Note: Descriptions are shown in the official language in which they were submitted.
CA 02360585 2001-07-23
SMB
Protease
The present invention relates to a protease, nucleic acids coding for the
protease,
and the related inhibitors, antibodies, medicaments and diagnostic agents.
The present invention provides a protease having two aspartate residues in a
catalytically active structure, wherein a first aspartate residue resides in
an
XiGX2GD motif and a second aspartate residue resides in;.~n X3X4DX5 motif,
wherein X1, X2, X3 and X5 are independently selected from Ala, Val, Leu, Met
and
Ile, and X4 is an aromatic amino acid, and the motifs X1GXZGD and X3X4DX5
reside
in a transmembrane region. For the motifs, the one-letter code of amino acids
has
been used, i.e., D = Asp, G = Gly, etc.
There is a high probability that such proteases are involved in the cleavage
of the
amyloid precursor protein (APP). In one embodiment of the invention, the
protease
according to the invention is the as yet unidentified y-secretase, which is
involved
in the processing of APP into the amyloid peptides referred to as A~i.
A survey of the role of y-secretases in the genesis of Alzheimer's disease is
given
by S.L. Ross et al. in J. of Biol. Chem. 273 (1998), 15309-15312.
Preferred proteases of the present invention additionally have a sequence
PALX6YX,V, wherein X6 and X, independently have the same meaning as X1.
However, it is preferred that X6 and X, are leucine or isoleucine.
In particular, the proteases are proteases from mammals, especially humans.
CA 02360585 2001-07-23
-2-
The proteases according to the invention preferably have catalytically active
aspartate residues in a region which lies within a transmembrane domain. When
the sequence of a protein is known, transmembrane domains can be predicted due
to different models. They are characterized by the fact that hydrophobic amino
acids are predominant in a region which is flanked by regions in which
hydrophilic
amino acids are predominant.
An aspartate in a transmembrane region can be detected, for example, by the
application of the program "GREASE" which is a part of the FASTA 2.0 program
package. For a window width of 17, a hydrophobicity value of at least 80 must
be
calculated for the aspartate using this program. The FASTA program package has
been described in W.R. Pearson and D.J. Lipman, Proc. Natl. Acad. Sci. U.S.A.
85
(1988), 2444-2448. The program GREASE makes use of the Kyte/Doolittle
algorithm, which has been described in J. Kyte and R.F. Doolittle, J. Mol.
Biol. 157
(1982), 105-132.
Particularly preferred proteases of the present invention are referred to as
psl 1-5
(human psl 1-5: SEQ ID Nos. 1 to 4 + 19; murine psl 2-4: SEQ ID Nos. 5-7;
Sacc.
cerevisiae psl 3: SEQ ID No. 8; human psl2L SEQ ID No. 18).
The invention further relates to variants of the proteases according to the
inven-
tion. Variants are proteins which are derived from the proteases according to
the
invention by one or more mutations, insertions and deletions, especially by
conservative substitutions, in particular, forms truncated or extended on the
N or C
terminus.
The invention also relates to nucleic acids coding for the proteases according
to the
invention. Preferred nucleic acids according to the invention are those having
the
SEQ ID Nos. 9 to 17 + 20 (human psl 1-5: SEQ ID Nos. 9 to 12 + 20; murine psl
2-4: SEQ ID Nos. 13-15, Sacc. cerevisiae psl 3: SEQ ID No. 16, human psl2L SEQ
ID No. 17). Complementary nucleic acids are also part of the invention.
The proteases according to the invention are involved in the cleavage of APP
into
Ap and are thus indirectly involved in the genesis of, for example,
Alzheimer's
CA 02360585 2001-07-23
-3-
disease. Therefore, the invention also relates to inhibitors which inhibit the
expression or activity of the proteases. Such inhibitors can be identified in
simple
methods. Appropriate inhibitors can be detected, for example, by measuring the
expression or activity of the proteases in the presence of potential
inhibitors.
Antibodies directed against the aspartate proteases are particularly suitable
for
measuring the expression and are thus also part of the invention.
The aspartate proteases according to the invention are also involved in the
cleavage of other transmembrane proteins, especially of the receptor protein
Notch
and related proteins which play a role in the development of the nervous
system.
The proteolytic cleavage in the interior of membranes is also involved in
other
important processes, e.g.:
- Proteolytic degradation of N-terminal signal peptides after, their cleavage
by
signal peptidase.
- Proteolytic degradation of C-terminal propeptides such as those formed by
the
transamidase-catalyzed cleavage in the posttranslational GPI anchoring of pro-
teins.
- Generation of peptides for the presentation by histocompatibility complex
molecules of types I and II. For soluble proteins, such peptides are predomi-
nantly produced by the proteasome. However, peptides are also formed from
transmembrane regions of proteins which can only be explained by a cleavage
in the interior of the membrane.
- Proteolytic cleavage of the ER stress sensor protein Irel. The endoplasmic
reticulum possesses a mechanism which detects the accumulation of unfolded
or incorrectly folded proteins and sends a signal into the nucleus. This mecha-
nism is referred to as "unfolded protein response" or UPR and results in the
increased formation of proteins which facilitate the folding. In mammals,
there
are two sensor proteins (Irelalpha and Irelbeta) which respond to folding de-
fects and are then proteolytically cleaved within the membrane.
CA 02360585 2001-07-23
-4-
By using the protease according to the invention or its inhibitors, the
mentioned
processes can be influenced therapeutically.
Useful cell lines include those, in particular, which do not express any of
the
proteases or contain any of the nucleic acids according to the invention, and
preferably those which do not contain any homologous proteases or nucleic
acids
either. Preferably, they can be used to test the activity of the proteases
according
to the method described in Example 1 or to establish inhibitors according to
Example 2. Particularly suitable is Saccharomyces cerevisiae. When the corre-
sponding protease or the nucleic acid coding for it (SEQ ID Nos. 8 and 16) is
known, yeast strains which no longer contain this protein or the nucleic acid
can be
produced by known methods. Therefore, they are preferably suitable as an
expression system for the characterization of the aspartate proteases
according to
the invention or for the identification of suitable inhibitors. Therefore, the
invention
also relates to the corresponding cell lines, preferably yeast cell' lines,
and to the
use of the protein of SEQ ID No. 8 as an aspartate protease, and of the
nucleic
acid of SEQ ID No. 16 for the expression of a protease.
The proteases, nucleic acids, inhibitors and antibodies according to the
invention
can be contained in medicaments and diagnostic agents. They are suitable, in
particular, for the treatment and diagnosis of diseases which are causally
related
with the cleavage of the amyloid precursor protein, especially Alzheimer's
disease.
Example i:
y-secretase assay
The putative y-secretases are stably or transiently transfected into cos-7
cells
which additionally stably express SpA4CT (signal peptide fused to ~3A4,
followed by
APP C-terminus). In this system, y-secretase activity can be detected by the
generation of a 4.6 kDa peptide or by the disappearance of the 11 kDa band of
the
complete SpA4CT. When the pathologically relevant y-secretase is present, both
fragments should be detectable in the interior of the cell. In the supernatant
of the
cells, (3A4 can always be found; it is generated by an endogenous y-secretase
CA 02360585 2001-07-23
-5-
activity residing in the plasma membrane, but which does not play a role in
the
pathogenesis of Alzheimer's disease.
The transfected cells are washed three times with cold DMEM and subsequently
harvested on ice with a squeegee. The cells (about 5 x 106 cells) are
collected by
centrifugation and lysed in 1 ml of lysis buffer (150 mM NaCI, 50 mM Tris-HCI,
pH
7.5, 1% NP-40, 1% Triton X-100, 2 mM EDTA). The nuclei are centrifuged off at
11,000 x g. The supernatant is subjected to immunoprecipitation. Thus, 1 ml of
the cell lysate is mixed with 2 pg/ml of W02 immunoglobulin (anti-~3A4
antibody)
and shaken upside down at 4 °C for 0.5 h. Subsequently, 20 pl of
protein G
sepharose suspension (1:1) is added, followed by shaking upside down at 4
°C for
h. The protein G sepharose is successively washed twice with buffers A, B and
C
(A: 150 mM NaCI, 10 mM Tris-HCI, pH 7.5, 0.2% NP-40, 2 mM EDTA; B: 500 mM
NaCI, 10 mM Tris-HCI, pH 7.5, 0.2% NP-40, 2 mM EDTA; C: 10 mM Tris-HCI, pH
7.5), mixed with 20 pl of 3x sample buffer, heated to 95 °C, and the
supernatant is
coated onto a 12% Tris-Tricine gel. After gel-electrophoretic size
fractionation, the
proteins are transferred to a PVDF membrane and subsequently detected with an
anti-~3A4 antibody.
Example 2:
Identification of a y-secretase inhibitor
For the identification of an inhibitor of the pathologically relevant y-
secretase, the
enzyme is co-expressed with SpA4CT in cos-7 cells according to the above
protocol. The cells are suitably contacted with the substance to be examined
(in
the presence or absence of membrane-permeabilizing agents). Subsequently, the
intracellularly formed ~A4 is detected as described above. A reduction of the
quantity of ~3A4 formed permits to conclude the activity of the substance as a
y-
secretase inhibitor.
CA 02360585 2001-07-23
SEQUENZPROTOKOLL
<110> Memorec Stoffel GmbH
<120> Protease
<130> Protease Memorec
<140>
<141>
<150> 19902550.9
<151> 1999-O1-22
<150> 19925946.1
<151> 1999-06-08
<150> 19929115.2
<151> 1999-06-29
<160> 20
<170> PatentIn Ver. 2.1
<210> 1
<211> 592
<212> PRT
<213> Homo sapiens
<400> 1
Met Ala Ala Ala Val Ala Ala Ala Leu Ala Arg Leu Leu Ala Ala Phe
1 5 10 15
Leu Leu Leu Ala Ala Gln Val Ala Cys Glu Tyr Gly Met Val His Val
20 25 30
Val Ser Gln Ala Gly Gly Pro Glu Gly Lys Asp Tyr Cys Ile Leu Tyr
35 40 45
f
Asn Pro Gln Trp Ala His Leu Pro His Asp Leu Ser Lys Ala Ser Phe
50 55 60
Leu Gln Leu Arg Asn Trp Thr Ala Ser Leu Leu Cys Ser Ala Ala Asp
65 70 75 80
Leu Pro Ala Arg Gly Phe Ser Asn Gln Ile Pro Leu Val Ala Arg Gly
85 90 95
Asn Cys Thr Phe Tyr Glu Lys Val Arg Leu Ala Gln Gly Ser Gly Ala
100 105 110
Arg Gly Leu Leu Ile Val Ser Arg Glu Arg Leu Val Pro Pro Gly Gly
115 120 125
Asn Lys Thr Gln Tyr Asp Glu Ile Gly Ile Pro Val Ala Leu Leu Ser
130 135 190
CA 02360585 2001-07-23
- 2 -
Tyr LysAsp Asp ArgPhe
Met Ile Gly
Leu Phe Arg
Thr Thr
Val
Arg
145 150 155 160
Ala AlaLeu TyrAlaPro LysGlu ValLeuAsp MetVal
Pro Tyr
Asn
165 170 175
Ile IlePhe IleMetAla ValGlyThr ValAlaIleGly TyrTrp
Gly
180 185 190
Ala GlySer ArgAspVal LysLysArg TyrMetLysHis LysArgAsp
195 200 205
Asp GlyPro GluLysGln GluAspGlu AlaValAspVal ThrProVal
210 215 2.20
Met ThrCys ValPheVal ValMetCys CysSerMetLeu ValLeuLeu
225 230 235 240
f.,w', Tyr TyrPhe TyrAspLeu LeuValTyr ValValle Gly IlePheCys
I
245 250 255
Leu AlaSer AlaThrGly LeuTyrSer CysLeuAlaPro CysValArg
260 265 2
70
Arg LeuPro PheGlyLys CysArgIle ProAsnAsnSer LeuProTyr
275 280 285
Phe HisLys ArgProGln AlaArgMet LeuLeuLeuAla LeuPheCys
290 295 300
Val AlaVal SerValVal TrpGlyVal PheArgAsnGlu AspGlnTrp
305 310 315 320
Ala TrpVal LeuGlnAsp AlaLeuGly IleAlaPheCys LeuTyrMet
325 330 335
Leu LysThr IleArgLeu ProThrPhe Lys CysThr LeuLeuLeu
Ala
.:. .
