelArtHis
835 840 845
ThrLeuGluHisPheCyaHisLYSTroCys ArglraGlnAsnLeuPro
850. a55 860
GlnGlnlysGluYalAIaGiyGlyCyaAle AlaGlnSerLysAspIle
865' 870 875 880
IleProLeuValIktGiuIAetLysAreGly SerGluThrGlnGluGlu
885 890 895
LeuGly11eLeuThrSerYalProLysThr LeuGiyYaiAreHisAsp
900 905 910
TrpThrTrpLeuAlaProLeuAlaGluGiu GluAspAsoYalGluPhe '
915 920 A25
SerGlyGluAspAsnAleGlnArgIleThr GlnProGluProGluGin
9a0 935 940
GlnAlaTyrGluLeuHisGinGluAsnLys LysProThrSerGlnArs
945 950 955 960
VaiGl~nSerVaiGluIleAsoIktPheSer GluAspGluProHiaLau
965 970 975
ThrIleGinAsaProAreLysLysSerAso VaiThrSerIleLeuSer
980 985 990
GluCysSerThrileAspLeuGlnAspGiy PheGlyTrpLeuProGlu
995 1000 1005
2s IrietYeiProLysLysGinProGluArgCys LeuProLysGlyPheGly
1010 1015 1020 _
CysCysPheProCysCrsSerYalAsaLys ArgLysProProTrpVal
1025 1030 1035 10,40 : F.;:y
IleTroTroAsnLeuArsLysThrCysTyr GlnIleValLysHisSer .
3D 1045 1050 1055
TrDPheGluSerPheIleIlePheYalile LeuLeuSerSecGlyAla
1060 1065 1070
LeuIliePheGluAaoYalHisleuGluAen GinProLyaIleGinGlu
1075 1080 1085
35 LeuL~ AsnCysThrAsvIleIlePheThr HisIlePheIleLeuGlu
1090 1095 1100 I
filetYalLeuLysTraVelAlaPheGlyPhe GlyLysTyrPheThrSer
1105 1110 1115 1120
AlaTrDCysCyaleuAsvPheIleIleV'I IleYelSerYalThrThr
40 1125 1130 1135
LeuIleAsnleuIletGluLeuLysSerPhe ArgThrLeuArgAlaLeu
f
1140 1145 1150 ,
ArgPrbleuAreAlaleuSerGinPheGlu GlyWetLysValYalVat
.1155 1160 1165 ._ ; ".'
46 Asn Ala leu (1e Gly Ala Ile Pro Ala Il.e leu Asn V'I Leu Leu Yal
CA 02412306 2002-11-22
31/55 '
ll~0 1175 11a0
Cys IlePheTrvLeuYalPheCysIIe.LeuGIy11,1TyrPhePhe
leu
11a5 1190 1195 1200
Ser LysPheGlyLyaCysIleAsnGly ThrAsvSerValIleAsn '
Cly
1205 1210 1215
Tyr IleIleThrAsnLyaSerGlnCys GluSerGiyAsnPheSer
Thr
1220 1225 1230
Tra AsnGinLysYalAsnPheAsvAsn Y,IGlyAsnAlaTyrLeu .
I~e
1235 7240 1245
Ala LeuGinYaiAlaThrPhelysGly TroaetAsalleIleTyr
Leu
1250 1255 1260
Ala YaiAaoSerThrGluLysGluGln GinProGluPheGluSer
Ala
1265 1270 1275 1280
Asn LeuGlyTyr(1eTyrPheV,IVal PheIleIlePheGlySer ''~
Ser
1285 1290 1295
Phe ThrLeuAsnLeuPhe(1eGlyYal (1eIleAspAsnPheAsn
Phe
1300 1305 1310
Gln GlnLrsLrsLeuGlyGlrGlnAsv ilePhefiletThrGluGlu
Gla
1315 1320 1325
Gin LysTyrTyrAsnAtabetLyaLys LeuGlySerLysLysPro
Lys
1330 1335 1340
Gin ProIleProArsProLeuAsnLys CysGlnGiyLeuYalPhe
Lys
1345 1350 1355 13B0 .
Asv VIIThrSerGinIlePheAsoIle IleIleIleSerLeuIle
Ile
?s 1365 1370 1375
I AsnI~etI Serfileti~etAlaGlu SerTyrAsnGlnProLYs
to 1e
Leu
13x0 1385 1390 ' '~.'
~'
Ala LysSerIloLeuAspHisLeuAan TrpValPheYalYalIle
Met
1315 1400 ~ 1405
3D Phe leuGluCyaLeuMlleLyaIlePhe AleLeuArgGlnTyrTyr
Thr
1410 . 1415 1420
.
Phe AsnGlyTrpAsnLeuPheAsoGys ValYalValLeuLeuSer ' ,
Th,r
1425 1430 1435 1440 ~
'
f
Ile Serlys
VII
r_'.
<2107
~
<211> 053
~,
<212> NA r i
O
40 <213> savens
lioea I
<220>
<221> CDS
<222> :111.. (5940)
46
*~,
CA 02412306 2002-11-22
CA 02412306 2002-11-22
32iss
<400~ 5 : . ,
ats B s acs Cps its Ctt act CC~ cCa ~(C Cct sIt aet ttc »~ CCt 48 .
flat A~a Ala Are Val Leu Ala Pro Pro Gly Pro Asp Ser Phe Lys Pro
1 , 5 10 15
6
ttc acc cat tae tca ets sca aac att eas ass csc att eat sae aee 96
Phe Thr Pro Glu Ser Leu Ala Asn Ile Glu Ars Are Ile Ala Gfu Ser
20 25 30
to aae c!e aas aaa eca cea ass acc eat ise ast cat es8 sas sac sat 144
Lys liu~Lra Lys Pro Pro Lya Ala Asp Giy Ser His Are Glu Asp Asa .
35 40 45 .
sas sic asc aas ccc aas cca aac asc pc cts saa gca ~ aas ast 192
15 Glu Asp Ser Lys Pro Lys Pro Asn Ser Asp Leu Glu Ala GIy Lys Ser
s0 55 60
tts cct ttc atc tac sss sac atc ccc caa ssc cts stt sca stt ccc 240
Leu Pro Phe ile Tyr GIy Asp Ile Pro Gln Glr Leu Val Ala Val Pro
?D 65 TO ~ 75 80
. .;
cts sas sac ttt eac cca tae tat tte acs eas aaa acc ttt eta sta 288
Leu Glu Asp Phe Asp Pro Tyr Tyr Leu Thr Gln lys Thr Phe Val Yal
85 90 g5
a
tta arc asa ~ aaa act ctc ttc aea ttt ast scc acs cct ecc tts 336
Leu Ann Ars Gly Lys Thr Leu Phe Arg Phe Ser Ala Thr Pro Ala Leu
100 105 110
i
tae aft tta ast~cct ttt aae~cts ata aea aea ata sct att aaa aft 384 '
Tyr il~e Leu Ser Pro Phe Asn Leu Ile Ars Ars Ile Ala Ile Lys (1e
115 120 125
tts ata tat tca eta ttt aec ats atc att ats tsc act att tts acc 432
35 Leu I i~e H i s Ser Va 1 Phe Ser liet I I a I 1 a flat Cys Thr I I a Leu
Thr
13;0 135 140
sat t t sta ttc ats act ttt ast aac cct cct sac tss tcs aas aat 480
Asn C Val Phe Ikt Thr Phe Ser Asn Pro Pro Asp Trv Ser Lys Asn .
40 145 '. 150 155 160
ste eas tac acs ttc aea sgs att tat aca ttt saa tca cta gts aaa 528
Yal Giu Tyr Thr Phe Thr Gly Ile Trr Thr Phe Glu Sar Leu Val Lrs
165 170 1T5
46
re
w..
CA 02412306 2002-11-22
i
33/55
atc t~sca aga itt ttc tsc ata sat g=c ttt acc 5T6
a~ ttt tta csg gat
Ile a Ala Ars Gly Phe Cys Ile Aao Cly Phe Thr
I Phe Leu Ars Asp
',
:
180
185
180
S CCs 624 '
t~.aac
tss
tta
sat
ttc
agt
stc
atc
ats
ats
sca
tat
ata
aca
Pro
Ttp
Asn
Trp
Leu
Asv
Phe
Ser
Vai
Ile
bet
blot
Ala
Tyr
Ile
Thr
185
200
205
sas 672
ttt
sta
sac
eta
ssc
aat
gtt
tca
get
cta
cse
act
ttc
ass
sta
Glu
Pile
Yal
Asn
Leu
Gly
Asn
Val
Ser
Ala
Leu
Arg
Thr
Phe
Ars
V'I
210
215
220
cts T20
'~s
sct
ttg
aaa
act
att
tcs
sta
atc
cca
ssc
ctg
sag
aca
att
Leu '""
Ars
Ala
Lsu
Lys
Thr
Ile
Ser
Yal
Ile
Pro
Gly
Leu
Lys
Thr
Ile
16 225
j
230
235
240
sts 768
stt
scc
cts
att
cas
tct
stg
aas
aaa
cts
tca
tat
$ts
ats
atc
Yal
Gly
Ala
Leu
ile
Gln
Ser
Yai
Lys
Lys
Leu
Ser
Asv
Yal
Ikt
Ile
245
250
255
ats 816
aca
sts
ttc
tsc
cts
ast
stt
ttt
scc
ttg
atc
ssa
cts
cas
cts
flat
Ttir
Yal
Phe
Cya
Leu
Ser
Val
Phe
AIa
Leu
Ile
Gly
Leu
Gin
Leu
260
265
2T0
25 ttt 864
cat
sss
saa
cct
tcs
aac
aas
tgt
stt
sts
tss
ccc
ata
aac
ttc
Phe ' .
His
Gly
Glu
Pro
Ser
Aan
Lys
Cya
Val
V,I
Tro
Pro
Ile
Asn
Phe
;;,.
?T5 . ~ ~ .:, ,.:
280
285
aac 912
tak
agc
tat
ctt
saa
aat
ssc
acc
aa~
stc
ttt
sat
tsa
saa
sas
Aan u Ser Trr Leu Giu A:n Giy Thr Lys Gly Phe
Gl Aso Trp Glu Glu
280
295
300
tat 960
atc
aac
aat
ass
aca
sat
ttc
tac
aca
stt
cct
ssc
ats
cts
saa
tyr
ile
Asn
Asn
Lys
Thr
Asn
Pho
Tyr
Thr
Val
Pro
61y
filet
Leu
Glu
36 305
310
315
320
cct 1008 .
ttP
ctc
tst
sss
aac
ast
tct
sat
sct
sgs
caa
tsc
cca
sas
ssa
Pro
Leu
Leu
Cys
Gly
Asn
Ser
Ser
Aso
Ala
Gly
Gin
Cys
Pro
Glu
Gly
325
330
335
tac 1056
ca;
tgt
ats
aaa
gca
gga
asg
aac
ccc
aac
tat
sgt
tac
aca
agt
Tyr ' ~ ' .
GIV
Cys
~ltt
ly:
Ala
Gly
Ars
Asn
Pro
Asn
Tyr
Gly
Tyr
Thr
Ser
' .
340
345
350
45 ttt 1104
sae
act
ttt
asc
tss
scc
ttc
tts
gca
tta
ttt
csc
ctt
atg
acc
rr
34is s
,.
Phe Abp PheSerTrp AlaPheLeuAlaleuPheArsLeu Thr,. '
Thr wkt
' '355 360 365
i
cas s4c~tattsssaaaac ttstatcaattsactttacsascaaccsss1152
Gln A#p TrpGluAsn leuTyrGinLeuThrLeuArsAlaAlaGly
Tyr
3~0 375 3E0
aaa era atsatcYtc ttcstctt8stcatctttstsssttctttc1200
tac
Lys Thr~TyrIktIlePhe PheValLeuValIlaPheValGlySerPhe
10385 390 395 400
tat cts aacttsatc ttssctstsstgBccatsscttatsaasaa1248
sts
Tyr Leu AsnLeuIle LeuAlaVaiValAlaIlletAlaTyrGluGlu
Val
; 405 d10 415 '
eas aft scaaeaets saseasseasaacaaasssasgetas ttt1296
eas
Gin Asn AlaThrLeu GluGiuAlaGluGinLysGluAlaGluPhe
Gin
420 425 430
aaa sqa ttsgagcaa cttaasasscaacagsaagasscacassct1344
ats
Lys A~a leuGluGln LeuLyslysGlnGinGluGluAlaGlnAla
Ilet
.' 440 445
435
sct ics sccaattca scassaactstctcasaasatsccatasas1392
ats
?aAla Ale AlaAsnSer AlaGlyThrValSerGluAspAlaIleGlu
Uet
450 455 460 . '
saa saa sst saa saa ssa sss sSc tcc cct ess asc 1440 .
ttt tct saa atc
Glu Glu Gly Giu Glu Gly GIy Gly Ser Pro Ars Ser
Phe Ser Giu Ile
3D 465 ; 4T0 4T5 480
tct a~a atc asc tca aas est sca aas pa asa~ast 1485 ' ~''''
aac ass asa aas
Ser Lya ile Ser Ser Lrs Ser Ala Lys Glu Ars Ser
Asn Are Ars Lys
485 490 495
36
aas ass aas caa~'ag saa ctc ttt gaa ssa sas sas 1536
aaa sss sat ccc
Lya Ars Lys Gln Lys Glu Leu Phe Glu Gly Giu Glu
Lys Gly Asp Pro
500 505 510
,
sas a ~~s sts ttt aas tca sag tca saa sat sgc atg .
aga ags aas scc 1584 '.
Glu Lyls Yal Phe Lys Ser Glu Ser Glu Asp Gly filet
Ars Arg Lys Ala
,
515 520 525
ttt cps cts cca sac aac aga ata sss ass aaa ttt 1632
tcc atc ats aat
46 Phe Ars Leu Pro Aso Asn Arg Ile Gly Ars Lys Phe ' ~v
Ser Ile Ilet Aan
CA 02412306 2002-11-22
CA 02412306 2002-11-22
3siss
530 535 540
cas tca ats ttc asc cca ssc tcs ccc ttc ctc tcc 1680
atc csc cac aac
Gin Ser bet Phe Ser Pro Gly Ser Pro Phe Leu Ser
Ile Ars His Asn
6 545 i 550 555 560 .
asc ass asc arc atc ast ttc a~ saa cct sss csg ttc 1728
ttc csa sac
Ser Lrs Ser Ser Ile Ser Phe Arg Giy Pro Gly Arg
Phe Phe Ars Aap
565 570 575
ccs s8c tcc sas aat ttc scs sat sac sas cac sac 1776
sas acs ats sas
Pro Gly Ser Glu Asn Phe Ala Asp Asp Glu Hi: Ser
Giu Thr Yal Glu w,
580 585 590 . ~,
sad a~tc sas tsc sac tcc ctc ttc atc ccc atc 1824
csc css css scc csc
Glu Ser Glu Gly Ars Asp Ser Leu Phe Ile Pro ile
Arg Arg Ala Ars
595 600 605
saa css aec asc tac asc ssc tac asc sac tac 1812
c~c asc cag ssc asc
2D Glu Ars Ser Ser Tyr Ser Gly Tyr Sar GIy Tyr
Ars Ser Gln Gly Ser
61.0 615 620
csc tcs cgc atc ttc ccc arc cts csi csc asc 1920
tcc sts aas c~c aac
Ars Ser Ars Ile Phe Pro Ser Leu Ars Ars Ser
Ser Yal Lys Ars Asn
625 630 635 640 .:
:,
~
.
asc sts sac tsc sac ssc sts sts tcc ctc atc 1968
acs ssc ssc ccc ssc
Ser Yal Asv Cys Asn Giy V,i Val Ser Leu Ile
Thr Gly Giy Pro GIy
646 650 sss
,. ~:
tcc atc ssc. its cst ctc cts cca ~s sct aca 2016 '
ca~c pct sas sts
saa
Ser .