340 345 350
Leu Val Leu PheLeuTyr IlePhe Phe PheIle ThrProPhe
Asp Val
355 360 365
Leu Thr Lys Ser Gly Ser Ser Ile Met Val Glu Val Ala Thr Gly Pro
370 375 380
Ser Asp Ser~Ala Thr Arg Glu Lys Leu Pro Met Val Leu Lys Val Pro
385 390 395 400
Arg Leu Asn Ser Ser Pro Leu Ala Leu Cys Asp Arg Pro Phe Ser Leu
405 410 415
Leu Gly Phe Gly Asp Ile Leu Val Pro Gly Leu Leu Val Ala Tyr Cys
420 425 430
His Arg Phe Asp Ile Gln Val Gln Ser Ser Arg Val Tyr Phe Val Ala
435 440 445
CA 02360585 2001-07-23
- 3 -
CysThrIle AlaTyrGly ValGlyLeu LeuValThr PheValAla Leu
950 455 960
AlaLeuMet GlnArgGly GlnProAla LeuLeuTyr LeuValPro Cys
465 470 475 480
ThrLeuVal ThrSerCys AlaValAla LeuTrpArg ArgGluLeu Gly
485 490 495
ValPheTrp ThrGlySer GlyPheAla LysValLeu ProProSer Pro
500 505 510
TrpAlaPro AlaProAla AspGlyPro GlnProPro LysAspSer Ala
515 520 525
ThrProLeu SerProGln ProProSer GluGluPro AlaThrSer Pro
530 535 590
Trp Pro Ala Glu Gln Ser Pro Lys Ser Arg Thr Ser Glu Glu Met Gly
545 550 555 560
Ala Gly Ala Pro Met Arg Glu Pro Gly Ser Pro Ala Glu Ser Glu Gly
565 570 575
Arg Asp Gln Ala Gln Pro Ser Pro Val Thr Gln Pro Gly Ala Sex Ala
580 585 590
<210> 2
<211> 520
<212> PRT
<213> Homo sapiens
<400> 2
Met Gly Pro Gln Arg Arg Leu Ser Pro Ala Gly Ala Ala Leu Leu Trp
1 5 10 15
Gly Phe Leu Leu Gln Leu Thr Ala Ala Gln Glu Ala Ile Leu His Ala
20 25 30
SerGly GlyThrThr LysAspTyr CysMetLeu TyrAsnPro Tyr
Asn
35 40 45
TrpThrAla LeuProSer ThrLeuGlu AsnAlaThr SerI1eSer Leu
50 55 60
MetAsnLeu ThrSerThr ProLeuCys AsnLeuSer AspIlePro Pro
65 70 75 80
ValGlyIle LysSerLys AlaValVal ValProTrp GlySerCys His
85 90 95
PheLeuGlu LysAlaArg IleAlaGln LysGlyGly AlaGluAla Met
100 105 110
LeuValVal AsnAsnSer ValLeuPhe ProProSer GlyAsnArg Ser
115 120 125
' CA 02360585 2001-07-23
- 4 -
Glu PheProAsp ValLys IleLeuIle AlaPheIle SerTyrLysAsp
130 135 140
Phe ArgAspMet AsnGln ThrLeuGly AspAsnIle ThrValLysMet
145 150 155 160
Tyr SerProSer TrpPro AsnPheAsp TyrThrMet ValValIlePhe
165 170 175
Val IleAlaVal PheThr ValAlaLeu GlyGlyTyr TrpSerGlyLeu
180 185 190
Val GluLeuGlu AsnLeu LysAlaVal ThrThrGlu AspArgGluMet
195 200 205
Arg LysLysLys GluGlu TyrLeuThr PheSerPro LeuThrValVal
210 215 220
Ile PheValVal IleCys CysValMet MetValLeu LeuTyrPhePhe
225 230 235 290
Tyr Lys Trp Leu Val Tyr Val Met Ile Ala Ile Phe Cys Ile Ala Ser
245 250 255
Ala MetSerLeu TyrAsnCysLeu AlaAlaLeu IleHisLys I.lePro
260 265 270 ,
Tyr GlyGlnCys ThrIleAlaCys ArgGlyLys AsnMetGlu ValArg
275 280 285
Leu IlePheLeu SerGlyLeuCys IleAlaVal AlaValVal TrpAla
290 295 300
Val PheArgAsn GluAspArgTrp AlaTrpIle LeuGlnAsp IleLeu
305 310 315 320
Gly IleAlaPhe CysLeuAsnLeu IleLysThr LeuLysLeu ProAsn
325 330 335
Phe LysSerCys ValIleLeuLeu GlyLeuLeu LeuLeuTyr AspVal
340 395 350
Phe Phe Val Phe Ile Thr Pro Phe Ile Thr Lys Asn Gly Glu Ser Ile
355 360 365
Met Val Glu Leu Ala Ala Gly Pro Phe Gly Asn Asn Glu Lys Leu Pro
370 375 380
Val Val Ile Arg Val Pro Lys Leu Ile Tyr Phe Ser Val Met Ser Val
385 390 395 900
Cys Leu Met Pro Val Ser Ile Leu Gly Phe Gly Asp Ile Ile Val Pro
905 410 415
Gly Leu Leu Ile Ala Tyr Cys Arg Arg Phe Asp Val Gln Thr Gly Ser
920 425 430
CA 02360585 2001-07-23
- 5 -
Ser Tyr Ile TyrTyr ValSerSer Thr Ala AlaIle
Val Tyr Gly
Met
935 440 945
Ile Leu Thr PheVal ValLeuVal Leu LysLys GlyGlnPro
Met Ala
450 455 460
Leu Leu Tyr LeuVal ProCysThr LeuIleThrAla SerValVal Ala
465 970 975 980
Trp Arg Arg LysGlu MetLysLys PheTrpLysGly AsnSerTyr Gln
485 490 495
Met Met Asp HisLeu AspCysAla ThrAsnGluGlu AsnProVal Ile
500 505 510
Ser Gly Glu GlnIle ValGlnGln
515 520
<210> 3
<211> 377
<212> PRT
<213> Homo Sapiens
<400> 3
Met Asp Ser AlaLeu SerAspPro HisAsnGlySer AlaGluAla Gly
1 5 10 15
Gly Pro Thr AsnSer ThrThrArg ProProSerThr ProGluGly Ile
20 25 30
Ala Leu Ala TyrGly SerLeuLeu LeuMetAlaLeu LeuProIle Phe
35 90 95
Phe Gly Ala LeuArg SerValArg AlaArgGly Lys Ala Ser
Cys Asn
50 55 60
Asp Met Pro GluThr IleThrSer AspAlaAla Pro Ile
Arg Arg
Phe
65 70 75 80
Ile Ala Ser Cys Thr Leu Leu Gly Leu Tyr Leu Phe Phe Lys Ile Phe
85 90 95
Ser Gln Glu Tyr Ile Asn Leu Leu Leu Ser Met Tyr Phe Phe Val Leu
100 105 110
Gly Ile Leu Ala Leu Ser His Thr Ile Ser Pro Phe Met Asn Lys Phe
115 120 125
Phe Pro Ala Ser Phe Pro Asn Arg Gln Tyr Gln Leu Leu Phe Thr Gln
130 135 140
Gly Ser Gly Glu Asn Lys Glu Glu Ile Ile Asn Tyr Glu Phe Asp Thr
145 150 155 160
Lys Asp Leu Val Cys Leu Gly Leu Ser Ser Ile Val Gly Val Trp Tyr
165 170 175
CA 02360585 2001-07-23
- 6 -
LeuLeu ArgLysHisTrp IleAlaAsn AsnLeu PheGlyLeu AlaPhe
180 185 190
SerLeu AsnGlyValGlu LeuLeuHis LeuAsn AsnValSer ThrGly
195 200 205
CysIle LeuLeuGlyGly LeuPheIle TyrAsp ValPheTrp ValPhe
210 215 220
GlyThr AsnValMetVal ThrValAla LysSer PheGluAla ProIle
225 230 235 290
LysLeu ValPheProGln AspLeuLeu GluLys GlyLeuGlu AlaAsn
295 250 255
AsnPhe AlaMetLeuGly LeuGlyAsp ValVal IleProGly IlePhe
260 265 270
Ile Ala Leu Leu Leu Arg Phe Asp Ile Ser Leu Lys Lys Asn Thr His
275 280 285
Thr TyrPheTyr ThrSerPheAla AlaTyrIle PheGlyLeu GlyLeu
290 295 300
Thr IlePheIle MetHisIlePhe LysHisAla GlnProAla LeuLeu
305 310 315 ,320
Tyr LeuValPro AlaCysIleGly PheProVal LeuValAla LeuAla
325 330 335
Lys GlyGluVal ThrGluMetPhe SerTyrGlu GluSerAsn ProLys
390 395 350
Asp ProAlaAla ValThrGluSer LysGluGly ThrGluAla SerAla
355 360 365
Ser LysGlyLeu GluLysLysGlu Lys
370 375
<210> 4
<211> 384
<212> PRT
<213> Homosapiens
<400> 4
Met Ala GlnThrTyr SerTrpAla TyrSerLeu ValAspSer Ser
Glu
1 5 10 15
Gln Val ThrPheLeu IleSerIle LeuLeuIle ValTyrGly Ser
Ser
20 25 30
Phe Arg LeuAsnMet AspPheGlu AsnGlnAsp LysG1uLys Asp
Ser
35 40 95
Ser Asn SerSerGly SerPheAsn GlyAsnSer ThrAsnAsn Ser
Ser
50 55 60
CA 02360585 2001-07-23
_ 7 _
Ile Gln Thr Ile Asp Ser Thr Gln Ala Leu Phe Leu Pro Ile Gly Ala
65 70 75 80
Ser Val Ser Leu Leu Val Met Phe Phe Phe Phe Asp Ser Val Gln Val
85 90 95
Val Phe Thr Ile Cys Thr Ala Val Leu Ala Thr Ile Ala Phe Ala Phe
100 105 110
Leu Leu Leu Pro Met Cys Gln Tyr Leu Thr Arg Pro Cys Ser Pro Gln
115 120 125
Asn Lys Ile Ser Phe Gly Cys Cys Gly Arg Phe Thr Ala Ala Glu Leu
130 135 140
Leu Ser Phe Ser Leu Ser Val Met Leu Val Leu Ile Trp Val Leu Thr
195 150 155 160
Gly His Trp Leu Leu Met Asp Ala Leu Ala Met Gly Leu Cys Val Ala
165 170 175
Met Ile Ala Phe Val Arg Leu Pro Ser Leu Lys Val. Ser Cys Leu Leu
180 185 190
Leu Ser Gly Leu Leu Ile Tyr Asp Val Phe Trp Val Phe Phe S.er Ala
195 200 205 ,
Tyr Ile Phe Asn Ser Asn Val Met Val Lys Val Ala Thr Gln Pro Ala
210 215 220
Asp Asn Pro Leu Asp Val Leu Ser Arg Lys Leu His Leu Gly Pro Asn
225 230 235 240
Val Gly Arg Asp Val Pro Arg Leu Ser Leu Pro Gly Lys Leu Val Phe
295 250 255
Pro Ser Ser Thr Gly Ser His Phe Ser Met Leu Gly Ile Gly Asp Ile
260 265 270
Val Met Pro Gly Leu Leu Leu Cys Phe Val Leu Arg Tyr Asp Asn Tyr
275 280 285
Lys Lys Gln Ala Ser Gly Asp Ser Cys Gly Ala Pro Gly Pro Ala Asn
290 295 300
Ile Ser Gly Arg Met Gln Lys Val Ser Tyr Phe His Cys Thr Leu Ile
305 310 315 320
Gly Tyr Phe Val Gly Leu Leu Thr Ala Thr Val Ala Ser Arg Ile His
325 330 335
Arg Ala Ala Gln Pro Ala Leu Leu Tyr Leu Val Pro Phe Thr Leu Leu
340 345 350
Pro Leu Leu Thr Met Ala Tyr Leu Lys Gly Asp Leu Arg Arg Met Trp
355 360 365
CA 02360585 2001-07-23
Ser Glu Pro Phe His Ser Lys Ser Ser Ser Ser Arg Phe Leu Glu Val
370 375 380
<210> 5
<211> 113
<212> PRT
<213> Mus musculus
<400> 5
Val Leu Gly Phe Gly Asp Ile Ile Val Pro Gly Leu Leu Ile Ala Tyr
1 5 10 15
Cys Arg Arg Phe Asp Val Gln Thr Gly Ser Ser Ile Tyr Tyr Ile Ser
20 25 30
Ser Thr Ile Ala Tyr Ala Val Gly Met Ile Ile Thr Phe Val Val Leu
35 90 45
Met Val Met Lys Thr Gly Gln Pro Ala Leu Leu Tyr Leu Val Pro Cys
50 55 60
Thr Leu Ile Thr Val Ser Val Val Ala Trp Ser Arg Lys Glu Met Lys
65 70 75 80
Lys Phe Trp Lys Gly Ser Ser Tyr Gln Val Met Asp His Leu AspITyr
85 90 95
Ser Thr Asn Glu Glu Asn Pro Val Thr Thr Asp Glu Gln Ile Val Gln
100 105 110
Gln
<210> 6
<211> 378
<212> PRT
<213> Mus musculus
<400> 6
Met Asp Ser Ala Val Ser Asp Pro His Asn Gly Ser Ala Glu Ala Gly
1 5 10 15
Thr Pro Ala Asn Gly Thr Thr Arg Pro Pro Ser Thr Pro Glu Gly Ile
20 25 30
Ala Leu Ala Tyr Gly Ser Leu Leu Leu Met Ala Leu Leu Pro Ile Phe
35 90 45
Phe Gly Ala Leu Pro Ser Val Arg Cys Ala Arg Gly Lys Ser Ser Ser
50 55 60
Asp Met Pro Glu Thr Ile Thr Ser Arg Asp Ala Ala Arg Phe Pro Ile
65 70 75 80
Ile Ala Ser Cys Thr Leu Leu Gly Leu Tyr Leu Phe Phe Lys Ile Phe
85 90 95
' CA 02360585 2001-07-23
_ g _
Ser Gln Glu Tyr Ile Asn Leu Leu Leu Ser Met Tyr Phe Phe Val Leu
100 105 110
Gly Ile Leu Ala Leu Ser His Thr Ile Ser Pro Phe Met Asn Lys Phe
115 120 125
Phe Pro Ala Asn Phe Pro Asn Arg Gln Tyr Gln Leu Leu Phe Thr Gln
130 135 140
Gly Ser Gly Glu Asn Lys Glu Glu Ile Ile Asn Tyr Glu Phe Asp Thr
145 150 155 160
Lys Asp Leu Val Cys Leu Gly Leu Ser Ser Val Val Gly Val Trp Tyr
165 170 175
Leu Leu Arg Lys His Trp Ile Ala Asn Asn Leu Phe Gly Leu Ala Phe
180 185 190
Ser Leu Asn Gly Val Glu Leu Leu His Leu Asn Asn Val Ser Thr Gly
195 200 205
Cys Ile Leu Leu Gly Gly Leu Phe Ile Tyr Asp Ile Phe Trp Val Phe
210 215 220
Gly Thr Asn Val Met Val Thr Val Ala Lys Ser Phe Glu Ala Pro Ile
225 230 235 ,290
Lys Leu Val Phe Pro Gln Asp Leu Leu Glu Lys Gly Leu Glu Ala Asp
245 250 255
Asn Phe Ala Met Leu Gly Leu Gly Asp Ile Val Ile Pro Gly Ile Phe
260 265 270
Ile Ala Leu Leu Leu Arg Phe Asp Ile Ser Leu Lys Lys Asn Thr His
275 280 285
Thr Tyr Phe Tyr Thr Ser Phe Ala Ala Tyr Ile Phe Gly Leu Gly Leu
290 295 300
f; ..
Thr Ile Phe Ile Met His Ile Phe Lys His Ala Gln Pro Ala Leu Leu
305 310 315 320
Tyr Leu Val Pro Ala Cys Ile Gly Phe Pro Val Leu Val Ala Leu Ala
325 330 335
Lys Gly Glu Val Ala Glu Met Phe Ser Tyr Glu Glu Ser Asn Pro Lys
340 345 350
Asp Pro Ala Ala Val Thr Glu Ser Lys Glu Glu Ser Thr Glu Ala Ser
355 360 365
Ala Ser Lys Arg Leu Glu Lys Lys Glu Lys
370 375
<210> 7
<211> 257
<212> PRT
<213> Mus musculus
CA 02360585 2001-07-23
- 10 -
<400> 7
Gln Asn Lys Ile Ser Phe Gly Cys Cys Gly Arg Phe Thr Ala Ala Glu
1 5 10 15
Leu Leu Ser Phe Tyr Leu Ser Val Met Leu Val Leu Ile Trp Val Leu
20 25 30
Thr Gly His Trp Leu Leu Met Asp Ala Leu Ala Met Gly Leu Cys Val
35 40 45
Ala Met Ile Ala Phe Val Arg Leu Pro Ser Leu Lys Val Ser Cys Leu
50 55 60
Leu Leu Ser Gly Leu Leu Ile Tyr Asp Val Phe Trp Val Phe Phe Ser
65 70 75 80
Ala Tyr Ile Phe Asn Ser Asn Val Met Val Lys Val Ala Thr Gln Pro
85 90 95
Ala Asp Asn Pro Leu Asp Val Leu Ser Arg Lys Leu His Leu Gly Pro
100 105 110
Asn Val Gly Arg Asp Val Pro Arg Leu Ser Leu Pro Gly Lys Leu Val
115 120 125
Phe Pro Ser Ser Thr Gly Ser His Phe Ser Met Leu Gly Tle Gly~Asp
130 135 140
Ile Val Met Pro Gly Leu Leu Leu Cys Phe Val Leu Arg Tyr Asp Asn
195 150 155 160
Tyr Lys Lys Gln Ala Ser Gly Asp Ser Cys Gly Ala Pro Gly Xaa Ala
165 170 175
Asn Ile Ser Gly Arg Met Gln Lys Val Ser Tyr Phe His Cys Thr Leu
180 185 190
Ile Gly Tyr Phe Val Gly Leu Leu Thr Ala Thr Val Ala Ser Arg Val
195 200 205
His Arg Ala Ala Gln Pro Ala Leu Leu Tyr Leu Val Pro Phe Thr Leu
210 215 220
Leu Pro Leu Leu Thr Met Ala Tyr Leu Lys Gly Asp Leu Arg Arg Met
225 230 235 290
Trp Ser Glu Pro Phe His Ser Lys Ser Ser Ser Ser Arg Phe Leu Glu
245 250 255
Val
<210> 8
<211> 587
<212> PRT
<213> Saccharomyces cerevisiae
<210> 7
<211> 257
<212> PRT
<213> Mus mu
w
' CA 02360585 2001-07-23
- 11 -
<400> 8
Met Asp Lys Tyr Leu Asn Ser Phe Val Asp His Leu Ser Glu Trp Ser
1 5 10 15
Ser Arg Ala Phe Arg Asn Asn Ser Ser Ser Ala Asn Gln Ser Ala Ser
20 25 30
Asn Lys Glu Leu Glu Gln Val Phe Glu Gln Ile Asn Ala Ile Val Glu
35 40 q5
Asn His Asn Asn Lys Leu Thr Thr Ala Phe Asp Lys Ile Ser Tyr Arg
50 55 60
Val Ala His Lys Ile Thr His Leu Val Glu Ser His Ser Leu Val Phe
65 70 75 80
Asn Tyr Ala Thr Leu Val Leu Ile Ala Ser Ala Leu Val Val Ile Gly
85 90 95
Ser Phe Thr Ser Ile Ser Ser Ile Pro Phe Thr Ala Leu Pro Pro Thr
100 105 110
Arg Glu His Ser Leu Phe Asp Pro Thr Asp Phe Asp Val Asp His Asp
115 120 125
Cys His Val Ile Tyr Arg Glu Asn Asp Glu Asp Lys Lys Lys Lys,Lys
130 135 190
Lys Ser Lys Arg Phe Phe Asp Met Met Asp Glu Lys His Ala Ile Ile
145 150 155 160
Leu Pro Leu Thr Ser Gly Cys Thr Leu Leu Ala Leu Tyr Phe Val Ile
165 170 175
Lys Lys Leu His Leu Asn Trp Leu Lys Tyr Val Val Lys Ile Leu Asn
180 185 190
Phe Asn Ile Thr Leu Leu Asn Ile Pro Ala Gly Thr Phe Val Tyr Ser
;, ; 195 200 205
Tyr Phe Leu Asn Ser Leu Phe Arg Asn Leu Ser His Leu Ala Ser Trp
210 215 220
Asn Pro Leu Val Val Leu Pro Arg Tyr Arg Val Thr Ile Ala Asp Asp
225 230 235 240
Asn Glu Asp Leu Asn Lys Ile Gly Gly Phe Val Thr Asn Leu Asn Tyr
295 250 255
Lys Asp Gly Leu Thr Asn Ser Val Val His Lys Lys Thr Leu Asp Glu
260 265 270
Ile Glu Lys Asp His Trp Met Lys His Phe Tyr Arg Arg Glu Leu Val
275 280 285
Glu Pro Lys Asp Ile Lys Ser Lys Arg Gln Ile Ser Asn Met Tyr Leu
290 295 300
CA 02360585 2001-07-23
- 12 -
Asn Ser Ala Leu Ile Val Ser Phe Val Leu Ser Ile Val Ser Thr Val
305 310 315 320
Tyr Phe Tyr Leu Ser Pro Asn Asp Trp Leu Ile Ser Asn Ala Val Ser
325 330 335
Met Asn Met Ala Ile Trp Ser Ile Ala Gln Leu Lys Leu Lys Asn Leu
340 395 350
Lys Ser Gly Ala Leu Ile Leu Ile Ala Leu Phe Phe Tyr Asp Ile Cys
355 360 365
Phe Val Phe Gly Thr Asp Val Met Val Thr Val Ala Thr Asn Leu Asp
370 375 380
Ile Pro Val Lys Leu Ser Leu Pro Val Lys Phe Asn Thr Ala Gln Asn
385 390 395 400
r'"<%y; Asn Phe Asn Phe Ser Ile Leu Gly Leu Gly Asp Ile Ala Leu Pro Gly
405 910 415
Met Phe Ile Ala Met Cys Tyr Lys Tyr Asp Ile Trp Lys Trp His Leu
420 425 430
Asp His Asp Asp Thr Glu Phe His Phe Leu Asn Trp Ser Tyr Val Gly
435 490 445
Lys Tyr Phe Ile Thr Ala Met Val Ser Tyr Val Ala Ser Leu Val Ser
450 455 460
Ala Met Val Ser Leu Ser Ile Phe Asn Thr Ala Gln Pro Ala Leu Leu
465 470 475 480
Tyr Ile Val Pro Ser Leu Leu Ile Ser Thr Ile Leu Val Ala Cys Trp
485 490 495
Asn Lys Asp Phe Lys Gln Phe Trp Asn Phe Gln Tyr Asp Thr Ile Glu
500 505 510
r.
a,
Val Asp Lys Ser Leu Lys Lys Ala Ile Glu Lys Lys Glu Asn Ser Ile
515 520 525
Thr Tyr Ser Thr Phe Ile Leu Ser Glu Tyr Tyr Asn Asp Ala Asp Lys
530 535 540
Tyr Ala Leu Leu Gly Asp Asp Val Asn Glu Asn Phe Asp Asp Asp Glu
545 550 555 560
Glu Phe Val Gln Glu Glu Asp Leu Ser Asp Ser Ser Glu Glu.Glu Leu
565 570 575
Ser Glu Glu Asp Leu Leu Asp Asp Glu Ser Ser
580 585
<210> 9
<211> 1776
<212> DNA
CA 02360585 2001-07-23
- 13 -
<213> Saccharomyces cerevisiae
<400> 9
atggcggcag cggtggcggc tgcgctggcg cggcttttgg cggcctttct gctcctcgcg 60
gcccaggtgg cctgtgagta cggcatggtg cacgtggtct cccaggccgg gggccccgaa 120
ggcaaagact actgcatcct ctacaacccg cagtgggccc atcttccgca cgacctcagc 180
aaggcatctt tcctgcagct gcgcaactgg acggcctccc tgctctgctc cgcagccgac 240
ctccccgccc gtggcttcag caaccagatc ccgctggtgg cgcgggggaa ctgcaccttc 300
tatgagaaag tgaggctggc ccagggcagc ggagcacgcg ggctgctcat cgtcagcagg 360
gagaggctgg tccccccggg gggtaataag acgcagtatg atgagattgg cattcccgtg 420
gccctgctca gctacaaaga catgctggac atcttcacgc gtttcggccg cacggtgagg 480
gcggcgctgt atgcgcctaa ggagccggtg ctggactaca acatggtcat catcttcatc 540
atggctgtgg gcaccgtcgc catcggcggc tactgggccg ggagtcggga cgtgaagaaa 600
aggtacatga agcacaagcg cgacgatggg cccgagaagc aggaggacga ggcggtggac 660
gtgacgccgg tgatgacctg cgtgtttgtg gtgatgtgct gctccatgct ggtgctgctc 720
tactacttct acgacctcct cgtgtacgtg gtcatcggga tcttctgcct ggcctccgcc 780
accggcctct acagctgcct ggcgccctgt gtgcggcggc tgcccttcgg caagtgcagg 840
atccccaaca acagcctgcc ctacttccac aagcgcccgc aggcccgtat gctgctcctg 900
gcgctcttct gcgtggccgt cagcgtggtg tggggcgtct tccgcaacga ggaccagtgg 960
gcctgggtcc tccaggatgc cctgggcatc gccttctgcc tctacatgct gaagaccatc 1020
cgtctgccca ccttcaaggc ctgcacgctg ctgctgctgg tgctgttcct ctacgacatc 1080
ttcttcgtgt tcatcacgcc cttcctgacc aagagtggga gcagcatcat ggtggaggtg 1140
gccactgggc cctcggactc agccacccgt gagaagctgc ccatggtcct gaaggtgccc 1200
aggctgaact cctcacctct ggccctgtgt gaccggccct tctccctcct gggtttcgga 1260
gacattttgg tgccagggct gctggtggcc tactgccaca ggtttgacat ccaggtacag 1320
tcctccaggg tatacttcgt ggcctgcacc atcgcctatg gcgttggcct ccttgtgaca 1380
ttcgtggcac tggccctgat gcagcgtggc cagcccgctc tcctctacct ggtgccctgc 1440
acgctggtga cgagctgcgc tgtggcgctc tggcgccggg agctgggcgt gttctggacg 1500
ggcagcggct ttgcgaaagt cctacctcca tctccgtggg ccccagcacc agccgacggc 1560
ccgcagcctc ccaaagactc tgccacgcca ctctccccgc agccgcccag cgaagaacca 1620
gccacatccc cctggcctgc tgagcagtcc ccaaaatcac gcacgtccga ggagatgggg 1680
gctggagccc ccatgcggga gcctgggagc ccagctgaat ccgagggccg ggaccaggcc 1790
cagccgtccc cggtaaccca gcctggcgcc tcggcc 1776
<210> 10
<211> 1560
<212> DNA
<213> Homo sapiens
<900> 10
atggggccgc agcggcggct gtcccctgcc ggggccgccc tactctgggg cttcctgctc 60
cagctgacag ccgctcagga agcaatcttg catgcgtctg gaaatggcac aaccaaggac 120
tactgcatgc tttataaccc ttattggaca gctcttccaa gtaccctaga aaatgcaact 180
tccattagtt tgatgaatct gacttccaca ccactatgca acctttctga tattcctcct 240
gttggcataa agagcaaagc agttgtggtt ccatggggaa gctgccattt tcttgaaaaa 300
gccagaattg cacagaaagg aggtgctgaa gcaatgttag ttgtcaataa~cagtgtccta 360
tttcctccct caggtaacag atctgaattt cctgatgtga aaatactgat tgcatttata 420
agctacaaag actttagaga tatgaaccag actctaggag ataacattac tgtgaaaatg 480
tattctccat cgtggcctaa ctttgattat actatggtgg ttatttttgt aattgcggtg 540
ttcactgtgg cattaggtgg atactggagt ggactagttg aattggaaaa cttgaaagca 600
gtgacaactg aagatagaga aatgaggaaa aagaaggaag aatatttaac ttttagtcct 660
cttacagttg taatatttgt ggtcatctgc tgtgttatga tggtcttact ttatttcttc 720
tacaaatggt tggtttatgt tatgatagca attttctgca tagcatcagc aatgagtctg 780
tacaactgtc ttgctgcact aattcataag ataccatatg gacaatgcac gattgcatgt 890
cgtggcaaaa acatggaagt gagacttatt tttctctctg gactgtgcat agcagtagct 900
gttgtttggg ctgtgtttcg aaatgaagac aggtgggctt ggattttaca ggatatcttg 960
gggattgctt tctgtctgaa tttaattaaa acactgaagt tgcccaactt caagtcatgt 1020
CA 02360585 2001-07-23
- 14 -
gtgatacttc taggccttct cctcctctat gatgtatttt ttgttttcat aacaccattc 1080
atcacaaaga atggtgagag tatcatggtt gaactcgcag ctggaccttt tggaaataat 1140
gaaaagttgc cagtagtcat cagagtacca aaactgatct atttctcagt aatgagtgtg 1200
tgcctcatgc ctgtttcaat attgggtttt ggagacatta ttgtaccagg cctgttgatt 1260
gcatactgta gaagatttga tgttcagact ggttcttctt acatatacta tgtttcgtct 1320
acagttgcct atgctattgg catgatactt acatttgttg ttctggtgct gatgaaaaag 1380
gggcaacctg ctctcctcta tttagtacct tgcacactta ttactgcctc agttgttgcc 1440
tggagacgta aggaaatgaa aaagttctgg aaaggtaaca gctatcagat gatggaccat 1500
ttggattgtg caacaaatga agaaaaccct gtgatatctg gtgaacagat tgtccagcaa 1560
<210> 11
<211> 1131
<212> DNA
<213> Homo sapiens
<900> 11
atggactcgg ccctcagcga tccgcataac ggcagtgccg aggcaggcgg ccccaccaac 60
agcactacgc ggccgccttc cacgcccgag ggcatcgcgc tggcctacgg cagcctcctg 120
ctcatggcgc tgctgcccat cttcttcggc gccctgcgct ccgtacgctg cgcccgcggc 180
aagaatgctt cagacatgcc tgaaacaatc.accagccggg atgccgcccg cttccccatc 240
atcgccagct gcacactctt ggggctctac ctctttttca aaatattctc ccaggagtac 300
atcaacctcc tgctgtccat gtatttcttc gtgctgggaa tcctggccct gtcccacacc 360
atcagcccct tcatgaataa gttttttcca gccagctttc caaatcgaca gtaccagctg 420
ctcttcacac agggttctgg ggaaaacaag gaagagatca tcaattatga atttgacacc 480
aaggacctgg tgtgcctggg cctgagcagc atcgttggcg tctggtacct gctgaggaag 540
cactggattg ccaacaacct ttttggcctg gccttctccc ttaatggagt agagctcctg 600
cacctcaaca atgtcagcac tggctgcatc ctgctgggcg gactcttcat ctacgatgtc 660
ttctgggtat ttggcaccaa tgtgatggtg acagtggcca agtccttcga ggcaccaata 720
aaattggtgt ttccccagga tctgctggag aaaggcctcg aagcaaacaa ctttgccatg 780
ctgggacttg gagatgtcgt cattccaggg atcttcattg ccttgctgct gcgctttgac 840
atcagcttga agaagaatac ccacacctac ttctacacca gctttgcagc ctacatcttc 900
ggcctgggcc ttaccatctt catcatgcac atcttcaagc atgctcagcc tgccctccta 960
tacctggtcc ccgcctgcat cggttttcct gtcctggtgg cgctggccaa gggagaagtg 1020
acagagatgt tcagttatga ggagtcaaat cctaaggatc cagcggcagt.gacagaatcc 1080
aaagagggaa~cagaggcatc agcatcgaag gggctggaga agaaagagaa a 1131
;~ ~; <210> 12
<211> 1152
<212> DNA
<213> Homo Sapiens
<400> 12
atggcggagc agacctactc gtgggcctat tccctggtgg attccagtca agtgtctaca 60
tttctgattt ccattcttct tatagtctat ggtagtttca ggtcccttaa tatggacttt 120
gaaaatcaag ataaggagaa agacagtaat agttcttctg ggtctttcaa tggcaacagc 180
accaataata gcatccaaac aattgactct acccaggctc tgttccttcc aattggagca 240
tctgtctctc ttttagtaat gttcttcttc tttgactcag ttcaagtagt ttttacaata 300
tgtacagcag ttcttgcaac gatagctttt gcttttcttc tcctcccgat gtgccagtat 360
ttaacaagac cctgctcacc tcagaacaag atttcctttg gttgctgtgg acgtttcact 420
gctgctgagt tgctgtcatt ctctctgtct gtcatgctcg tcctcatctg ggttctcact 480
ggccattggc ttctcatgga tgcactggcc atgggcctct gtgtcgccat gatcgccttt 540
gtccgcctgc cgagcctcaa ggtctcctgc ctgcttctct cagggcttct catctatgat 600
gtcttttggg tatttttctc agcctacatc ttcaatagca acgtcatggt gaaggtggcc 660
actcagccgg ctgacaatcc ccttgacgtt ctatcccgga agctccacct ggggcccaat 720
gttgggcgtg atgttcctcg cctgtctctg cctggaaaac tggtcttccc aagctccact 780
ggcagccact tctccatgtt gggcatcgga gacatcgtta tgcctggtct cctactatgc 840
CA 02360585 2001-07-23
- 15 -
tttgtccttc gctatgacaa ctacaaaaag caagccagtg gggactcctg tggggcccct 900
ggacctgcca acatctccgg gcgcatgcag aaggtctcct actttcactg caccctcatc 960
ggatactttg taggcctgct cactgctact gtggcgtctc gcattcaccg ggccgcccag 1020
cccgcccttc tctatttggt gccatttact ttattgccac tcctcacgat ggcctattta 1080
aagggcgacc tccggcggat gtggtctgag cctttccact ccaagtccag cagctcccga 1190
ttcctggaag to 1152
<210> 13
<211> 339
<212> DNA
<213> Mus musculus
<400> 13
gtattgggtt tcggagatat cattgtacca ggcctgttga ttgcatattg tagaagattc 60
gatgttcaga ctggttcttc tatatactat atttcatcca caattgccta tgctgttggc 120
atgatcatta cctttgttgt cctgatggtg atgaaaacag ggcagcctgc tctcctctac 180
ttggtacctt gtacacttat tactgtctca gtcgttgctt ggagtcgtaa ggaaatgaaa 240
aagttctgga aaggcagcag ctatcaggtg atggaccacc tggactattc aacaaatgaa 300
gaaaatccag tgacgactga tgagcagatt gtacaacag 339
<210> 14
<211> 1134
<212> DNA
<213> Mus musculus
<400> 14
atggattcgg ctgtcagcga tccgcacaac ggcagcgccg aggctggcac cccagccaac 60
ggcacgacgc ggccgccctc cacgcccgag ggcatcgcgc tggcctacgg cagcctcctg 120
ctcatggcgc tgctgcccat cttcttcggc gccctgccgt cggtgcgctg cgcccgcggc 180
aagagctctt cggacatgcc agaaaccatc accagtcgag atgccgcccg cttccccatc 240
atcgccagct gcacactcct ggggctctac ctctttttca aaatattctc ccaggagtac 300
atcaacctct tgctgtccat gtatttcttc gtgctgggga tcctggccct gtcacacacc 360
atcagcccct tcatgaataa gttttttcca gccaacttcc caaaccgcca gtatcagctg 420
ctcttcacac agggctctgg ggaaaacaaa gaagagatca tcaactatga gtttgacact 480
aaggacctgg tgtgcctggg cctaagcagc gtcgttggtg tctggtacct tctgaggaag 540
cactggattg ccaacaacct gtttggcctg gccttctccc ttaatggggt agagctcctg 600
cacctgaaca acgtgagcac tggctgtatc ctgctcggag gactcttcat ctatgacatc 660
ttctgggtat tcggcaccaa cgtgatggtg acagtggcca agtcctttga ggcaccaata 720
aaattggtgt tcccccagga tctgctggag aagggccttg aagcagacaa ctttgccatg 780
ctgggacttg gagacattgt cattccaggg atcttcattg ccttactgct tcgttttgac 840
atcagcttga agaagaacac gcacacctac ttctacacca gcttcgccgc ctacatcttc 900
ggcctgggtc tcaccatctt catcatgcac atcttcaagc acgcccagcc ggctctcctg 960
tacctggtcc ctgcctgcat cggctttcct gtcctggtgg cactagccaa gggagaagtg 1020
gccgagatgt tcagttatga ggagtccaac cctaaagatc cagcagccgt gactgaatcc 1080
aaagaggagt caacagaggc gtcggcatcg aagaggctag agaagaagga gaaa 1134
<210> 15
<211> 771
<212> DNA
<213> Mus musculus
<400> 15
cagaacaaga tttccttcgg ttgctgtggg cgtttcactg ctgccgagct gctgtcgttc 60
tacctgtctg tcatgctcgt cctcatctgg gttctcactg gccactggct tctcatggat 120
gctctggcca tgggtctctg tgttgccatg atcgccttcg tccgcctgcc aagcctcaag 180
CA 02360585 2001-07-23
- 16 -
gtttcctgcc tgcttctctc agggcttctc atctacgatg tcttctgggt gttcttctca 240