Hile Ile Gly Gly Ars Leu Leu Pro Glu Ala Thr
Thr Glu Yal Glu
660 665 670 v
. ~ ,
3s att aas aaa ssc cct ssa tct ctt tta stt tcc 2064
aa~ ats sac caa tta
Ile Lys Lys Gly Pro Gly Ser Leu Leu Y,I Ser
ly:c Ikt Aap Gln Leu
675 680 685
scc tac sss css aas sac asa atc sac ast ata 2112
tcc atg ast stt stt * ~-~'
'
40 Ala Tyr Giy Ars Lys Aap Ars Ile Asn Ser Ile
Ser Itet Ser Val Val
69b 695 700 ,
aca aca cta sta saa saa cts ~aa sas tct cas 2160 , ~.~~
aat asa aas tsc ccs
Thr Thr Leu Val Glu Glu Leu Glu Glu Ser Gln
Ash Arg Lys Cys Pro
r16705 710 715 120
,._
- -9,5
.. :,:a-: .
;... ~'
---'-"" '-"' CA 02412306 2002-11-22
I
36/55
~'w
i
cca tOc t~ tat aaa ttt scc aac act ttc ctc atc tss ~a8 tsc cac 2208
Pro~Ctrs Trp Tyr Lys Phe Ala Asn Thr Phe leu Ile 1rp Glu Cys Hi:
T25 T30 T35
a
ccc tic tss ata aaa cts aaa eas att 't~ aac tts ata stt its sac 2256
Pro T~rr Trp Ile Lys Leu Lys Glu Ile Val Asn Leu ile Yal Wet Aav '
i T40 T45 750
cct ttt 8tB tat tta scc atc acc atc tsc atc stc cts aat acs cts 2304
Pro Phe Yal Asp Leu Ala Ile Thr Ile Cys Ile Y'I Leu Asn Thr Leu
T55 750 T65 ~ . ; ::,v.
ttt ats sca ats Oas cac cat cct its aca cca caa ttt saa cat stC 2352
Phe Vet Ala Wet Glu His His Pro Wet Thr Pro Gln Phe Glu His Val
T10 TT5 T80
tts sct sta ~a aat cts att ttc act ~a att ttc aca scs saa ats 2400
Leu Als Yal Gly Asn Leu Val Phe Thr Gly Ile Phe Thr Ala Glu Wet
T85 T90 ~ T95 800
ttc c1s aa~ ctc ata scc at8 tat ccc tac tat tat ttc caa saa sst 2448
Phe Leu Lys Leu Ile Ala ttet Asv Pro Tyr Tyr Tyr Phe Gin Giu Gly
805 810 815
..
tss aac att ttt sac ~a ttt att stc tcc ctc ast tta ats saa cts 2496
Tro Asn Ile Phe Asp Gly Phe Ile Val Ser Leu Ser Leu Wet Glu Lau
820 825 830
ast cta sca pc sts has sse ctt tca stg cts csa tct ttc cga tts 2544
Ser Ldu Ala Asp Val Glu Gly Leu Ser Ysl leu Ars Ser Phe Ars Leu
835 840 845
cte c~ ste tte aaa tts scc aaa tcc tss ecc acc ets sac ats eta 2692
35 Leu ArW Val Phe Lys Leu Ala Lys Ser Trv Pro Thr Leu Asn Wet Leu
85b 855 860 ~ '
atc aas att att ssa sat tca stg sst scC cts s8c aac cts aca cts 2640 ,.,
.,~.~:
Ile Lys Ile Ile Gly Asn Ser V,i Gly Ala Leu Gly Asn Leu Thr Leu ''-~~W 'v'
40 865 870 8T5 880 .
. ,.
ata cta scc att ~tt stc ttc atc ttt scc sts sts sss ats caa ctc 2688
Val Leu Ala Ile Ile Vai Phe ilo Phe Ala Val Val Giy Wet Gin Leu
885 890 895
.,
>;
CA 02412306 2002-11-22
3mss
ttt g~a aaa asc tac aaa sag tst stc tsc aas atc aac cas sac ttt 2736
Phe Giy Lys Ser Tyr Lys Glu Cys Val Cys Lys Ile Asn Gln Asv Cys
900 905 910
6 saa ctc cct csC tts cat ats cat sac ttt ttc cat tcc ttc ctc att 2184
Glu leu Pro Ars Trp His filet Hia Aao Phe Phe HIs Ser Phe leu Ile . '
915 920 925
stc ttt csa sts tts tsc sss sas tas att sat acc 2832
ats tss sac tgc
Yal Phe Art Val leu Cys Gly Glu Trp Ile Glu Thr
Wet Tr0 Asv Cys
930 935 940
ats saa sts sca ssc cas scc ats tgc ctc att stc 2880
ttt ats ats stc
Ile t G l a Va l A l a G l y G l n A l a Ills t '
Cys Leu I l s Va l Phe fYle t Ale t Va i
945 950 955 960
ats gtt att ssc aac tts ats sts cts aac cts ttt 2928
cts scc tts ctc
filet Val Ile Gly Asn leu Vat Val leu Asn Leu Phe
Leu Ala teu leu
965 970 9T6 ~ '
cts asc tcc ttc ast sca sac aac cts sct scc acs 2976
sat sac sat sss
1.1u Ser Ser Phe Ser Ala Aao Asn leu Ala Ala thr
Asp Aao Aao Gly
980 985 990
taa at~g aac aac ctc cas atc tca ats atc cst atc 3024
aas aas sst stg
Glu Olet Aan Aan leu Gin Ile Ser Val Ile Arg Ile
lys lys Gly Yal
'
995 1000 1005
tcc cac ttt 3072
tss aaa
acc
aaa
cta
aas
stg
cac
tcc
ttc
ats
cat
scc
Ala His Phe
Trp t.ys
Thr
lys
Leu
Lys
Val
His
Ala
Phe
filet
Gln
Ala
1010
1015
1020
cas tat saa 3120
cat aas
sas
sct
sat
sas
sts
aas
cct
cts
sat
sas
tts
Gln Tyr Glu
Ars lys
Glu
Ala
Aso
Glu
Val
lys
Pro
Leu
Asp
Glu
Leu
36 1025 1030 1035 1040
I
aas cac cs8 3168
scc aat
aac
tst
atc
scc
aat
cac
acc
sst
sca
sac
atc
lys His Ars
Ala Asn
Asn
Cys
Ile
Ala
Asn
His
Thr
Gly
Ala
Aso
Ile
t045 1055
1050
40 . ..
.
sst att gsc ,
sac asc " -a
ttc 3216
cat
aas
aat
sgc
aat
ssc
aca
acc
asc
ssc
Gly Ile Gly
Aap Ser
Phe
Gln
Lya
Asn
Gly
Asn
Gly
Thr
Thr
Ser
Gly
1060 070
1065 -...y:.. r -q
1
.
46 asc ttc atc 3254
gt~ aac
sat
aas
tac
atc
att
sat
sag
sac
cac
ats
tcc
CA 02412306 2002-11-22
3$iss
Ser Y~tl Glu Lys Tyr Ile Ile Aso Glu Asp His Wet Ser Phe Ile Asn ~ .