gcctacatct tcaacagtaa tgtcatggtg aaagtggcca cacagccagc tgacaatccc 300
ctcgacgttc tgtccaggaa gctccacctg ggacccaatg tggggcgtga tgttcctcgc 360
ctgtctttgc ctggaaaatt ggtcttccca agctccactg gcagtcactt ctctatgctg 420
ggcatcgggg acattgtgat gcccggcctc ctgttatgct ttgttcttcg ctatgacaac 980
tacaagaaac aagccagtgg tgactcgtgt ggggcccctg gcanngccaa tatctctggg 540
cgcatgcaga aggtctccta cttccactgc accctcatcg ggtactttgt aggtctgctc 600
actgcgactg tggcgtctcg cgtccaccga gctgcccagc cagctctcct ctacttggtg 660
ccatttaccc tattgccact cctcaccatg gcctacctaa agggtgactt acggaggatg 720
tggtctgagc ccttccactc caagtccagc agctcccggt tcctggaagt a 771
<210> 16
<211> 1761
<212> DNA
<213> Saccharomyces cerevisiae
<400> 16
atggacaagt atttgaattc atttgttgac cacctttcag agtggtcatc tcgtgccttt 60
aggaacaatt catcaagcgc taaccaaagt gcgtcgaaca aggaattaga acaagttttt 120
gaacagatca atgctatagt tgaaaaccac aataacaaat taaccactgc ctttgataag 180
atatcatatc gcgttgctca caagattaca cacttggtgg aaagccattc tttagtattc 240
aactacgcca ctttagttct catcgcaagt gctttggtcg ttattggctc atttacgtct 300
atttcttcta ttccatttac agctctacct cctacgagag aacactcatt gtttgatcct 360
acagattttg atgtggacca cgactgtcat gttatctacc gcgagaatga cgaagataaa 420
aagaaaaaga agaaaagcaa gaggtttttc gatatgatgg atgaaaaaca tgcgattata 480
ctgcccttaa ctagtggctg tactttactc gctctctatt ttgtgatcaa gaaactacac 540
ctaaactggc taaaatatgt ggtgaaaatt ttgaatttta atataacact gctaaatatc 600
ccagctggca catttgtcta ctcctacttt ctcaactcac ttttcagaaa cctatcacat 660
ttagcttctt ggaatcccct ggttgtttta ccaaggtatc gtgtaacaat agctgatgat 720
aacgaagacc tgaacaagat aggcgggttt gttaccaatt tgaattacaa agatggattg 780
accaactcag ttgttcacaa gaaaacattg gatgagattg aaaaagatca ttggatgaag 840
catttttaca gaagagaatt agttgaaccg aaggatatta aatcgaagag gcagatcagc 900
aacatgtatt tgaatagcgc attaattgtt tcgttcgttc tgtccatcgt ttctaccgta 960
tatttctatt tatcacccaa tgattggtta atatccaatg ctgtcagtat gaatatggct 1020
atttggtcca ttgctcaatt aaaattgaag aatttaaaat caggggccct aatcctaatt 1080
gctctatttt tttacgacat ttgctttgtc tttggtaccg atgtaatggt tacagtagct 1140
actaaccttg atattcccgt aaaactaagc ttaccagtca agtttaatac agctcaaaac 1200
aacttcaatt tttcaatact tggtctgggt gatattgcct tgcctggtat gtttattgcg 1260
atgtgctaca aatatgacat ctggaagtgg caccttgatc atgatgacac tgaattccac 1320
tttttgaact ggtcatacgt tggaaaatat tttattactg ctatggttag ttacgttgct 1380
tctttggtat ctgccatggt ctccttgtcc attttcaata ctgctcaacc ggctttatta 1490
tacattgttc cttccttgtt gattagtact attttggtag cttgctggaa caaggatttt 1500
aagcagtttt ggaattttca gtatgatacg attgaagtgg ataaaagttt aaaaaaagcg 1560
atagaaaaaa aggagaactc tataacttat tcgaccttca tcctatcaga atactataat 1620
gatgccgaca agtatgcctt gcttggtgat gatgtaaacg aaaattttga cgatgatgaa 1680
gaattcgtgc aagaggaaga tctcagtgac agctctgagg aagagctttc tgaagaagat 1740
ctcttggatg acgaatcttc t 1761
<210> 17
<211> 1560
<212> DNA
<213> Homo sapiens
<900> 17
atggggccgc agcggcggct gtcccctgcc ggggccgccc tactctgggg cttcctgctc 60
cagctgacag ccgctcagga agcaatcttg catgcgtctg gaaatggcac aaccaaggac 120
CA 02360585 2001-07-23
- 17 -
tactgcatgc tttataaccc ttattggaca gctcttccaa gtaccctaga aaatgcaact 180
tccattagtt tgatgaatct gacttccaca ccactatgca acctttctga tattcctcct 240
gttggcataa agagcaaagc agttgtggtt ccatggggaa gctgccattt tcttgaaaaa 300
gccagaattg cacagaaagg aggtgctgaa gcaatgttag ttgtcaataa cagtgtccta 360
tttcctccct caggtaacag atctgaattt cctgatgtga aaatactgat tgcatttata 420
agctacaaag actttagaga tatgaaccag actctaggag ataacattac tgtgaaaatg 480
tattctccat cgtggcctaa ctatgattat actatggtgg gtatttttgg aattgcggtg 540
ttcactgggg cattaagtgg atactggagt ggactagttg aattggaaaa cttgaaagca 600
gtgacaactg aagatagaga aatgaggaaa aagaaggaag aatatttaac ttttagtcct 660
cttacagttg taatatttgt ggtcatctgc tgtgttatga tggtcttact ttatttcttc 720
tacaaatggt tggtttatgt tatgatagca attttctgca tagcatcagc aatgagtctg 780
tacaactgtc ttgctgcact aattcataag ataccatatg gacaatgcac gattgcatgt 840
cgtggcaaaa acatggaagt gagacttatt tttctctctg gactgtgcat agcagtagct 900
gttgtttggg ctgtgtttcg aaatgaagac aggtgggctt ggattttaca ggatatcttg 960
gggattgctt tctgtctgaa tttaattaaa acactgaagt tgcccaactt caagtcatgt 1020
gtgatacttc taggccttct cctcctctat gatgtatttt ttgttttcat aacaccattc 1080
atcacaaaga atggtgagag tatcatggtt gaactcgcag ctggaccttt tggaaataat 1140
gaaaagttgc cagtagtcat cagagtacca aaactgatct atttctcagt aatgagtgtg 1200
!' tgcctcatgc ctgtttcaat attgggtttt ggagacatta ttgtaccagg cctgttgatt 1260
gcatactgta gaagatttga tgttcagact ggttcttctt acatatacta tgtttcgtct 1320
acagttgcct atgctattgg catgatactt acatttgttg ttctggtgct gatgaaaaag 1380
gggcaacctg ctctcctcta tttagtacct tgcacactta ttactgcctc agttgttgcc 1440
tggagacgta aggaaatgaa aaagttctgg aaaggtaaca gctatcagat gatggaccat 1500
ttggattgtg caacaaatga agaaaaccct gtgatatctg gtgaacagat tgtccagcaa 1560
<210> 18
<211> 520
<212> PRT
<213> Homo Sapiens
<400> 18
Met Gly Pro Gln Arg Arg Leu Ser Pro Ala Gly Ala Ala Leu Leu Trp
1 5 10 15
Gly Phe Leu Leu Gln Leu Thr Ala Ala Gln Glu Ala Ile Leu His Ala
20 25 30
Ser Gly Asn Gly Thr Thr Lys Asp Tyr Cys Met Leu Tyr Asn Pro Tyr
35 40 45
Trp Thr Ala Leu Pro Ser Thr Leu Glu Asn Ala Thr Ser Ile Ser Leu
50 55 60
Met Asn Leu Thr Ser Thr Pro Leu Cys Asn Leu Ser Asp Ile Pro Pro
65 70 75 80
Val Gly Ile Lys Ser Lys Ala Val Val Val Pro Trp Gly Ser Cys His
85 90 95
Phe Leu Glu Lys Ala Arg Ile Ala Gln Lys Gly Gly Ala Glu Ala Met
100 105 110
Leu Val Val Asn Asn Ser Val Leu Phe Pro Pro Ser Gly Asn Arg Ser
115 120 125
Glu Phe Pro Asp Val Lys Ile Leu Ile Ala Phe Ile Ser Tyr Lys Asp
130 135 190
CA 02360585 2001-07-23
- 1$ -
Phe Arg Asp Met Asn Gln Thr Leu Gly Asp Asn Ile Thr Val Lys Met
145 150 155 160
Tyr Ser Pro Ser Trp Pro Asn Tyr Asp Tyr Thr Met Val Gly Ile Phe
165 170 175
Gly IleAla ValPheThr GlyAlaLeu SerGlyTyr TrpSerGlyLeu
180 185 190
Val GluLeu GluAsnLeu LysAlaVal ThrThrGlu AspArgGluMet
195 200 205
Arg LysLys LysGluGlu TyrLeuThr PheSerPro LeuThrValVal
210 215 220
Ile PheVal ValIleCys CysValMet MetValLeu LeuTyrPhePhe
225 230 235 240
( Tyr LysTrp LeuValTyr ValMetIle AlaIlePhe CysIleAlaSer
245 250 255
Ala MetSer LeuTyrAsn CysLeuAla AlaLeuIle HisLysIlePro
260 265 27p
Tyr GlyGln CysThrIle AlaCysArg GlyLysAsn MetGluValArg
275 280 285 ,
Leu IlePhe LeuSerGly LeuCysIle AlaValAla ValValTrpAla
290 295 300
Val PheArg AsnGluAsp ArgTrpAla TrpIleLeu GlnAspIleLeu
305 310 315 320
Gly IleAla PheCysLeu AsnLeuIle LysThrLeu LysLeuProAsn
325 330 335
Phe LysSer CysValIle LeuLeuGly LeuLeuLeu LeuTyrAspVal
340 345 350
Phe Phe Val Phe Ile Thr Pro Phe Ile Thr Lys Asn Gly Glu Ser Ile
355 360 365
Met Val Glu Leu Ala Ala Gly Pro Phe Gly Asn Asn Glu Lys Leu Pro
370 375 380
Val Val Ile Arg Val Pro Lys Leu Ile Tyr Phe Ser Val Met Ser Val
385 390 395 400
Cys Leu Met Pro Val Ser Ile Leu Gly Phe Gly Asp Ile Ile Val Pro
405 410 415
Gly Leu Leu Ile Ala Tyr Cys Arg Arg Phe Asp Val Gln Thr Gly Ser
420 425 430
Ser Tyr Ile Tyr Tyr Val Ser Ser Thr Val Ala Tyr Ala Ile Gly Met
435 940 445
' CA 02360585 2001-07-23
- 19 -
IleLeuThr-PheValValLeu ValLeuMet LysLysGly GlnProAla
450 455 460
LeuLeuTyrLeu ValProCys ThrLeuIle ThrAlaSer ValValAla
965 470 475 480
TrpArgArgLys GluMetLys LysPheTrp LysGlyAsn SerTyrGln
985 490 495
MetMetAspHis LeuAspCys AlaThrAsn GluGluAsn ProValIle
500 505 510
SerGlyGluGln IleValGln Gln
515 520
<210> 19
<211> 684
~':.<212> PRT
<213> Homo Sapiens
<400> 19
Met Ala Cys Leu Gly Phe Leu Leu Pro Val Gly Phe Leu Leu Leu Ile
1 5 10 15
Ser Thr Val Ala Gly Gly Lys Tyr Gly Val Ala His Val Val Ser.Glu
20 25 30
Asn Trp Ser Lys Asp Tyr Cys Ile Leu Phe Ser Ser Asp Tyr Ile Thr
35 40 45
Leu Pro Arg Asp Leu His His Ala Pro Leu Leu Pro Leu Tyr Asp Gly
50 55 60
Thr Lys Ala Pro Trp Cys Pro Gly Glu Asp Ser Pro His Gln Ala Gln
65 70 75 80
Leu Arg Ser Pro Ser Gln Arg Pro Leu Arg Gln Thr Thr Ala Met Val
C. ~ 85 90 95
Met Arg Gly Asn Cys Ser Phe His Thr Lys Gly Trp Leu Ala Gln Gly
100 105 110
Gln Gly Ala His Gly Leu Leu Ile Val Ser Arg Val Ser Asp Gln Gln
115 120 125
Cys Ser Asp Thr Thr Leu Ala Pro Gln Asp Pro Arg Gln Pro Leu Ala
130 135 140
Asp Leu Thr Ile Pro Val Ala Met Leu His Tyr Ala Asp Met Leu Asp
145 150 155 160
Ile Leu Ser His Thr Arg Gly Glu Ala Val Val Arg Val Ala Met Tyr
165 170 175
Ala Pro Pro Glu Pro Ile Ile Asp Tyr Asn Met Leu Val Ile Phe Ile
180 185 190
CA 02360585 2001-07-23
- 20 -
Leu Ala Val Gly Thr Val Ala Ala Gly Gly Tyr Trp Ala Gly Leu Thr
195 200 205
Glu Ala Asn Arg Leu Gln Arg Arg Arg Ala Arg Arg Gly Gly Gly Ser
210 215 220
Gly Gly His His Gln Leu Gln Glu Ala Ala Ala Ala Glu Gly Ala Gln
225 230 235 240
Lys Glu Asp Asn Glu Asp Ile Pro Val Asp Phe Thr Pro Ala Met Thr
245 250 255
Gly Val Val Val Thr Leu Ser Cys Ser Leu Met Leu Leu Leu Tyr Phe
260 265 270
Phe Tyr Asp His Phe Val Tyr Val Thr Ile Gly Ile Phe Gly Leu Gly
275 280 285
Ala Gly Ile Gly Leu Tyr Ser Cys Leu Ser Pro Leu Val Cys His Leu
290 295 300
Ser Leu Arg Gln Tyr Gln Arg Pro Pro His Ser Leu Trp Ala Ser Leu
305 310 315 320
Pro Leu Pro Leu Leu Leu Leu Ala Ser Leu Cys Ala Thr Val Lle Ile
325 330 335,
Phe Trp Val Ala Tyr Arg Asn Glu Asp Arg Trp Ala Trp Leu Leu Gln
340 395 350
Asp Thr Leu Gly Ile Ser Tyr Cys Leu Phe Val Leu His Arg Val Arg
355 360 365
Leu Pro Thr Leu Lys Asn Cys Ser Ser Phe Leu Leu Ala Leu Leu Ala
370 375 380
Phe Asp Val Phe Phe Val Phe Val Thr Pro Phe Phe Thr Lys Thr Gly
385 390 395 400
w
Glu Ser Ile Met Ala Gln Val Ala Leu Gly Pro Ala Glu Ser Ser Ser
405 410 415
His Glu Arg Leu Pro Met Val Leu Lys Val Pro Arg Leu Arg Val Ser
420 425 430
Ala Leu Thr Leu Cys Ser Gln Pro Phe Ser Ile Leu Gly Phe Gly Asp
435 440 445
Ile Val Val Pro Gly Phe Leu Val Ala Tyr Cys Cys Arg Phe Asp Val
450 455 460
Gln Val Cys Ser Arg Gln.Ile Tyr Phe Val Ala Cys Thr Val Ala Tyr
965 970 475 480
Ala Val Gly Leu Leu Val Thr Phe Met Ala Met Val Leu Met Gln Met
485 490 495
CA 02360585 2001-07-23
- 21 -
GlyGlnPro AlaLeuLeu TyrLeuValSer SerThrLeu LeuThr Ser
500 505 510
LeuAlaVal AlaAlaCys ArgGlnGluLeu SerLeuPhe TrpThr Gly
515 520 525
GlnGlyArg AlaLysMet CysGlyLeuGly CysAlaPro SerAla Gly
530 535 540
SerArgGln LysGlnGlu GlyAlaAlaAsp AlaHisThr AlaSer Thr
545 550 555 560
LeuGluArg GlyThrSer ArgGlyAlaGly AspLeuAsp SerAsn Pro
565 570 575
GlyGluAsp ThrThrGlu IleValThrIle SerGluAsn GluAla Thr
580 585 590
t~, . Asn Pro Glu Asp Arg Ser Asp Ser Ser Glu Gly Trp Ser Asp Ala His
595 600 605
Leu Asp Pro Asn Glu Leu Pro Phe Ile Pro Pro Gly Ala Ser Glu Glu
610 615 620
Leu Met Pro Leu Met Pro Met Ala Met Leu Ile Pro Leu Met Pro Leu
625 630 635 640
Met Pro Pro Pro Ser Glu Leu Gly His Val His Ala Gln Ala Gln Ala
645 650 655
His Glu Thr Gly Leu Pro Trp Ala Gly Leu His Lys Arg Lys Gly Leu
660 665 670
Lys Val Arg Lys Ser Met Ser Thr Gln Ala Pro Leu
675 680
<210> 20
<211> 2052
<212> DNA
<213> Homo sapiens
<400> 20
atggcgtgcc tgggcttcct cctccccgtg ggcttcctcc tcctcatcag caccgtggcc 60
gggggaaagt acggcgtggc ccacgtggtg tcggagaatt ggagcaagga ctactgtatc 120
ctgttcagct ccgactacat caccctcccc cgggacctgc accacgcccc actcctgccc 180
ctgtatgatg gcaccaaggc accctggtgc ccgggtgagg attcccccca ccaggcccag 240
ctccgctccc ccagccagcg gcccctccgc cagaccactg ccatggtcat gaggggtaac 300
tgcagcttcc acacgaaagg ctggctggct cagggccaag gtgcccacgg gctgctcatc 360
gtgagccggg tcagtgacca acagtgctca gacaccaccc tggcacccca ggatccccgc 420
cagcccctgg cagacctcac catccctgtg gctatgctcc actatgctga catgctggac 480
atcctcagcc acactcgtgg ggaggccgtc gtccgcgtgg ccatgtacgc acccccagag 540
cccatcatcg actacaacat gctggtcatc ttcatcctgg ctgtgggcac agtggctgca 600
ggcggctact gggccggcct gaccgaagcc aaccggctac agcggcgccg tgcccgaaga 660
ggaggggggt ctggtggtca ccatcagctg caggaagctg cagcagctga gggagcccag 720
aaggaagata atgaggacat cccagtggac ttcacgccgg ccatgacagg cgtggtggtc 780
accctgtcct gctcgctcat gctgctgctc tacttcttct atgaccactt tgtctatgtc 840
accattggga tctttggcct gggtgctggc attggcctct acagctgcct gtcacccctg 900
~' ~ CA 02360585 2001-07-23
- 22 -
gtgtgccacc tgtccctgcg gcaataccag aggcctccgc acagcctctg ggcctctctg 960
ccgctgcctc tgctgctgct ggcgagcctg tgcgcaaccg tgatcatctt ctgggtggcc 1020
taccgcaatg aggaccgctg ggcgtggctc ctgcaggaca cactgggcat ttcctactgc 1080
ctgttcgtcc tgcaccgtgt gcggctgccc actctcaaga actgctcctc cttcctgctg 1140
gccctgctgg cctttgatgt cttctttgtc ttcgtcaccc ccttcttcac caaaaccggt 1200
gagagcatca tggcgcaggt tgccttgggc cctgcagagt cttcaagcca tgagaggctg 1260
cccatggtac tcaaagtgcc ccggctaaga gtctccgcct tgaccctgtg cagccagccc 1320
ttctccatcc ttggcttcgg tgacattgtg gtccccggct tcctggttgc ttactgttgc 1380
cgctttgatg tgcaagtctg ctcccgtcag atctacttcg tggcctgcac cgtggcctat 1440
gctgtgggcc tgctggtcac attcatggcc atggtcctca tgcagatggg ccaacctgcc 1500
ttgctctacc tagtgtccag caccctgctc accagcctgg ctgtggctgc ctgccgccaa 1560
gagctcagcc tcttctggac tggccagggc agagctaaga tgtgtgggct cggctgtgcc 1620
ccttcggctg gctctaggca gaagcaggag ggcgcagcag atgcccacac agccagcaca 1680
cttgagagag gcaccagccg aggagcaggg gacttagaca gcaaccctgg agaagacacc 1740
actgagattg tcaccatatc tgagaatgaa gccaccaatc cagaggaccg cagtgatagc 1800
tccgagggct ggagtgacgc ccacttggat cctaatgagc tgcccttcat cccccctggg 1860
gcctcggagg agctgatgcc actgatgcca atggccatgc tgatcccact catgcccctg 1920
atgcccccgc cctcagagct gggccatgtc catgcccagg cccaggccca cgagactggc 1980
~'''\' ctgccctggg cgggactcca caagaggaag ggtttgaaag taagaaagag catgtcgacc 2040
caggctccct tg 2052
CA 02360585 2001-07-23
LEDIGLICH ZUR INFORMATION
Codes zur Identifizierung von PCT-Vertragsstaaten auf den Kopfbogen der
Schriften, die intelnationale Anmeldungen gemass dem
PCT veroffentlichen.
ALAlbanien ES Spanien LS Lesotho SI Slowenien
AMAnnenien FI Finnland LT Litauen SK Slowakei
ATOsterreich FR Frankreich LU Luxemburg SN Senegal
AUAustralien GA Gabun LV Lettland SZ Swasiland
AZAserbaidschan GB Vereinigtes MC Monaco TD Tschad
K6nigreich
BABosnien-HerzegowinaGE Georgien MD Republik MoldauTG Togo
BBBarbados GH Ghana MG Madagaskar TJ Tadschikistan
BEBelgien GN Guinea MK Die ehemaligeTM Turkmenistan
jugoslawische
BFBurkina Faso GR Griechenland Republik MazedonienTR Tiirkei
BGBulgarien HU Ungarn ML Mali TT Trinidad
and Tobago
BJBenin IE Trland MN Mongolei UA Ukraine
BRBrasilien IL Israel MR Mauretanien UG Uganda
BYBelarus IS Island MW Malawi US Vereinigte
Staaten
von
CAKanada IT Italien MX Mexiko Amerika
CFZentralafrikanischeJP Japan NE Niger UZ Usbekistan
Republik
CGKongo KE Kenia NL Niederlande VN Vietnam
CHSchweiz KG Kirgisistan NO Norwegen YU Jugoslawien
CIC8te d'Ivoire KP Demokratische NZ Neuseeland ZW Zimbabwe
Volksrepublik
CMKamerun Korea PL Polen
CNChina KR Republik KoreaPT Portugal
CUKuba KZ Kasachstan RO Rum~nien
CZTschechische LC St. Lucia RU Russische
Republik Ftideration
DEDeutschland LI Liechtenstein SD Sudan
DKDanemark LK Sri Lanka SE Schweden
EEEstland LR Liberia SG Singapur
CA 02360585 2001-07-23
WO 00/43505 PCT/EP00/00390
1
SEQUENZPROTOKOLL
<110> Memorec Stoffel GmbH
<120> Protease
<130> Protease Memorec
<140>
<141>
<150> 19902550.9
<151> 1999-O1-22
<150> 19925946.1
<151> 1999-06-08
<150> 19929115.2
<151> 1999-06-29
<160> 20
<170> PatentIn Ver. 2.1
<210> 1
<211> 592
<212> PRT
<213> Homo sapiens
<400> 1
Met Ala Ala Ala Val Ala Ala Ala Leu Ala Arg Leu Leu Ala Ala Phe
1 5 10 15
Leu Leu Leu Ala Ala Gln Val Ala Cys Glu Tyr Gly Met Val His Val
20 25 30
Val Ser Gln Ala Gly Gly Pro Glu Gly Lys Asp Tyr Cys Ile Leu Tyr
35 40 45
Asn Pro Gln Trp Ala His Leu Pro His Asp Leu Ser Lys Ala Ser Phe
50 55 60
Leu Gln Leu Arg Asn Trp Thr Ala Ser Leu Leu Cys Ser Ala Ala Asp
65 70 75 80
Leu Pro Ala Arg Gly Phe Ser Asn Gln Ile Pro Leu Val Ala Arg Gly
85 90 95
Asn Cys Thr Phe Tyr Glu Lys Val Arg Leu Ala Gln Gly Ser Gly Ala
100 105 110
Arg Gly Leu Leu Ile Val Ser Arg Glu Arg Leu Val Pro Pro Gly Gly
115 120 125
Asn Lys Thr Gln Tyr Asp Glu Ile Gly Ile Pro Val Ala Leu Leu Ser
130 135 140
CA 02360585 2001-07-23
WO 00/43505 PCT/EP00/00390
- 2 -
Tyr Asp
Lys Met
Leu
Asp
Ile
Phe
Thr
Arg
Phe
Gly
Arg
Thr
Val
Arg
145 150 155 160
Ala Leu Glu Val
Ala Tyr Pro
Ala Val
Pro Leu
Lys Asp
Tyr
Asn
Met
165 170 175
IleIle PheIleMet Ala Gly Ala Ile Trp
Val Thr Gly
Val Gly
Tyr
180 185 190
AlaGly SerArgAsp ValLysLys Arg LysHisLys ArgAsp
Tyr
Met
195 200 205
AspGly ProGluLys GlnGluAsp GluAlaVal AspValThr ProVal
210 215 220
MetThr CysValPhe ValValMet CysCysSer MetLeuVal LeuLeu
225 230 235 240
TyrTyr PheTyrAsp LeuLeuVal TyrValVal IleGlyIle PheCys
295 250 255
LeuAla SerAlaThr GlyLeuTyr SerCysLeu AlaProCys ValArg
260 265 270
ArgLeu ProPheGly LysCysArg IleProAsn AsnSerLeu ProTyr
275 280 285
PheHis LysArgPro GlnAlaArg MetLeuLeu LeuAlaLeu PheCys
290 295 300
ValAla ValSerVal ValTrpGly ValPheArg AsnGluAsp GlnTrp
305 310 315 320
AlaTrp ValLeuGln AspAlaLeu GlyIleAla PheCysLeu TyrMet
325 330 335
LeuLys ThrIleArg LeuProThr PheLysAla CysThrLeu LeuLeu
340 345 350
LeuVal LeuPheLeu TyrAspIle PhePheVal PheIleThr ProPhe
355 360 365
LeuThr LysSerGly SerSerIle MetValGlu ValAlaThr GlyPro
370 375 380
SerAsp SerAlaThr ArgGluLys LeuProMet ValLeuLys ValPro
385 390 395 400
ArgLeu SerSer ProLeu LeuCysAsp ArgProPhe Ser
Asn Ala Leu
405 410 415
LeuGly PheGlyAsp IleLeu ProGlyLeu LeuVal Tyr
Val Ala Cys
420 425 430
His Ile GlnVal SerSerArg Tyr
Arg Gln Val Phe
Phe Val
Asp Ala
435 440 445
CA 02360585 2001-07-23
WO 00/43505 PCT/EP00/00390
- 3 -
Cys ThrIleAla TyrGlyVal GlyLeuLeu ValThrPhe ValAlaLeu
450 455 460
Ala LeuMetGln ArgGlyGln ProAlaLeu LeuTyrLeu ValProCys
465 470 475 480
Thr LeuValThr SerCysAla ValAlaLeu TrpArgArg GluLeuGly
485 490 495
Val PheTrpThr GlySerGly PheAlaLys ValLeuPro ProSerPro
500 505 510
Trp AlaProAla ProAlaAsp GlyProGln ProProLys AspSerAla
515 520 525
Thr ProLeuSer ProGlnPro ProSerGlu GluProAla ThrSerPro
530 535 540
Trp ProAlaGlu GlnSerPro LysSerArg ThrSerGlu GluMetGly
545 550 555 560
Ala GlyAlaPro MetArgGlu ProGlySer ProAlaGlu SerGluGly
565 570 575
Arg AspGlnAla GlnProSer ProValThr GlnProGly AlaSerAla
580 585 590
<210> 2
<211> 520
<212> PRT
<213> Homo sapiens
<400> 2
Met Gly Pro Gln Arg Arg Leu Ser Pro Ala Gly Ala Ala Leu Leu Trp
1 5 10 15
Gly Phe Leu Leu Gln Leu Thr Ala Ala Gln Glu Ala Ile Leu His Ala
20 25 30
Ser Gly Asn Gly Thr Thr Lys Asp Tyr Cys Met Leu Tyr Asn Pro Tyr
35 40 45
Trp Thr Ala Leu Pro Ser Thr Leu Glu Asn Ala Thr Ser Ile Ser Leu
50 55 60
Met Asn Leu Thr Ser Thr Pro Leu Cys Asn Leu Ser Asp Ile Pro Pro
65 70 75 80
Val Gly Ile Lys Ser Lys Ala Val Val Val Pro Trp Gly Ser Cys His
85 90 95
Phe Leu Glu Lys Ala Arg Ile Ala Gln Lys Gly Gly Ala Glu Ala Met
100 105 110
Leu Val Val Asn Asn Ser Val Leu Phe Pro Pro Ser Gly Asn Arg Ser
115 120 125
CA 02360585 2001-07-23
WO 00/43505 PCT/EP00/00390
- 4 -
Glu Pro
Phe Asp
Val
Lys
Ile
Leu
Ile
Ala
Phe
Ile
Ser
Tyr
Lys
Asp
130 135 190
Phe Asp Asn Leu
Arg Met Gln Gly
Thr Asp
Asn
Ile
Thr
Val
Lys
Met
145 150 155 160
Tyr SerPro TrpPro PheAsp Val
Ser Asn Tyr Ile
Thr Phe
Met
Val
165 170 175
Val IleAlaVal PheThrVal AlaLeu Trp
Gly Ser
Gly Gly
Tyr Leu
180 185 190
Val GluLeuGlu AsnLeuLys AlaValThr Asp Met
Thr Arg
Glu Glu
195 200 205
Arg LysLysLys GluGluTyr LeuThrPhe ProLeu Thr Val
Ser Val
210 215 220
Ile PheValVal IleCysCys ValMetMet LeuLeu Tyr Phe
Val Phe
225 230 235 240
Tyr LysTrpLeu ValTyrVal MetIleAla PheCys Ile Ser
Ile Ala
245 250 255
Ala MetSerLeu TyrAsnCys LeuAlaAla IleHis Lys Pro
Leu Ile
260 265 270
Tyr GlyGlnCys ThrIleAla CysArgGly AsnMet Glu Arg
Lys Val
275 280 285
Leu IlePheLeu SerGlyLeu CysIleAla AlaVal Val Ala
Val Trp
290 295 300
Val PheArgAsn GluAspArg TrpAlaTrp LeuGln Asp Leu
Ile Ile