' 1075 1080 1085 ~ '.
sac c!c sac tts act sta css sta ccc att sct sts sgc sag tct sac 3312
Asn Pro Asn Leu Thr Val Are Yal Pro Ile Ala Yal Gly Glu Ser Asp
1090 1095 1100
tit ssg sac ctc aac :ca gag sat stt asc asc sas tcs sat cct gaa 3360
Phe Glu Asn Leu Asn Thr Glu Asp Val Ser Ser Glu Ser Aap Pro Glu
1105 1110 1115 1120
ssc agc aaa gat aaa Cta sat gac aCC a$c tcc tct gaa gsa asc acc 3408
Gly Ser Lys Aso Lys Leu Asp Asp Thr Ser Ser Ser Glu Gly Ser Thr .-~;r~
1125 1130 1135
att tit atc aaa cca gaa sta gaa sag stc cct stg saa cas cct sas 345s
Ile A!~ ile Lys Pro Glu Yal Glu G1u Val Pro Yal Glu Gln Pro Glu
1140 1145 1150
saa tac ttg sst cca gst scc tsc ttc aca sas sgt tst stc cas css 350d
Glu Tyr Leu Asp Pro Asp Ala Cys Phe Thr Glu Gly Cys Val Gln Ars
1155 1160 1165
ttc aas tgc tsc cas stc sac atc sas gsa ssg cta ssc aag tct tsg 3b52
?5 Phe Lrt Cys Cya Gln Yal Asn Ile Glu Glu Gly Leu Gly Lys Ser Tro
11 TO 1175 1180 : M°. ~:
i
tss atc ctg csg aaa acc tsc ttc ctc atc sts sag cac aac tst ttt 3600
Trp Ile Leu Arg Lys Thr Cys Phe Leu Ile Yal Glu Ht: Asn Try Phe
30 1185 1190 1195 1200 ~ '
gag acc ttc atc atc ttc sts att ctg cts asc agt ssc gcc cts scc 3848
~Iu Thr Phe Ile ile Phe Ilet Ile Leu Leu Ser Ser Gly Ala Leu Ala .
1205 1210 1215
ttc sa~ sac atc tsc att sas cag aaa sag acc stc csc acc atc ctg 369s
Phe CI~ Atp Ile Tyr Ile Glu Gln Arg lys Thr Ile Ars Thr ile Leu
1220 1225 1280
i ~~ ' 4"_
i =,~ ~..:; ~<
40 saa tat ict sac aaa stc ttc acc tat atc ttc atc ctg sas ate ttg 3744
Glu Tyr Ala Asp Lys Yal Phe Thr Tyr Ile Phe Ile Leu Glu Wet Leu
i 1235 1240 1245
ctc ash tgg aca gcc tat gsc ttc stc aag ttc ttc acc sat scc tsg 3792
Leu Ly= Trp Thr AIs Tyr Giy Phe Yal lys Phe Phe Thr Asn Ata Trp
r .Y
a.. .'..~:,.~y: .?
i
39/55
12 0 1255 1260 '
tst t s cts sac ttc ctc att sts sct stc tct tta stc asc ctt ata 3840
Cys Tip Leu Aso Phe Leu Ile Yal Ala Val Ser leu Val Ser Leu Ile
1265 . 1270 1275 1280
sct a~t scc cts ssc tac tcs as cta sst scc ata aas tcc ctt ass 3888
Ala A!n Ala leu Gly Tyr Ser Glu Leu Gly Ala Ile Lys Ser Leu Ars i
1285 1290 1295
. '
acc cta asa sct ttg asa ccc tta asa scc tta tca csa ttt gaa sss 3936
Thr LIu Art Ala Leu Ars Pro Leu Ars Ala Leu Ser Ars Phe Giu Gly
1300 1305 1310 ,
16 ats ads sts sts sts aat scc tts sts ssc scc atc ccc tcc atc ats 3984
Ikt Ars Val V,I.VeI Asn Ala leu Yal Gly Ala Ile Pro Ser Ile flat .
. 1315 1320 1325 '
aat s~s cts cts sts tst ctc atc ttc tss cts aft ttc asc atc ate 4032
SD Asn Vai Lsu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser Ile wet
1330 1335 1340
isa stt aac tts ttt sc' ssa aas tac cac tac tsc 40x0
ttt aat sag act
Gly Yai Asn Leu Phe Ala Giy Lys Tyr His Tyr Cys
Phe Asn Glu Thr
a5 1345 1350 1355 1360
i
tct s~s .atc csa ttt saa att saa pt stc sac aat 4128
aaa act gaa tst
Ser Gl~u Ile Ars Phe Glu Ile Glu As~ Val Asn Asn
Lrs Thr Glu Cys
1365 1370 1375
'
w
saa ads ctt ats sas sss aac aat aca sas atc asa 4176 ' w
tss aas aac sts
Glu LYS Leu flat Glu Gly Asn Asn Thr Glu Ile Ars
Trp Lys Asn Y,I
1380 1385 1390
315ass atc aac ttt sac sat stt sss sca ssa tac cts 4224
tcc ctt ctt caa
Lys Il:e Asn Phe Asp Asn Yal Gly Ala Gly Tyr Leu
Aia Leu Leu Gin
1395 1400 1405
sta spa acc ttc aaa ssc tss ats sac atc ats tat 4212 ~ s
sca sct sta sat
40 Val Ala Thr Phe Lys Glr Trv Net Asp Ile filet .:
Tyr Ala Ala Vai Aso
1410 1415 1420
tce esi: sas act sat ps cas act aas tat gag sac 4320 . ~'-
aat ate tac atg
Ser Art Lys Pro Asp Glu Gln Pro Lys Tyr Glu Asp ~'
Asn Ile Tyr filet
46 1425 .. 1430 1435 1440
.
CA 02412306 2002-11-22
CA 02412306 2002-11-22
4oiss
i
~,
tac ttc atc ttc ssc tcc ttc cts 43sa
a atc ttc ecc
c
1st
ttt
gtc
atc
Tyr Phe Ile Phe Gly Ser Phe Leu '
I~e~Tyr Ile Phe Thr
Phe
Val
Ile
I 1115 1450 1455
aac s ttc att atc att sac ttc aat caa aaa ,416
c sgt stc gat caa aag
~
Asn u Phe Ile ile Ile A:n Phe Asn Gin Lys
L Gly Yal Asp Gin Lys
1460 1485 . 1470
aas atc ttc acc saa saa cas tac 1464
tic ats ass aas
ssa
gst
cas
sac
Lys Ile Phe Thr Glu Glu Gln Tyr
Phe Wet Lys Lys
Giy
Gly
Gin
Aso
1475 1480 1485 .
:.;
tac cts ssc aas aas cca cas att 4512
aat tca aaa cct
scc
ats
aaa
aas
16 Tyr Leu Gly Lys Lya Pro Gln Ile
Asn Ser Lys Pro
Ale
ibt
Lys
lys
1490 1500
1495
ccc atc caa atc stc ttt sat act 4560
c!c gga ttt stc
ccc
tts
aac
aaa
Pro Ile Gln (1e Val Phe Asp Thr v
Ars Gly Phe Val
Pro
Leu
Asn
lys
9p 1505 1515 1520 .
.
1510
cas caa scc ttt gac att stt atc ats ats ctc atc tsc ctt aac ats 4608
Gln Gin Ala Phe Asp Ile Val Ile Wet Wet Leu lie Cys Leu Asn Wet
1525 1530 1535
gts aca ats atg gts sas aca sac act caa asc ass cas ats sas aac 4656
Vai Tltr filet Wet Val Giu Thr Asp Thr Gln Ser Lys Gin Wet Glu Asn
1540 1545 1550 '
atc ct~C tac tss att sac cts sts ttt stt- atc ttc ttc acc tst sas 4704
Ile Lets Tyr Trp Ile Asn Leu Yal Phe Val Ile Phe Phe Thr Cys Glu
1555 1560 1565 . '
tst sts ctc aaa att ttt scs tts asg cac tac tac ttc acc att ssc 4752
Cys Yal Leu Lys Wet Phe Ala Leu Arg Nis Tyr Tyr Phe Thr Ile Gly
1570 1575 1580
tss aac atc ttc sac ttc sts sta stc atc ctc tcc att sts ssa ats 4800
Trp Asn (1e Phe Asp Phe Yai Yal Val ile Leu Ser Ile Yai Gly Wet
1585 : 1590 1595 1600
ttc ctlt sca sat ata att sas aaa tac ttt stt tcc cca acc cta ttc 4846
Phe Lei Ala Asp (1e Ile Glu Lys Tyr Phe Val Ser Pro Thr Leu Phe
1605 1610 1615
4s : : .