305 310 315 320
Gly IleAlaPhe CysLeuAsn LeuIleLys LeuLys Leu Asn
Thr Pro
325 330 335
Phe LysSerCys ValIleLeu LeuGlyLeu LeuLeu Tyr Val
Leu Asp
340 345 350
Phe PheValPhe IleThrPro PheIleThr AsnGly Glu Ile
Lys Ser
355 360 365
Met ValGluLeu AlaAlaGly ProPheGly AsnGlu Lys Pro
Asn Leu
370 375 380
Val ValIleArg ValProLys LeuIleTyr SerVal Met Val
Phe Ser
385 390 395 400
Cys Leu Pro ValSerIle GlyPhe AspIle Ile Pro
Met Leu Gly Val
405 410 415
Gly Leu Ile TyrCys Phe ValGln Thr Ser
Leu Ala Arg Asp Gly
Arg
420 425 430
CA 02360585 2001-07-23
WO 00/43505 PCT/EP00/00390
- 5 -
Ser Tyr Ile Tyr Tyr Val Ser Ser Thr Val Ala Tyr Ala Ile Gly Met
435 440 445
Ile Leu Thr Phe Val Val Leu Val Leu Met Lys Lys Gly Gln Pro Ala
450 455 460
Leu Leu Tyr Leu Val Pro Cys Thr Leu Ile Thr Ala Ser Val Val Ala
465 470 475 480
Trp Arg Arg Lys Glu Met Lys Lys Phe Trp Lys Gly Asn Ser Tyr Gln
485 490 495
Met Met Asp His Leu Asp Cys Ala Thr Asn Glu Glu Asn Pro Val Ile
500 505 510
Ser Gly Glu Gln Ile Val Gln Gln
515 520
<210> 3
<211> 377
<212> PRT
<213> Homo sapiens
<400> 3
Met Asp Ser Ala Leu Ser Asp Pro His Asn Gly Ser Ala Glu Ala Gly
1 5 10 15
Gly Pro Thr Asn Ser Thr Thr Arg Pro Pro Ser Thr Pro Glu Gly Ile
20 25 30
Ala Leu Ala Tyr Gly Ser Leu Leu Leu Met Ala Leu Leu Pro Ile Phe
35 40 45
Phe Gly Ala Leu Arg Ser Val Arg Cys Ala Arg Gly Lys Asn Ala Ser
50 55 60
Asp Met Pro Glu Thr Ile Thr Ser Arg Asp Ala Ala Arg Phe Pro Ile
65 70 75 80
Ile Ala Ser Cys Thr Leu Leu Gly Leu Tyr Leu Phe Phe Lys Ile Phe
85 90 95
Ser Gln Glu Tyr Ile Asn Leu Leu Leu Ser Met Tyr Phe Phe Val Leu
100 105 110
Gly Ile Leu Ala Leu Ser His Thr Ile Ser Pro Phe Met Asn Lys Phe
115 120 125
Phe Pro Ala Ser Phe Pro Asn Arg Gln Tyr Gln Leu Leu Phe Thr Gln
130 135 140
Gly Ser Gly Glu Asn Lys Glu Glu Ile Ile Asn Tyr Glu Phe Asp Thr
145 150 155 160
Lys Asp Leu Val Cys Leu Gly Leu Ser Ser Ile Val Gly Val Trp Tyr
165 170 175
CA 02360585 2001-07-23
WO 00/43505 PCT/EP00/00390
- 6 -
LeuLeuArg LysHisTrp IleAla AsnAsnLeu PheGlyLeu AlaPhe
180 185 190
SerLeuAsn GlyValGlu LeuLeu HisLeuAsn AsnValSer ThrGly
195 200 205
CysIleLeu LeuGlyGly LeuPhe IleTyrAsp ValPheTrp ValPhe
210 215 220
GlyThrAsn ValMetVal ThrVal AlaLysSer PheGluAla ProIle
225 230 235 240
LysLeuVal PheProGln AspLeu LeuGluLys GlyLeuGlu AlaAsn
245 250 255
AsnPheAla MetLeuGly LeuGly AspValVal IleProGly IlePhe
260 265 270
IleAlaLeu LeuLeuArg PheAsp IleSerLeu LysLysAsn ThrHis
275 280 285
ThrTyrPhe TyrThrSer PheAla AlaTyrIle PheGlyLeu GlyLeu
290 295 300
ThrIlePhe IleMetHis IlePhe LysHisAla GlnProAla LeuLeu
305 310 315 320
TyrLeuVal ProAlaCys IleGly PheProVal LeuValAla LeuAla
325 330 335
LysGlyGlu ValThrGlu MetPhe SerTyrGlu GluSerAsn ProLys
340 345 350
AspProAla AlaValThr GluSer LysGluGly ThrGluAla SerAla
355 360 365
SerLysGly LeuGluLys LysGlu Lys
370 375
<210>
4
<211>
384
<212>
PRT
<213> Sapiens
Homo
<400>
4
Met Ala Gln ThrTyr SerTrpAla Tyr Leu ValAspSer Ser
Glu Ser
1 5 10 15
Gln Val Thr PheLeu IleSerIle Leu Ile ValTyrGly Ser
Ser Leu
20 25 30
Phe Arg Leu AsnMet AspPheGlu Asn Asp LysGluLys Asp
Ser Gln
35 40 45
Ser Asn Ser SerGly SerPheAsn Gly Ser ThrAsnAsn Ser
Ser Asn
50 55 60
CA 02360585 2001-07-23
WO 00/43505 PCT/EP00/00390
Ile Gln Thr Ile Asp Ser Thr Gln Ala Leu Phe Leu Pro Ile Gly Ala
65 70 75 80
Ser Val Ser Leu Leu Val Met Phe Phe Phe Phe Asp Ser Val Gln Val
85 90 95
Val Phe Thr Ile Cys Thr Ala Val Leu Ala Thr Ile Ala Phe Ala Phe
100 105 110
Leu Leu Leu Pro Met Cys Gln Tyr Leu Thr Arg Pro Cys Ser Pro Gln
115 120 125
Asn Lys Ile Ser Phe Gly Cys Cys Gly Arg Phe Thr Ala Ala Glu Leu
130 135 140
Leu Ser Phe Ser Leu Ser Val Met Leu Val Leu Ile Trp Val Leu Thr
145 150 155 160
Gly His Trp Leu Leu Met Asp Ala Leu Ala Met Gly Leu Cys Val Ala
165 170 175
Met Ile Ala Phe Val Arg Leu Pro Ser Leu Lys Val Ser Cys Leu Leu
180 185 190
Leu Ser Gly Leu Leu Ile Tyr Asp Val Phe Trp Val Phe Phe Ser Ala
195 200 205
Tyr Ile Phe Asn Ser Asn Val Met Val Lys Val Ala Thr Gln Pro Ala
210 215 220
Asp Asn Pro Leu Asp Val Leu Ser Arg Lys Leu His Leu Gly Pro Asn
225 230 235 240
Val Gly Arg Asp Val Pro Arg Leu Ser Leu Pro Gly Lys Leu Val Phe
245 250 255
Pro Ser Ser Thr Gly Ser His Phe Ser Met Leu Gly Ile Gly Asp Ile
260 265 270
Val Met Pro Gly Leu Leu Leu Cys Phe Val Leu Arg Tyr Asp Asn Tyr
275 280 285
Lys Lys Gln Ala Ser Gly Asp Ser Cys Gly Ala Pro Gly Pro Ala Asn
290 295 300
Ile Ser Gly Arg Met Gln Lys Val Ser Tyr Phe His Cys Thr Leu Ile
305 310 315 320
Gly Tyr Phe Val Gly Leu Leu Thr Ala Thr Val Ala Ser Arg Ile His
325 330 335
Arg Ala Ala Gln Pro Ala Leu Leu Tyr Leu Val Pro Phe Thr Leu Leu
340 345 350
Pro Leu Leu Thr Met Ala Tyr Leu Lys Gly Asp Leu Arg Arg Met Trp
355 360 365
CA 02360585 2001-07-23
WO 00/43505 PCT/EP00/00390
_ g _
Ser Glu Pro Phe His Ser Lys Ser Ser Ser Ser Arg Phe Leu Glu Val
370 375 380
<210>
<211> 13
1
<212> RT
P
<213> us lus
M muscu
<400>
5
Val GlyPhe GlyAspIle IleVal ProGlyLeu LeuIleAla Tyr
Leu
1 5 10 15
Cys ArgPhe AspValGln ThrGly SerSerIle TyrTyrIle Ser
Arg
20 25 30
Ser IleAla TyrAlaVal GlyMet IleIleThr PheValVal Leu
Thr
35 40 45
Met MetLys ThrGlyGln ProAla LeuLeuTyr LeuValPro Cys
Val
50 55 60
Thr IleThr ValSerVal ValAla TrpSerArg LysGluMet Lys
Leu
65 70 75 80
Lys TrpLys GlySerSer TyrGln ValMetAsp HisLeuAsp Tyr
Phe
85 90 95
Ser AsnGlu GluAsnPro ValThr ThrAspGlu GlnIleVal Gln
Thr
100 105 110
Gln
<210>
6
<211>
378
<212>
PRT
<213> usculus
Mus m
<400>
6
Met Asp Ala ValSerAsp ProHisAsn GlySerAla GluAlaGly
Ser
1 5 10 15
Thr Pro Asn GlyThrThr ArgProPro SerThrPro GluGlyIle
Ala
20 25 30
Ala Leu Tyr GlySerLeu LeuLeuMet AlaLeuLeu ProIlePhe
Ala
35 40 45
Phe Gly Leu ProSerVal ArgCysAla ArgGlyLys SerSerSer
Ala
50 55 60
Asp Met Glu ThrIleThr SerArgAsp AlaAlaArg PheProIle
Pro
65 70 75 80
Ile Ala Cys ThrLeuLeu GlyLeuTyr LeuPhePhe LysIlePhe
Ser
85 90 95
CA 02360585 2001-07-23
WO 00/43505 PCT/EP00/00390
- 9 _
Ser Gln Glu Tyr Ile Asn Leu Leu Leu Ser Met Tyr Phe Phe Val Leu
100 105 110
Gly Ile Leu Ala Leu Ser His Thr Ile Ser Pro Phe Met Asn Lys Phe
115 120 125
Phe Pro Ala Asn Phe Pro Asn Arg Gln Tyr Gln Leu Leu Phe Thr Gln
130 135 140
Gly Ser Gly Glu Asn Lys Glu Glu Ile Ile Asn Tyr Glu Phe Asp Thr
145 150 155 160
Lys Asp Leu Val Cys Leu Gly Leu Ser Ser Val Val Gly Val Trp Tyr
165 170 175
Leu Leu Arg Lys His Trp Ile Ala Asn Asn Leu Phe Gly Leu Ala Phe
180 185 190
Ser Leu Asn Gly Val Glu Leu Leu His Leu Asn Asn Val Ser Thr Gly
195 200 205
Cys Ile Leu Leu Gly Gly Leu Phe Ile Tyr Asp Ile Phe Trp Val Phe
210 215 220
Gly Thr Asn Val Met Val Thr Val Ala Lys Ser Phe Glu Ala Pro Ile
225 230 235 240
Lys Leu Val Phe Pro Gln Asp Leu Leu Glu Lys Gly Leu Glu Ala Asp
245 250 255
Asn Phe Ala Met Leu Gly Leu Gly Asp Ile Val Ile Pro Gly Ile Phe
260 265 270
Ile Ala Leu Leu Leu Arg Phe Asp Ile Ser Leu Lys Lys Asn Thr His
275 280 285
Thr Tyr Phe Tyr Thr Ser Phe Ala Ala Tyr Ile Phe Gly Leu Gly Leu
290 295 300
Thr Ile Phe Ile Met His Ile Phe Lys His Ala Gln Pro Ala Leu Leu
305 310 315 320
Tyr Leu Val Pro Ala Cys Ile Gly Phe Pro Val Leu Val Ala Leu Ala
325 330 335
Lys Gly Glu Val Ala Glu Met Phe Ser Tyr Glu Glu Ser Asn Pro Lys
340 345 350
Asp Pro Ala Ala Val Thr Glu Ser Lys Glu Glu Ser Thr Glu Ala Ser
355 360 365
Ala Ser Lys Arg Leu Glu Lys Lys Glu Lys
370 375
<210> 7
<211> 257
<212> PRT
<213> Mus musculus
CA 02360585 2001-07-23
WO 00/43505 PCT/EP00/00390
- 10 -
<400> 7
Gln Asn Lys Ile Ser Phe Gly Cys Cys Gly Arg Phe Thr Ala Ala Glu
1 5 10 15
Leu Leu Ser Phe Tyr Leu Ser Val Met Leu Val Leu Ile Trp Val Leu
20 25 30
Thr Gly His Trp Leu Leu Met Asp Ala Leu Ala Met Gly Leu Cys Val
35 40 45
Ala Met Ile Ala Phe Val Arg Leu Pro Ser Leu Lys Val Ser Cys Leu
50 55 60
Leu Leu Ser Gly Leu Leu Ile Tyr Asp Val Phe Trp Val Phe Phe Ser
65 70 75 80
Ala Tyr Ile Phe Asn Ser Asn Val Met Val Lys Val Ala Thr Gln Pro
85 90 95
A1a Asp Asn Pro Leu Asp Val Leu Ser Arg Lys Leu His Leu Gly Pro
100 105 110
Asn Val Gly Arg Asp Val Pro Arg Leu Ser Leu Pro Gly Lys Leu Val
115 120 125
Phe Pro Ser Ser Thr Gly Ser His Phe Ser Met Leu Gly Ile Gly Asp
130 135 140
Ile Val Met Pro Gly Leu Leu Leu Cys Phe Val Leu Arg Tyr Asp Asn
145 150 155 160
Tyr Lys Lys Gln Ala Ser Gly Asp Ser Cys Gly Ala Pro Gly Xaa Ala
165 170 175
Asn Ile Ser Gly Arg Met Gln Lys Val Ser Tyr Phe His Cys Thr Leu
180 185 190
Ile Gly Tyr Phe Val Gly Leu Leu Thr Ala Thr Val Ala Ser Arg Val
195 200 205
His Arg Ala Ala Gln Pro Ala Leu Leu Tyr Leu Val Pro Phe Thr Leu
210 215 220
Leu Pro Leu Leu Thr Met Ala Tyr Leu Lys Gly Asp Leu Arg Arg Met
225 230 235 240
Trp Ser Glu Pro Phe His Ser Lys Ser Ser Ser Ser Arg Phe Leu Glu
245 250 255
Val
<210> 8
<211> 587
<212> PRT
<213> Saccharomyces cerevisiae
CA 02360585 2001-07-23
WO 00/43505 PCT/EP00/00390
- 11 -
<400> 8
Met Asp Lys Tyr Leu Asn Ser Phe Val Asp His Leu Ser Glu Trp Ser
1 5 10 15
Ser Arg Ala Phe Arg Asn Asn Ser Ser Ser Ala Asn Gln Ser Ala Ser
20 25 30
Asn Lys Glu Leu Glu Gln Val Phe Glu Gln Ile Asn Ala Ile Val Glu
35 40 45
Asn His Asn Asn Lys Leu Thr Thr Ala Phe Asp Lys Ile Ser Tyr Arg
50 55 60
Val Ala His Lys Ile Thr His Leu Val Glu Ser His Ser Leu Val Phe
65 70 75 80
Asn Tyr Ala Thr Leu Val Leu Ile Ala Ser Ala Leu Val Val Ile Gly
85 90 95
Ser Phe Thr Ser Ile Ser Ser Ile Pro Phe Thr Ala Leu Pro Pro Thr
100 105 110
Arg Glu His Ser Leu Phe Asp Pro Thr Asp Phe Asp Val Asp His Asp
115 120 125
Cys His Val Ile Tyr Arg Glu Asn Asp Glu Asp Lys Lys Lys Lys Lys
130 135 140
Lys Ser Lys Arg Phe Phe Asp Met Met Asp Glu Lys His Ala Ile Ile
145 150 155 160
Leu Pro Leu Thr Ser Gly Cys Thr Leu Leu Ala Leu Tyr Phe Val Ile
165 170 175
Lys Lys Leu His Leu Asn Trp Leu Lys Tyr Val Val Lys Ile Leu Asn
180 185 190