41155
', ;
cse stc atc teat tts gcc cst att sis csc atc tts cst cts atc aaa 4896
Ars Yfl Ile Ars Leu Ala Ars Ile Gly Ars Ile Leu Arg Leu Ile Lys
1620 1625 1630
sic sic aaa us att cst act cts ctc ttt scc tta ets ats tcc tts 4944
Gly Ala Lya Gly Ile Ars Thr Leu Leu Phe Ala Leu ikt r~et Ser Leu
1635 1640 1645
cct scc cts ttc aac stc ssc ctt cts ctc ttc ctg stc ate ttc atc 4992
t0 Pro Ala Leu Phe Asn Ile Gly Leu Leu leu Phe Leu Yal Ilet Phe Ile
1650 1655 1660
ttc tcc att ttt sss ats tcc aat ttt sca tat stg aas cat sas sct 5040
Phe Ser Ile Phe Gly Ilet Ser Asn Phe Ala Tyr Val Lys His Glu Ala
1865 1670 1675 1680
sst atc sat sac ats ttc aac ttt sas aca ttt ssc aac asc ats atc 5088
Glr Ile Asp Aso Ikt Pha Asn Phe Glu Thr Phe Gly Asn Ser llet Ile
16x5 1890 1695
i
tsc cts ttt caa atc sca act tca sct sst tss sat ssc cts cts cts 5136
Cys L~u Phe Gln Ile Ala Thr Ser Ala Gly Trp Asp Gly Leu Leu Leu
1700 1705 1710
2S CCt atc cta sac csc ccc cct sat tsc asC cta sat aas saa cat cca 5184 .
Pro Ile Leu Asn Ars Pro Pro Asp Cys Ser Leu Asa Lys Glu His Pro ,
1715 1120 1725
sss ast sec ttt aas ssa eat tst sss sac ccc tca sts ssc atc ttc 5232
a7 Gly S~r Gly Phe Ly: Gly Aav Cys Gly Asn Pro Scr Val Gly Ile Phe ,
1t 0 1735 1740
ttt tit sta asc tat atc atc atc tct ttc cta att stc sts aac ats 5280
Phe Phe Val Ser Tyr Ile Ile Ile Ser Phe Leu Ile Yal Val Asn filet
1745 ~ 1750 1755 1760
tat att scc atc atc cts sas sac ttc ast sta scc aca sas saa ast 5328
Tyr Ile Ala Ile Ile Leu Glu Asn Phe Ser Val Ala Thr Giu Glu Ser
1765 1770 1775
sca s c cct cts ast sas sat sac ttt ps act ttc tat sag att tss 5376
Ala A a Pro Leu Ser Glu Asp Asp Phe Glu Thr Phe Trr Glu Ile Trp
1780 1785 1790
~6 sas ass ttc sac ccc sat scc act cas ttc att gas tat tst aas cts 5424
CA 02412306 2002-11-22
s2iss
~
Glu s Phe Asv Pro Aao Ala Thr Gln Phe Ile Glu .,
L Trr Cxs lys leu
' '.
1795
1800
1805
sca 5472 ' '-
slc.ttt
sca
gat
scc
tts
tas
cat
cct
ctc
csa
gtg
ccc
aas
ccc
AI~
Ado
Phe
Ala
Asv
Ala
Leu
Glu
His
Pro
Leu
Arg
Val
Pro
Lxs
Pro
1810
1815
1820
aat 5520
arc
att
tas
ctc
atc
tct
atg
sat
cts
cca
ats
sts
agc
1st
sat
Asn
T~r
Ile
Glu
Leu
Ile
Ala
filet
Asv
Leu
Pro
I~t
Val
Ser
Glx
Asv
1825
~
1830
1835
1840
cgc 5568
atc
cac
ttc
ttt
sac
atc
ctt
ttt
gcc
ttc
acc
aas
cst
stc
cts
Art
Il.e
Hls
Crs
Leu
Aao
Ile
Leu
Phe
Ala
Phe
Thr
Lrs
Art
Val
Leu
1845 ''
1850
18$5
16
sta 5616
sat
agc
sss
as
ttg
sac
atc
cts
css
cag
cag
ats
gaa
as
css
Glx
Asv
Ser
Glr
Glu
leu
Asv
tle
Leu
Arg
Gln
Gln
Vet
Glu
Glu
Ars
1860
1865
1870
ttc 5664
a
g
sca
tcc
aat
cct
tcc
aaa
sts
tct
tac
sat
cca
atc
aca
acc
Phe
V
I
Ala
Ser
Asn
Pro
Ser
Lxs
Val
Ser
Trr
Glu
Pro
Ile
Thr
Thr
. .
1875
1880
1885
aca 5712
ctg
cst
ctc
aag
cag
tag
sas
sta
tct
tca
tts
ttc
ctt
cat
ctt
25 Thr
leu
Arg
Ars
Lxs
Gln
Glu
Glu
V,I
Ser
Ala
Val
Val
Leu
Gln
Arg
1890
1895
1900
~ .,
tcc 5760
tac
est
sta
cat
ttt
tca
ats
ett
ttc
ttc
ate
ttc
aaa
aat
aea
Ala
Tyr
Art
Glr
Nis
Leu
Ala
Art
Art
Glr
Phe
Ile
Crs
Lrs
Lrs
Thr
~
1905 ~ 1910 - 1815 1920
~
act t sat aas cts ws aat ssa ssc aaa cac css tat 5808 ~ .
t4 a aaa sas
T
a
hr r Asn Lxs Leu Glu Asn Gly Gly Thr Hls Arg
S Glu Lxs Lrs Glu
1925
1930
1935
agc 5856 ' r
aqc
cca
tct
aca
gcc
tcc
ctc
ccs
tcc
tat
sac
agt
gtA
act
aaa
Ser
tlir
Pro
Ser
Thr
Ala
Ser
Leu
Pro
Ser
Trr
Aav
Ser
Val
Thr
Lrs
1940
1945
1950
X10cct 5904 ~.. '.
g~a
aat
sas
aaa
cag
tag
css
tca
gas
gaa
tta
aga
agg
gaa
ata
Pro
Gl.u
Lxs
Glu
Lys
Gln
Gln
Arg
A1a
Glu
Glu
Glx
Arg
Arg
Glu
Arg
1955
1
lala0
1965
<; ~ ,~.
gcc 5950
ae~a
aga
caa
aaa
sat
ttc
aga
gaa
tcc
aas
tgt
tagassasaa
d5 Ala Lys Arg Gln Lrs Glu V'I Art Glu Ser Lxs Cys
f
'. :1
CA 02412306 2002-11-22
43is s
I
19'0 1915 1980
caaaa~ttca gtattataca satctaaaac tcscaastga aasattsttt acaaacttcc 6010
i
S tsaatlttat caatgcasaa cagctgtua sactctaacc tgauatcta taccaaacst 6070
cstct~ctta ccacttaaca casctgcatc ttsagcaets acctccaasg gcaaastacc 6130
ccsct6cCta sacttacasa ttttctaats cttsucau tuttactsc atsttccaca 6190
to ,
tcist~aatt caacttaua caaaactaac casatacap aacasaagag auctsccu 6250
i .
sacca~cata tttccgttsc asccaaatu attttatttt ttcattttat tsattctcas 6310 w
,.
15 aasca~aaa$ catcacttta aaasttcstt tsttcatsca aactatattt scattcttac 6370
attasttaas ctaascasca aaaasaaaac acacacacac actcacattt ascccatstc 6430 ;
atttaattgt castttcttt sacataaasc scatcttctc cacatacuct tcacstutt 6480 ~ ''
tuasa;~tug tsssssaaaa caatcautt tcttcauct sagsauact tgctcaucc 6550
sattcaaaac attstsctcg ttcaatscst asaaatsatt tscatsatu catsccstsa 6610
25 tcasaastca tscatsasat ccatacacca casaacacta ctutctast cccttscact 6610
sutcascct ttuacaua cccascccta caccsttcac tptatttsga gaaaatuta 6730
asasttccat accuctaca attctttgag ttcttaaaas tccttcatac accttct~css 6790
tagua~aca accaactaat tsactaacac caccaacaac aaaaaacaaa cccaatccaa 6850
caa4ca~st' satccsttsc ststatatst ttaacasaca tctccaacat acasccatts 6810
i ..
36 ttscac~ttt tgcaasatga actatttaat sctsctctst stccastaca tsuuagac 6970
tttsatccca aatucttgt actatttats tcactstaaa accaaatcct asuctaaaa 1030
aaaaaapaaa aaaaaaaaaa aaa 7053
<210> 6
<211> 1980
<21?> ART -, ~,
~16 <213> Iloro sap f ens
i ~ .
~.:
CA 02412306 2002-11-22
CA 02412306 2002-11-22
44/55
1
i
<400>~ ;
6
tr>etA~a AiaArkVaiLeuAlaProProGlyProAtpSerPheLysPro .
1 ; 5 10 15
i
Phe Thr ProGluSerLeuAlaAsnIleGluArgArkIleAlaGluSer j
20 25 30
Lys Leu LysLysProProLysAlaAspGiySerHiaArkGluAspAsp
35 40 45
Glu A~o~ SerLysProLysProAsnSerAsoLeuGluAlaGlyLysSer
50: 55 60 _- i 1
. :.~~:
Leu P'ro PheIleTyrGlyAspIleProGlnGlyleuValAlaYalPro
65 10 T5 80
4eu Giu AapPheAspProTrrTyrLeuThrGinLysThrPheVa!Yal '
85 90 95
Leu Asn ArkGlyLysThrLeuPheArsPheSerAlaThrProAlaLeu
i00 105 110
Tyr Ile LeuSerProPheAsnleuIleArtArcIleAlaIleLysIle
115 120 125
Leu lie Hi:SerYaiPheSerlistIletiebetCysThrIleLeuThr
130 135 140
30 Asn Crs VaiPheletThrPheSerAsnProProAspTrpSerLysAsn
145 . , 150 155 160 .
Val G,u TyrThrPheThrGiyIleTyrThrPheGluSerLeuValLys
165 17O 175 ~
.-
Ile 11e AlaArkGlyPheCysIleAspGiyPheThrPheLeuArkAsp -
180 185 190
Pro Trp AsnTrpLeuAspPheSerYattleWetfiatAlaTyrIleThr
~i ~ ~'
40 ~ 195 200 205 '
"'v
Glu Pl~e ValAanLeuGlyAanYalSerAlaLeuArkThrPheArtYai ~ ~~~
210 215 220
46 Leu Are AI'LeuLysThrIleSerYalileProGlyLeuLyaThrIle . - -
4siss
,
225 ' 230 235 240
Vai Gly Aia Leu lie Gln Ser Yal Lys Lys Leu Ser Asp
Yal Wet Ile
245 250 255
,
filet Tiir Y'I Phe Cys Leu Ser Ilal Phe Ala Leu Ile
Gly Leu Gin Leu
260 265 270
Phe Hia Gly Glu Pro Ser Asn Lys Cys Y,I Val Trp Pro
Ile Asn Phe
2T5 280 285
Asn Gl;u Ser Tyr leu Glu Asn Gly Thr Lys Gly Phe Aso .
Tro Glu Glu
2~0 295 300 .
Tyr Il~e Asn Aan Lys Thr Asn Phe Tyr Thr Val Pro Gly .
Wet Leu Glu
305 310 315 320
Pro Leu Leu Cys Gly Asn Ser Ser Asp Ala Gly Gln Cys
Pro Glu Gly
325 330 335
Tyr Gin Cys ikt Lys Ala Gly Ar' Asn Pro Asn Tyr Gly , w
Tyr Thr Ser ::r
340 345 350
Phe Asp Thr Phe Ser Trp Ala Phe Leu Ala Leu Phe Are ,
Leu Ilet Thr
855 360 365 ~ ,
Gln Asp Tyr Trv Glu Asn Leu Tyr Gin Leu Thr Leu Arg
Ala Ale Gly
3T0 3T5 380
30 Lys Th~r Tyr Wet lie Phe Phe Yal Leu Val~lle Phe Yai
Gly Ser Phe
385 ' 390 395. 400 : '
Tyr Lelr Val A:n Leu Ile Leu Ala Val Val Ala ikt Ala . ~
Tyr Giu Glu ,
405 410 415 i . ...
'.:,
'.
3G . '~-
Gln Ash Gln Ala Thr Leu G1u Glu Ala Giu G1n Lys Glu
Ala Giu Phe
420 4z5 430 .
-~~.
lys Alj~ Wet leu Glu Gln Leu Lys Lys Gln Gln Glu Glu ~~
Ala Gin Ala : .
. .
40 a 435 440 4d5
Ala AI~ Akt Ala Asn Ser Ale Gly Thr Val Ser Glu Aav
Ala Ile Glu
45Q d55 460 ,
Glu Glu Gly Giu Glu Gly Gly Gly Ser Pro Ars Ser Phe ~ ..
Ser Glu Ile ~ ~''
C,~
CA 02412306 2002-11-22
CA 02412306 2002-11-22
4siss
.
~
465 4T0 4t5 180
Ser s Ile Ser Ser Lya Ser Ala Lya Glu Art Ser Asn Ark
L~ Arls Lyi
485 490 495 ,
~ : I
Lys g Lys Gtn Lys Glu leu Phe Glu Gly Glu Glu Lys Gly
A Aso Pro
500 505 510 ;
'
Glu
Lys
Val
Phe
Lys
Ser
Glu
Ser
Glu
Asp
Gly
llet
Ars
Arg
Lys
Ale
515
520
525
Phe
Ars
Leu
Pro
Aso
Asn
Ars
Ile
Gly
Ars
Lys
Phe
Ser
Ile
filet
Asn
53 0 535 540 _
,
i..r=:y
Gin r llet Phe Ser file Pro Gly Ser Pro Phe Leu Ser Ark
Sa Nis Asn
545
550
665
560
i
Ser
Lys
Ser
Ser
Ile
Phe
Ser
Phe
Ars
Gly
Pro
Gly
Arg
Phe
Ars
Asp
~
565
5T0
575
Pro
GI'y
Ser
Giu
Asn
Glu
Phe
Ala
Asp
Asp
Glu
His
Ser
Thr
Val
Glu
580 ,
~
585
590
Giu
Ser
Glu
GIY
Arg
Ars
Aso
Ser
Leu
Phe
Ile
Pro
file
Ars
Ala
Ars
595
600
605
.:'
Glu
Ark
Ars
Ser
Ser
Tyr
Ser
Gly
Tyr
Ser
Gfy
Tyr
Ser
Gin
Gly
Ser
810
615
620
3D Ars
Se~~
Ser
Ars
Ile
Phe
Pro
Ser
Leu
Ar5
Art
Ser
Vai
Lys
Ark
Asn
625
~
630
635
640
r
Ser ~~
Tttr
Yal
Asp
Cys
Asn
GIy
Val
Val
Ser
Leu
Ile
Gly
Gly
Pro
Gly
645
650
655
Ser
Nis
Ila
Gly
Gly
Ars
Leu
Leu
Pro
Glu
Ala
Thr
Thr
Glu
Val
Glu
660
665
6T0
tto
Ly8
lys~Lys
Gly
Pro
Giy
Ser
Leu
Leu
V,i
Ser
tlet
Asp
Gln
Leu
~
40 6T5
680'
685
A .
l .
a =-.~;:
Se
Tyr
Gl
y
Ars
Lys
Asp
Ars
t
t
o
Asn
Ser
t
l
a
ir>et
Ser
Va
l
Va
l
690 ~
695 ~
T00 ~'
46 Thr
Asn
Thr
Leu
Val
Glu
Glu
Leu
Glu
Glu
Ser
Gln
Arg
Lys
Cys
Pro
CA 02412306 2002-11-22
I
i '
X7/35
_~
T05 ~ T10 115 T20
Pro C~s Tro Tyr Lys Phe Ala Asn Thr Phe Leu Ile Trp Glu Cys Hts
725 730 135
6 ~ ~
Pro T~rr Trp ile lys Leu Lys Glu Ile Val Asn Leu Ile Val Met Aso
T40 ~ T45 T50
Pro Phe Y~I Asp Leu Ala Ile Thr Ile Cys Ile Vai Leu Asn Thr Leu
T55 T60 T65
Phe Wet Ala Met Glu Hls Hi: Pro Met Thr Pro Gln Phe Glu His Yel
TTO TT5 T80 .