Phe Asn Ile Thr Leu Leu Asn Ile Pro Ala Gly Thr Phe Val Tyr Ser
195 200 205
Tyr Phe Leu Asn Ser Leu Phe Arg Asn Leu Ser His Leu Ala Ser Trp
210 215 220
Asn Pro Leu Val Val Leu Pro Arg Tyr Arg Val Thr Ile Ala Asp Asp
225 230 235 240
Asn Glu Asp Leu Asn Lys Ile Gly Gly Phe Val Thr Asn Leu Asn Tyr
245 250 255
Lys Asp Gly Leu Thr Asn Ser Val Val His Lys Lys Thr Leu Asp Glu
260 265 270
Ile Glu Lys Asp His Trp Met Lys His Phe Tyr Arg Arg Glu Leu Val
275 280 285
Glu Pro Lys Asp Ile Lys Ser Lys Arg Gln Ile Ser Asn Met Tyr Leu
290 295 300
CA 02360585 2001-07-23
WO 00/43505 PCT/EP00/00390
- 12 -
Asn
Ser
Ala
Leu
Ile
Val
Ser
Phe
Val
Leu
Ser
Ile
Val
Ser
Thr
Val
305 310 315 320
Tyr Ser Asp Trp
Phe Pro Leu
Tyr Asn Ile
Leu Ser
Asn
Ala
Val
Ser
325 330 335
Met MetAlaIle Trp Ala LeuLys
Asn Ser Gln Asn
Ile Leu Leu
Lys
340 345 350
Lys Gly Leu Ile Ile Ala Phe TyrAsp Cys
Ser Ala Leu Leu Phe Ile
355 360 365
Phe PheGlyThr Asp Met ValThrValAla ThrAsn Asp
Val Val Leu
370 375 380
Ile ValLysLeu Ser Pro ValLysPheAsn ThrAla Asn
Pro Leu Gln
385 390 , 395 400
Asn AsnPheSer Ile Gly LeuGlyAspIle AlaLeu Gly
Phe Leu Pro
405 410 415
Met IleAlaMet Cys Lys TyrAspIleTrp LysTrp Leu
Phe Tyr His
420 425 430
Asp AspAspThr Glu His PheLeuAsnTrp SerTyr Gly
His Phe Val
435 440 445
Lys PheIleThr Ala Val SerTyrValAla SerLeu Ser
Tyr Met Val
450 455 460
Ala ValSerLeu Ser Phe AsnThrAlaGln ProAla Leu
Met Ile Leu
465 470 475 480
Tyr ValProSer Leu Ile SerThrIleLeu ValAla Trp
Ile Leu Cys
485 490 495
Asn AspPheLys Gln Trp AsnPheGlnTyr AspThr Glu
Lys Phe Ile
500 505 510
Val LysSerLeu Lys Ala IleGluLysLys GluAsn Ile
Asp Lys Ser
515 520 525
Thr SerThrPhe Ile Ser GluTyrTyrAsn Asp Lys
Tyr Leu Ala
Asp
530 535 540
Tyr LeuLeuGly Val GluAsnPhe Asp Glu
Ala Asp Asn Asp
Asp Asp
545 550 555 560
Glu ValGln Leu AspSerSer Glu Leu
Phe Glu Ser Glu
Glu Glu
Asp
565 570 575
Ser GluAsp SerSer
Glu Leu
Leu
Asp
Asp
Glu
580 585
<210>
9
<211> 76
17
<212>
DNA
CA 02360585 2001-07-23
WO 00/43505 PCT/EP00/00390
- 13 -
<213> Saccharomyces cerevisiae
<400> 9
atggcggcag cggtggcggc tgcgctggcg cggcttttgg cggcctttct gctcctcgcg 60
gcccaggtgg cctgtgagta cggcatggtg cacgtggtct cccaggccgg gggccccgaa 120
ggcaaagact actgcatcct ctacaacccg cagtgggccc atcttccgca cgacctcagc 180
aaggcatctt tcctgcagct gcgcaactgg acggcctccc tgctctgctc cgcagccgac 240
ctccccgccc gtggcttcag caaccagatc ccgctggtgg cgcgggggaa ctgcaccttc 300
tatgagaaag tgaggctggc ccagggcagc ggagcacgcg ggctgctcat cgtcagcagg 360
gagaggctgg tccccccggg gggtaataag acgcagtatg atgagattgg cattcccgtg 420
gccctgctca gctacaaaga catgctggac atcttcacgc gtttcggccg cacggtgagg 480
gcggcgctgt atgcgcctaa ggagccggtg ctggactaca acatggtcat catcttcatc 540
atggctgtgg gcaccgtcgc catcggcggc tactgggccg ggagtcggga cgtgaagaaa 600
aggtacatga agcacaagcg cgacgatggg cccgagaagc aggaggacga ggcggtggac 660
gtgacgccgg tgatgacctg cgtgtttgtg gtgatgtgct gctccatgct ggtgctgctc 720
tactacttct acgacctcct cgtgtacgtg gtcatcggga tcttctgcct ggcctccgcc 780
accggcctct acagctgcct ggcgccctgt gtgcggcggc tgcccttcgg caagtgcagg 840
atccccaaca acagcctgcc ctacttccac aagcgcccgc aggcccgtat gctgctcctg 900
gcgctcttct gcgtggccgt cagcgtggtg tggggcgtct tccgcaacga ggaccagtgg 960
gcctgggtcc tccaggatgc cctgggcatc gccttctgcc tctacatgct gaagaccatc 1020
cgtctgccca ccttcaaggc ctgcacgctg ctgctgctgg tgctgttcct ctacgacatc 1080
ttcttcgtgt tcatcacgcc cttcctgacc aagagtggga gcagcatcat ggtggaggtg 1140
gccactgggc cctcggactc agccacccgt gagaagctgc ccatggtcct gaaggtgccc 1200
aggctgaact cctcacctct ggccctgtgt gaccggccct tctccctcct gggtttcgga 1260
gacattttgg tgccagggct gctggtggcc tactgccaca ggtttgacat ccaggtacag 1320
tcctccaggg tatacttcgt ggcctgcacc atcgcctatg gcgttggcct ccttgtgaca 1380
ttcgtggcac tggccctgat gcagcgtggc cagcccgctc tcctctacct ggtgccctgc 1440
acgctggtga cgagctgcgc tgtggcgctc tggcgccggg agctgggcgt gttctggacg 1500
ggcagcggct ttgcgaaagt cctacctcca tctccgtggg ccccagcacc agccgacggc 1560
ccgcagcctc ccaaagactc tgccacgcca ctctccccgc agccgcccag cgaagaacca 1620
gccacatccc cctggcctgc tgagcagtcc ccaaaatcac gcacgtccga ggagatgggg 1680
gctggagccc ccatgcggga gcctgggagc ccagctgaat ccgagggccg ggaccaggcc 1740
cagccgtccc cggtaaccca gcctggcgcc tcggcc 1776
<210> 10
<211> 1560
<212> DNA
<213> Homo Sapiens
<400> 10
atggggccgc agcggcggct gtcccctgcc ggggccgccc tactctgggg cttcctgctc 60
cagctgacag ccgctcagga agcaatcttg catgcgtctg gaaatggcac aaccaaggac 120
tactgcatgc tttataaccc ttattggaca gctcttccaa gtaccctaga aaatgcaact 180
tccattagtt tgatgaatct gacttccaca ccactatgca acctttctga tattcctcct 240
gttggcataa agagcaaagc agttgtggtt ccatggggaa gctgccattt tcttgaaaaa 300
gccagaattg cacagaaagg aggtgctgaa gcaatgttag ttgtcaataa cagtgtccta 360
tttcctccct caggtaacag atctgaattt cctgatgtga aaatactgat tgcatttata 420
agctacaaag actttagaga tatgaaccag actctaggag ataacattac tgtgaaaatg 480
tattctccat cgtggcctaa ctttgattat actatggtgg ttatttttgt aattgcggtg 540
ttcactgtgg cattaggtgg atactggagt ggactagttg aattggaaaa cttgaaagca 600
gtgacaactg aagatagaga aatgaggaaa aagaaggaag aatatttaac ttttagtcct 660
cttacagttg taatatttgt ggtcatctgc tgtgttatga tggtcttact ttatttcttc 720
tacaaatggt tggtttatgt tatgatagca attttctgca tagcatcagc aatgagtctg 780
tacaactgtc ttgctgcact aattcataag ataccatatg gacaatgcac gattgcatgt 840
cgtggcaaaa acatggaagt gagacttatt tttctctctg gactgtgcat agcagtagct 900
gttgtttggg ctgtgtttcg aaatgaagac aggtgggctt ggattttaca ggatatcttg 960
gggattgctt tctgtctgaa tttaattaaa acactgaagt tgcccaactt caagtcatgt 1020
CA 02360585 2001-07-23
WO 00/43505 PCT/EP00/00390
- 14 -
gtgatacttc taggccttct cctcctctat gatgtatttt ttgttttcat aacaccattc 1080
atcacaaaga atggtgagag tatcatggtt gaactcgcag ctggaccttt tggaaataat 1140
gaaaagttgc cagtagtcat cagagtacca aaactgatct atttctcagt aatgagtgtg 1200
tgcctcatgc ctgtttcaat attgggtttt ggagacatta ttgtaccagg cctgttgatt 1260
gcatactgta gaagatttga tgttcagact ggttcttctt acatatacta tgtttcgtct 1320
acagttgcct atgctattgg catgatactt acatttgttg ttctggtgct gatgaaaaag 1380
gggcaacctg ctctcctcta tttagtacct tgcacactta ttactgcctc agttgttgcc 1440
tggagacgta aggaaatgaa aaagttctgg aaaggtaaca gctatcagat gatggaccat 1500
ttggattgtg caacaaatga agaaaaccct gtgatatctg gtgaacagat tgtccagcaa 1560
<210> 11
<211> 1131
<212> DNA
<213> Homo Sapiens
<400> 11
atggactcgg ccctcagcga tccgcataac ggcagtgccg aggcaggcgg ccccaccaac 60
agcactacgc ggccgccttc cacgcccgag ggcatcgcgc tggcctacgg cagcctcctg 120
ctcatggcgc tgctgcccat cttcttcggc gccctgcgct ccgtacgctg cgcccgcggc 180
aagaatgctt cagacatgcc tgaaacaatc.accagccggg atgccgcccg cttccccatc 240
atcgccagct gcacactctt ggggctctac ctctttttca aaatattctc ccaggagtac 300
atcaacctcc tgctgtccat gtatttcttc gtgctgggaa tcctggccct gtcccacacc 360
atcagcccct tcatgaataa gttttttcca gccagctttc caaatcgaca gtaccagctg 420
ctcttcacac agggttctgg ggaaaacaag gaagagatca tcaattatga atttgacacc 480
aaggacctgg tgtgcctggg cctgagcagc atcgttggcg tctggtacct gctgaggaag 540
cactggattg ccaacaacct ttttggcctg gccttctccc ttaatggagt agagctcctg 600
cacctcaaca atgtcagcac tggctgcatc ctgctgggcg gactcttcat ctacgatgtc 660
ttctgggtat ttggcaccaa tgtgatggtg acagtggcca agtccttcga ggcaccaata 720
aaattggtgt ttccccagga tctgctggag aaaggcctcg aagcaaacaa ctttgccatg 780
ctgggacttg gagatgtcgt cattccaggg atcttcattg ccttgctgct gcgctttgac 840
atcagcttga agaagaatac ccacacctac ttctacacca gctttgcagc ctacatcttc 900
ggcctgggcc ttaccatctt catcatgcac atcttcaagc atgctcagcc tgccctccta 960
tacctggtcc ccgcctgcat cggttttcct gtcctggtgg cgctggccaa gggagaagtg 1020
acagagatgt tcagttatga ggagtcaaat cctaaggatc cagcggcagt gacagaatcc 1080
aaagagggaa cagaggcatc agcatcgaag gggctggaga agaaagagaa a 1131
<210> 12
<211> 1152
<212> DNA
<213> Homo sapiens
<400> 12
atggcggagc agacctactc gtgggcctat tccctggtgg attccagtca agtgtctaca 60
tttctgattt ccattcttct tatagtctat ggtagtttca ggtcccttaa tatggacttt 120
gaaaatcaag ataaggagaa agacagtaat agttcttctg ggtctttcaa tggcaacagc 180
accaataata gcatccaaac aattgactct acccaggctc tgttccttcc aattggagca 240
tctgtctctc ttttagtaat gttcttcttc tttgactcag ttcaagtagt ttttacaata 300
tgtacagcag ttcttgcaac gatagctttt gcttttcttc tcctcccgat gtgccagtat 360
ttaacaagac cctgctcacc tcagaacaag atttcctttg gttgctgtgg acgtttcact 420
gctgctgagt tgctgtcatt ctctctgtct gtcatgctcg tcctcatctg ggttctcact 480
ggccattggc ttctcatgga tgcactggcc atgggcctct gtgtcgccat gatcgccttt 540
gtccgcctgc cgagcctcaa ggtctcctgc ctgcttctct cagggcttct catctatgat 600
gtcttttggg tatttttctc agcctacatc ttcaatagca acgtcatggt gaaggtggcc 660
actcagccgg ctgacaatcc ccttgacgtt ctatcccgga agctccacct ggggcccaat 720
gttgggcgtg atgttcctcg cctgtctctg cctggaaaac tggtcttccc aagctccact 780
ggcagccact tctccatgtt gggcatcgga gacatcgtta tgcctggtct cctactatgc 840
CA 02360585 2001-07-23
WO 00/43505 PCT/EP00/00390
- 15 -
tttgtccttc gctatgacaa ctacaaaaag caagccagtg gggactcctg tggggcccct 900
ggacctgcca acatctccgg gcgcatgcag aaggtctcct actttcactg caccctcatc 960
ggatactttg taggcctgct cactgctact gtggcgtctc gcattcaccg ggccgcccag 1020
cccgcccttc tctatttggt gccatttact ttattgccac tcctcacgat ggcctattta 1080
aagggcgacc tccggcggat gtggtctgag cctttccact ccaagtccag cagctcccga 1140
ttcctggaag to 1152
<210> 13
<211> 339
<212> DNA
<213> Mus musculus
<400> 13
gtattgggtt tcggagatat cattgtacca ggcctgttga ttgcatattg tagaagattc 60
gatgttcaga ctggttcttc tatatactat atttcatcca caattgccta tgctgttggc 120
atgatcatta cctttgttgt cctgatggtg atgaaaacag ggcagcctgc tctcctctac 180
ttggtacctt gtacacttat tactgtctca gtcgttgctt ggagtcgtaa ggaaatgaaa 240
aagttctgga aaggcagcag ctatcaggtg atggaccacc tggactattc aacaaatgaa 300
gaaaatccag tgacgactga tgagcagatt gtacaacag 339
<210> 14
<211> 1134
<212> DNA
<213> Mus musculus
<400> 14
atggattcgg ctgtcagcga tccgcacaac ggcagcgccg aggctggcac cccagccaac 60
ggcacgacgc ggccgccctc cacgcccgag ggcatcgcgc tggcctacgg cagcctcctg 120