Leu Ads Val Gly Asn Leu Yal Phe Thr Gly Ile Phe Thr Ala Glu Ikt
T85 ~ T90 T95 800
Phe Leu Lys Leu Ile Ale Met Asp Pro Tyr Tyr Tyr Phe Gln Glu Gly
809 810 815
Tro Asn Ile Phe Aso Gly Phe Ile Val Ser leu Ser Leu Ikt Glu Leu
820 825 830
Ser Leu Ala Aso Val Glu GIy Leu Ser YaI Leu Ars Ser Phe Are Leu .
?b 835 840 845
Leu Ats Val Phe Lys Leu Aia Lys Ser Tro Pro Thr Leu Asn Alet Leu
850 855 860
ile L~s Ile Ile Giy Asn Ser Yai Gly Ala Leu Gly Asn Leu Thr Leu
865 870 ..8T5 880 , ,'
Val Liu AI~ Ile Ile Val Phe Ile Phe Ala Val Yal Gly Wet Gin Leu
885 890 895
36 . .
Phe Gly Lys Ser Tyr Lys Glu Cy: Yal Cys lya Ile Asn Gln Asp Cys
900 905 ~ 910
Glu Leu Pro Ars Tro His Wet His A:o Phe Phe Hia Ser Phe Leu ile
40 ~ 915 920 925 ' -:
Yal t Ara Vai Leu Cys Gly Glu Trp (1e Glu Thr Wet Trp Asp Cys
935 9d0
~.
46 Wet GI'u Val Ala Glr Gin Ala Met Cys Leu Ile Yal Phe Wet Met Yal
.w
.",
CA 02412306 2002-11-22
t
~a~ss
a
9~5 ' 950 955 960
Ilet Yal Ile Gir Asn Leu Y~I Yal Leu Asn Leu Phe Leu Ala Leu Leu
965 970 9f5 '
. .i
Leu S r Ser Phe Ser Ala Asv Asn Leu Ala Ala Thr Asv Asv Asv Gly
980 985 990
Glu ~t Asn Asn Leu Gin Ile Ser Val lie Are Ile Lys Lya GIY Yai
' 995 1000 1005
Ala Trp Thr Lxs Leu Lys Val His Ala Phe filet Gin Ala His Phe Lrs
1010 1015 1020
Gin Ats Gtu Ala Aav Glu Val Lys Pro Leu Asa Glu Leu Trr Giu Lxs ;
1025 j 1030 1035 1040
Lxs A~a Asn Cxs Ile Ala Asn Hls Thr Gly Ala Asp Ile His Are Asn '
1045 1050 1055
Gix Asv Phe Gln Lys Asn Glx Asn Glx Thr Thr Ser GIy Ile Glx Ser
1080 1065 1070 ;
Ser Yal Glu Lxs Tyr Ile Iie Asp Giu A:v Hls filet Ser Phe Ile Asn
1075 1080 1085
Asn Pro Asn Leu Thr Val Are Yal Pro Ile Ala Vsl Gly Glu Ser Asv
1090 1095 1100
Phe Gip Asn Leu Asn Thr Giu Asv Yal Ser Ser Giu Ser Asv Pro Glu ..r'-.~
1105 ; 1110 1115 1120
' ~ r
Glx Se~ Lxs Aso Lya Leu Asv Asv Thr Ser Ser Ser Glu Glx Ser Thr . .
11Z$ 1130 1135 . ; '
Ile Asp Ile Lxs Pro Glu Yal Glu Glu Yal Pro Yal Glu Gln Pro Glu
1140 1145 1150 '
Glu Ty Leu Asv Pro Asp Ala Cys Phe Thr Glu Gix Cys Val Gin Are
1155 1160 1165
Phe Ly Cxs Cxs Gln Yal Asn ile Glu Glu Gix Leu Gly Lys Ser Trv ;
117 1175 1180 ' '..a
.Trp iie Leu Are Lys Thr Cxs Phe leu Ile Yal Glu His Asn Tro Phe
S . .
i
1
CA 02412306 2002-11-22
49iss .
1185 ' 1190 1195 1200 '
Giu T6r Phe lie Ile Phe IAet Ile Leu Leu Ser Ser Glx Ala leu Ala
105 1210 1215
Phe G a Asv Ile Tyr Ile Gfu Gln Ars 1x: Thr Ile Ars Thr Ite Leu
1220 1225 1230
Giu Tyr Ala Aav Lxs Val Phe Thr Tyr ile Phe Ile Leu Glu ~kt Leu
1235 1240 1245
Leu Lys Trp Thr Ala Tyr Gly Phe Val lys Phe Phe Thr Asn Ala Trp ' r
1250 1255 1260
16 Cys Trp Leu Asp Phe Leu lie Val Ala Val Ser Leu Val Ser Leu Ile ~-~
1265 ~ 1270 1275 1280
Ala Asn Ala Leu Glx Txr Ser Glu Ltu Gly Ala ile Lys Ser Leu Ars
1285 1290 1295
thr leu Ars Ala leu Ars Pro Leu Ars Ala Leu Ser Ars Phe Glu Gly
1300 1305 1310
tlet Ars Val Val Yal Asn Ala Leu Val Gly Ala Ile Pro Ser ile bet
?5 1315 1320 1325 . ~;
Asn Yal Leu leu Ysl Cys Leu Ile Phe Trp Leu Ile Phe Ser Ile Met .
1330 1335 1340
3D Gly Yell Asn Leu Phe Ala Glx Lys Tyr His Txr Cxs Phe Asn Glu Thr
1345 1350 1355 1360 . . . ,< .
Ser GI Ile Ars Phe Glu Ile Glu Aav Va) Asn Asn Lya Thr Glu Cxs
1365 1370 1375 ' '
Glu Ly~t Leu filet Glu GIy Asn Aan Thr Glu Ile Ars Trv Lys Asn Yal '
1380 1385 1390
.-:',i
.a
lxa Ile Asn Phe Aso Asn Vsl Gly Ala Glx Tyr Leu Ala Leu Leu Gln ~ ,
4D 1395 1400 1405
Val Ai, Thr Phe Lxs Gly Trp Ikt Asv Ile Ilet Tyr Ala Ala Val Asv '
ldl~ 1415 1420
,.
Ser Ark Lys Pro Asv Glu Gln Pro Lys Tyr Glu Asp Asn Ile Txr Vet , '
;..,-t
_ . . , t;:.,r~ ; r;~'
x:
i
j soiss
i
. ,,
1425 , 1430 1435 1440 ,
Tyr 14e Tyr Phe Y~I Ile Phe Ile Ile Phe Gly Ser Phe Phe Thr Leu
' 1445 1450 1455
Asn L~u Phe Ile Gly Y,I Ile ile Asp Asn Phe Aan Gin Gln Lys Lys ~
1460 ~ 1465 1470 '
Lys Plte Gly Gly Gln Asp Ile Phe bet Thr Glu Glu Gln Lya lys Tyr -
1475 1480 1485
Tyr A=n Ala bet Lys Lys Leu Gly Ser Lys Lys Pro Gtn Lys Pro Ile
1490 1495 1500
18 Pra Ark Pro leu Asn lys Ile Gln Gly Ile Val Phe Asv Phe Val Thr
1505 1510 1515 1520
Gln Gle Ala Phe Asv Ile Val Ile Wet Ikt Leu Ile Cys Leu Asn Wet
1525 1530 1535
2D ; ..
Yal The Wet Wet Yal Glu Thr Asv Thr Gln Ser LVs Gln Wet Glu Asn
1540 1545 1550 ~ .
Ile Leu Trr Trv Ile Asn Leu Val Phe Val Ile Phe Phe Thr Cys Glu
25 1555 15&0 1565 ~ . ,.
Crs Yal Leu Lys wet Phe A!a leu Ars His Tyr Tyr Phe Thr Ile Gly
1570 1575 1580
30 Trp Asn 11e Phe Aso Phe Val Vti Va1 Ile Leu Ser.lle Vat Gly Ikt
1585 ; 1590 1595 1600
Phe La~ Ala Aap Ile ile Glu Lys Tyr Phe Vai Ser Pro Thr Leu Phe
1605 1610 1615
Ars Vat Ile Ars Leu Ala Ars Ile Gly Ars Ile leu Ars Leu Ile Lys .
1620 1625 1630
. f~
Gly Ala Lys Gly ( 1e Arg Thr Leu Leu Phe Ala Leu Ikt filet Ser Leu v ,
40 1635 1640 1$45 .
i
Pro AI Leu Phe Aan Ile Gly Leu Leu Leu Phe Leu Val klet Phe Ile '
165 1655 1660 ~ b
~16 Phe Ser;l~s Phe Gly Wet Ser Asn Phe Ala Trr Val Lys His Glu Ala
,.
CA 02412306 2002-11-22
CA 02412306 2002-11-22
1
suss , .
1
~:
1665
~
1670
1675
1680
;
Gly
Ile
Aso
Aap
Wet
Phe
Asn
Phe
Glu
Thr
Phe
Gly
Asn
Ser
I~et
fte
'
. 1685
1890
1695
Cys
L~u
Phe
Gln
Ile
Ala
Thr
Ser
Ala
Gly
Trn
Aao
Gty
Leu
Leu
Leu
1700
1705
1710
i
Pro
I!e
leu
Aan
Art
Pro
Pro
Asp
Cys
Ser
Leu
Aap
Lys
Glu
His
Pro
10' 'fTlS
1720
1725
GIy v
Ser
Giy
Phe
Lys
G!y
Asp
Cys
GIy
Asn
Pro
Ser
VaI
GIy
tIa
Phe
~
1730 ,
1735 i
1740
15Phe
Pile
Vot
Ser
Tyr
Ile
ile
tie
Ser
Phe
Leu
ile
Val
Vel
Asn
Wet
1745
'
~
1750
1755
1760
Tyr
Ile
Ala
Ile
Ile
leu
Glu
Asn
Phe
Ser
Vat
Ala
Thr
Glu
Glu
Ser
lTSS
1770
1775
AI,
Asp
Pro
Leu
Ser
Glu
Aso
Asp
Phe
Glu
Thr
Phe
Tyr
Glu
iIe
Tro
1780
1785
1790
Glu
Lya
Phe
A:p
Pro
Aso
Ala
thr
Gin
Phe
Ile
Glu
Tyr
Cys
Lys
Leu
a 1195
1800 ,;; .__. y
1805 ~ ~''
v
Aia
Asp
Phe
Ata
Aap
Ala
Leu
Glu
His
Pro
Leu
Art
Val
Pro
Lys
Pro
1810 '
1815
1820
.
3nAsn
Thr~Ile
Glu
Leu
Ile
Alr
Wet
Asv
leu
Pro
list,Y,1
Ser
Gly
Aso
1825
i
1830
1835
1840
Art
II~
Hi:
Cya
Leu
Aaa
tle
Leu
Phe
Ala
Phe
Thr
Lys
Art
Vel
Leu
' 1845 1850 1855
Gly , Ser Gly Glu Leu Aso Ile Leu Art Gln Gln I~et Glu '
As Gtu Art
1860
1865
1870
Phe
V,1~
Ala
Ser
Asn
Pro
Ser
Lys
V~1
Ser
Tyr
Glu
Pro
Ile
Thr
Thr
40;1875
1880 .
1885 _
Thr i .
Le Art Art lya Gln Gtu Glu Yel Ser Ala Vsl Val Leu Gln
Art
~
t
90 : . 1.
89
;
i
895
1
0
46AI~
Tyr'Art '.
Gly
His
Leu
AI~
Art
Art
Gly
Phe
Ile
Cys
Lys~Lys
Thr
..
N ~~ ~xiSa
CA 02412306 2002-11-22
1
1
suss ,
1905 1910 1915 1920
Thr Ser Asn Lya Leu Glu Asn Gly Gly Thr His Arg Glu lys Lys Glu
1925 1930 1935
g
Ser Tir Pro Ser Thr Ala Ser Leu Pro Ser Tyr Asv Ser Yal Thr lys
1940 1945 1950
Pro G a Lys Glu Lys Gln Gln Ars Ala Glu Glu Gly Arg Arg Glu Arg
1955 1960 1965 .
Ali Lys Arg Gln LYs Glu VII Ara Glu Ser lys Cys ,
19)0 19T5 1980
1b
<210> T
<211) 2T
<212> DIiIA
<Z13> Artifioi~l Sevuence ~ ,~
2D <220~ '
<221>
<222>
<223> Artificial SeQUence: Synthesi:ed Olleonucleotide
. ,.
Z5 <480> T
atcggcteCt ctgtcssagc ccttg~a 2T
<210> a
30 <21i~ 4
<212>
<213> rtificlal Seauence ~
<220> . - .
<221>
36 <222>
<223> Nrt.iticlal SeQUence: Synthesized Oligonucleotide
<400~ 8 , ., .
teectSt~t cCtgstcatt i~tgs 24
<210> 9
<211> 2 .
<212> A
~6 <213> Ar t i f i c i, l Seauence . ~._~.
CA 02412306 2002-11-22
I
53/53
'h:
<220>~
<221>
<222>
<223> Artifict>,I Seouence: Synthesized Oliaonucleotide
a
<400>,9 ;
ttcatf~acrt trtaateytt cttcte ' 26
<210> ~ 10 '
<211> 21
<212> DNA f
<213> Artificial Sequence '
<220>
<221> . '
<22Z> . ;
<223> llrtificisl Seouence: Synthesized Oliaonucleotide
U00> 10.
~D pt~aafttrtcwatgatpa cna~at 27
<210> 11 ,
<211> 29
<212> QNA ~
<213> Artiftctel Sequence
<220~ ~ F .,,,
<221>
<222>
<223> ~lrtiticiel Seouence: SYntheaited Oiieortucleotide
<d00~ 1
s 2s ' , .
i ..
<210> ~2
<211> 4
<212> ffNA ..
<213> Artificial Sequence . ,
<220> . . ~ . "'
<221>
<222> i
<223> rttficiall Seouence: Synthesized Oliaonucleotide '
X16 <400~ 1~2
~~~ oi1~ ~
__
CA 02412306 2002-11-22
I
' suss
t
I
<210>~ 13
<211>. 36
a <212>.ONA
<213>iArtlficial Seouence
<220>;
<221>'
<222>.
<223>~Artificiel Seauence: Synthesized Oli~onucleotide ,
<40Q>.13
.
~a '
<210>i14
<211>i21 ; , .
<212>~OMA '
<213>:Artifici'I St4uence '
2~ <2?0> !
<221 ) ; '
<222~
<223>~Artificial Seauence: Synthesized Oli~onucleotide '
2S <400> 114
ccstcctatt ac~actcact etagggc 27
7
<210> 15
3D <211> 23 . .
<212> 'DNA
<213> Artificial Seauence
<220>
<221> ~
36 <222>
<223> rtificial Seauence: Synthesized Oli~onucleotide
<400> ~ 5
~ 0~ 49c 23 ,
r10 I . :~: .
<210> 6
<211> T
<212> NA
46 <213> rtifici~i Seouence
<220>
l
ssiss ,
<221 >;
<222>~ . '
<223> Artificial Sequence: Synths:i:ed Oiieonucleotide
<~100> 16
8a9 99
I i
<210> 17
to <211 > ~ 2~1
<212> DNA
<213> Artificial Seouence
<220>~
<221>,
<222> ~ '
<223>'Artificial Sequence: Synthesized Oli~onucieotide i
U00> 17
99~~ ~a09~~ ~ 24 ' ~ _ .
<210> I18
<211> f
<212> 'DNA
<213> Artificial Sequence j
<220>
<221> '
<222>
<223> Artificial Sequence: Synthesized Olisonucieotide
<400> 8
aaptooctct gactgcoga . 29
I
I
i
I
~':r
1
I
i
i
CA 02412306 2002-11-22