ctcatggcgc tgctgcccat cttcttcggc gccctgccgt cggtgcgctg cgcccgcggc 180
aagagctctt cggacatgcc agaaaccatc accagtcgag atgccgcccg cttccccatc 240
atcgccagct gcacactcct ggggctctac ctctttttca aaatattctc ccaggagtac 300
atcaacctct tgctgtccat gtatttcttc gtgctgggga tcctggccct gtcacacacc 360
atcagcccct tcatgaataa gttttttcca gccaacttcc caaaccgcca gtatcagctg 420
ctcttcacac agggctctgg ggaaaacaaa gaagagatca tcaactatga gtttgacact 480
aaggacctgg tgtgcctggg cctaagcagc gtcgttggtg tctggtacct tctgaggaag 540
cactggattg ccaacaacct gtttggcctg gccttctccc ttaatggggt agagctcctg 600
cacctgaaca acgtgagcac tggctgtatc ctgctcggag gactcttcat ctatgacatc 660
ttctgggtat tcggcaccaa cgtgatggtg acagtggcca agtcctttga ggcaccaata 720
aaattggtgt tcccccagga tctgctggag aagggccttg aagcagacaa ctttgccatg 780
ctgggacttg gagacattgt cattccaggg atcttcattg c~ttactgct tcgttttgac 840
atcagcttga agaagaacac gcacacctac ttctacacca gcttcgccgc ctacatcttc 900
ggcctgggtc tcaccatctt catcatgcac atcttcaagc acgcccagcc ggctctcctg 960
tacctggtcc ctgcctgcat cggctttcct gtcctggtgg cactagccaa gggagaagtg 1020
gccgagatgt tcagttatga ggagtccaac cctaaagatc cagcagccgt gactgaatcc 1080
aaagaggagt caacagaggc gtcggcatcg aagaggctag agaagaagga gaaa 1134
<210> 15
<211> 771
<212> DNA
<213> Mus musculus
<400> 15
cagaacaaga tttccttcgg ttgctgtggg cgtttcactg ctgccgagct gctgtcgttc 60
tacctgtctg tcatgctcgt cctcatctgg gttctcactg gccactggct tctcatggat 120
gctctggcca tgggtctctg tgttgccatg atcgccttcg tccgcctgcc aagcctcaag 180
CA 02360585 2001-07-23
WO 00/43505 PCT/EP00/00390
- 16 -
gtttcctgcc tgcttctctc agggcttctc atctacgatg tcttctgggt gttcttctca 240
gcctacatct tcaacagtaa tgtcatggtg aaagtggcca cacagccagc tgacaatccc 300
ctcgacgttc tgtccaggaa gctccacctg ggacccaatg tggggcgtga tgttcctcgc 360
ctgtctttgc ctggaaaatt ggtcttccca agctccactg gcagtcactt ctctatgctg 420
ggcatcgggg acattgtgat gcccggcctc ctgttatgct ttgttcttcg ctatgacaac 480
tacaagaaac aagccagtgg tgactcgtgt ggggcccctg gcanngccaa tatctctggg 590
cgcatgcaga aggtctccta cttccactgc accctcatcg ggtactttgt aggtctgctc 600
actgcgactg tggcgtctcg cgtccaccga gctgcccagc cagctctcct ctacttggtg 660
ccatttaccc tattgccact cctcaccatg gcctacctaa agggtgactt acggaggatg 720
tggtctgagc ccttccactc caagtccagc agctcccggt tcctggaagt a 771
<210> 16
<211> 1761
<212> DNA
<213> Saccharomyces cerevisiae
<400> 16
atggacaagt atttgaattc atttgttgac cacctttcag agtggtcatc tcgtgccttt 60
aggaacaatt catcaagcgc taaccaaagt gcgtcgaaca aggaattaga acaagttttt 120
gaacagatca atgctatagt tgaaaaccac aataacaaat taaccactgc ctttgataag 180
atatcatatc gcgttgctca caagattaca cacttggtgg aaagccattc tttagtattc 240
aactacgcca ctttagttct catcgcaagt gctttggtcg ttattggctc atttacgtct 300
atttcttcta ttccatttac agctctacct cctacgagag aacactcatt gtttgatcct 360
acagattttg atgtggacca cgactgtcat gttatctacc gcgagaatga cgaagataaa 420
aagaaaaaga agaaaagcaa gaggtttttc gatatgatgg atgaaaaaca tgcgattata 480
ctgcccttaa ctagtggctg tactttactc gctctctatt ttgtgatcaa gaaactacac 540
ctaaactggc taaaatatgt ggtgaaaatt ttgaatttta atataacact gctaaatatc 600
ccagctggca catttgtcta ctcctacttt ctcaactcac ttttcagaaa cctatcacat 660
ttagcttctt ggaatcccct ggttgtttta ccaaggtatc gtgtaacaat agctgatgat 720
aacgaagacc tgaacaagat aggcgggttt gttaccaatt tgaattacaa agatggattg 780
accaactcag ttgttcacaa gaaaacattg gatgagattg aaaaagatca ttggatgaag 840
catttttaca gaagagaatt agttgaaccg aaggatatta aatcgaagag gcagatcagc 900
aacatgtatt tgaatagcgc attaattgtt tcgttcgttc tgtccatcgt ttctaccgta 960
tatttctatt tatcacccaa tgattggtta atatccaatg ctgtcagtat gaatatggct 1020
atttggtcca ttgctcaatt aaaattgaag aatttaaaat caggggccct aatcctaatt 1080
gctctatttt tttacgacat ttgctttgtc tttggtaccg atgtaatggt tacagtagct 1140
actaaccttg atattcccgt aaaactaagc ttaccagtca agtttaatac agctcaaaac 1200
aacttcaatt tttcaatact tggtctgggt gatattgcct tgcctggtat gtttattgcg 1260
atgtgctaca aatatgacat ctggaagtgg caccttgatc atgatgacac tgaattccac 1320
tttttgaact ggtcatacgt tggaaaatat tttattactg ctatggttag ttacgttgct 1380
tctttggtat ctgccatggt ctccttgtcc attttcaata ctgctcaacc ggctttatta 1440
tacattgttc cttccttgtt gattagtact attttggtag cttgctggaa caaggatttt 1500
aagcagtttt ggaattttca gtatgatacg attgaagtgg ataaaagttt aaaaaaagcg 1560
atagaaaaaa aggagaactc tataacttat tcgaccttca tcctatcaga atactataat 1620
gatgccgaca agtatgcctt gcttggtgat gatgtaaacg aaaattttga cgatgatgaa 1680
gaattcgtgc aagaggaaga tctcagtgac agctctgagg aagagctttc tgaagaagat 1740
ctcttggatg acgaatcttc t 1761
<210> 17
<211> 1560
<212> DNA
<213> Homo Sapiens
<400> 17
atggggccgc agcggcggct gtcccctgcc ggggccgccc tactctgggg cttcctgctc 60
cagctgacag ccgctcagga agcaatcttg catgcgtctg gaaatggcac aaccaaggac 120
CA 02360585 2001-07-23
WO 00/43505 PCT/EP00/00390
- 17 -
tactgcatgc tttataaccc ttattggaca gctcttccaa gtaccctaga aaatgcaact 180
tccattagtt tgatgaatct gacttccaca ccactatgca acctttctga tattcctcct 240
gttggcataa agagcaaagc agttgtggtt ccatggggaa gctgccattt tcttgaaaaa 300
gccagaattg cacagaaagg aggtgctgaa gcaatgttag ttgtcaataa cagtgtccta 360
tttcctccct caggtaacag atctgaattt cctgatgtga aaatactgat tgcatttata 420
agctacaaag actttagaga tatgaaccag actctaggag ataacattac tgtgaaaatg 480
tattctccat cgtggcctaa ctatgattat actatggtgg gtatttttgg aattgcggtg 540
ttcactgggg cattaagtgg atactggagt ggactagttg aattggaaaa cttgaaagca 600
gtgacaactg aagatagaga aatgaggaaa aagaaggaag aatatttaac ttttagtcct 660
cttacagttg taatatttgt ggtcatctgc tgtgttatga tggtcttact ttatttcttc 720
tacaaatggt tggtttatgt tatgatagca attttctgca tagcatcagc aatgagtctg 780
tacaactgtc ttgctgcact aattcataag ataccatatg gacaatgcac gattgcatgt 840
cgtggcaaaa acatggaagt gagacttatt tttctctctg gactgtgcat agcagtagct 900
gttgtttggg ctgtgtttcg aaatgaagac aggtgggctt ggattttaca ggatatcttg 960
gggattgctt tctgtctgaa tttaattaaa acactgaagt tgcccaactt caagtcatgt 1020
gtgatacttc taggccttct cctcctctat gatgtatttt ttgttttcat aacaccattc 1080
atcacaaaga atggtgagag tatcatggtt gaactcgcag ctggaccttt tggaaataat 1140
gaaaagttgc cagtagtcat cagagtacca aaactgatct atttctcagt aatgagtgtg 1200
tgcctcatgc ctgtttcaat attgggtttt ggagacatta ttgtaccagg cctgttgatt 1260
gcatactgta gaagatttga tgttcagact ggttcttctt acatatacta tgtttcgtct 1320
acagttgcct atgctattgg catgatactt acatttgttg ttctggtgct gatgaaaaag 1380
gggcaacctg ctctcctcta tttagtacct tgcacactta ttactgcctc agttgttgcc 1440
tggagacgta aggaaatgaa aaagttctgg aaaggtaaca gctatcagat gatggaccat 1500
ttggattgtg caacaaatga agaaaaccct gtgatatctg gtgaacagat tgtccagcaa 1560
<210> 18
<211> 520
<212> PRT
<213> Homo sapiens
<400> 18
Met Gly Pro Gln Arg Arg Leu Ser Pro Ala Gly Ala Ala Leu Leu Trp
1 5 10 15
Gly Phe Leu Leu Gln Leu Thr Ala Ala Gln Glu Ala Ile Leu His Ala
20 25 30
Ser Gly Asn Gly Thr Thr Lys Asp Tyr Cys Met Leu Tyr Asn Pro Tyr
35 40 45
Trp Thr Ala Leu Pro Ser Thr Leu Glu Asn Ala Thr Ser Ile Ser Leu
50 55 60
Met Asn Leu Thr Ser Thr Pro Leu Cys Asn Leu Ser Asp Ile Pro Pro
65 70 75 80
Val Gly Ile Lys Ser Lys Ala Val Val Val Pro Trp Gly Ser Cys His
85 90 95
Phe Leu Glu Lys Ala Arg Ile Ala Gln Lys Gly Gly Ala Glu Ala Met
100 105 110
Leu Val Val Asn Asn Ser Val Leu Phe Pro Pro Ser Gly Asn Arg Ser
115 120 125
Glu Phe Pro Asp Val Lys Ile Leu Ile Ala Phe Ile Ser Tyr Lys Asp
130 135 140
CA 02360585 2001-07-23
WO 00/43505 PCT/EP00/00390
- 18 -
Phe Arg Asp Met Asn Gln Thr Leu Gly Asp Asn Ile Thr Val Lys Met
145 150 155 160
Tyr Ser Pro Ser Trp Pro Asn Tyr Asp Tyr Thr Met Val Gly Ile Phe
165 170 175
Gly Ile Ala Val Phe Thr Gly Ala Leu Ser Gly Tyr Trp Ser Gly Leu
180 185 190
Val Glu Leu Glu Asn Leu Lys Ala Val Thr Thr Glu Asp Arg Glu Met
195 200 205
Arg Lys Lys Lys Glu Glu Tyr Leu Thr Phe Ser Pro Leu Thr Val Val
210 215 220
Ile Phe Val Val Ile Cys Cys Val Met Met Val Leu Leu Tyr Phe Phe
225 230 235 240
Tyr Lys Trp Leu Val Tyr Val Met Ile Ala Ile Phe Cys Ile Ala Ser
245 250 255
Ala Met Ser Leu Tyr Asn Cys Leu Ala Ala Leu Ile His Lys Ile Pro
260 265 270
Tyr Gly Gln Cys Thr Ile Ala Cys Arg Gly Lys Asn Met Glu Val Arg
275 280 285
Leu Ile Phe Leu Ser Gly Leu Cys Ile Ala Val Ala Val Val Trp Ala
290 295 300
Val Phe Arg Asn Glu Asp Arg Trp Ala Trp Ile Leu Gln Asp Ile Leu
305 310 315 320
Gly Ile Ala Phe Cys Leu Asn Leu Ile Lys Thr Leu Lys Leu Pro Asn
325 330 335
Phe Lys Ser Cys Val Ile Leu Leu Gly Leu Leu Leu Leu Tyr Asp Val
340 345 350
Phe Phe Val Phe Ile Thr Pro Phe Ile Thr Lys Asn Gly Glu Ser Ile
355 360 365
Met Val Glu Leu Ala Ala Gly Pro Phe Gly Asn Asn Glu Lys Leu Pro
370 375 380
Val Val Ile Arg Val Pro Lys Leu Ile Tyr Phe Ser Val Met Ser Val
385 390 395 400
Cys Leu Met Pro Val Ser Ile Leu Gly Phe Gly Asp Ile Ile Val Pro
405 410 415
Gly Leu Leu Ile Ala Tyr Cys Arg Arg Phe Asp Val Gln Thr Gly Ser
420 425 430
Ser Tyr Ile Tyr Tyr Val Ser Ser Thr Val Ala Tyr Ala Ile Gly Met
435 440 445
CA 02360585 2001-07-23
WO 00/43505 PCT/EP00/00390
- 19 -
Ile Leu Thr Phe Val Val Leu Val Leu Met Lys Lys Gly Gln Pro Ala
450 455 460
Leu Leu Tyr Leu Val Pro Cys Thr Leu Ile Thr Ala Ser Val Val Ala
465 470 475 480
Trp Arg Arg Lys Glu Met Lys Lys Phe Trp Lys Gly Asn Ser Tyr Gln
485 490 495
Met Met Asp His Leu Asp Cys Ala Thr Asn Glu Glu Asn Pro Val Ile
500 505 510
Ser Gly Glu Gln Ile Val Gln Gln
515 520
<210>
19
<211> 684
<212> PRT
<213> Homosapiens
<400> 19
MetAla LeuGlyPhe LeuLeuPro ValGlyPhe LeuLeu LeuIle
Cys
1 5 10 15
SerThr AlaGlyGly LysTyrGly ValAlaHis ValVal SerGlu
Val
20 25 30
AsnTrp LysAspTyr CysIleLeu PheSerSer AspTyr IleThr
Ser
35 40 45
LeuPro AspLeuHis HisAlaPro LeuLeuPro LeuTyr AspGly
Arg
50 55 60
ThrLys ProTrpCys ProGlyGlu AspSerPro HisGln AlaGln
Ala
65 70 75 80
LeuArg ProSerGln ArgProLeu ArgGlnThr ThrAla MetVal
Ser
85 90 95
MetArg AsnCysSer PheHisThr LysGlyTrp LeuAla GlnGly
Gly
100 105 110
GlnGly HisGlyLeu LeuIleVal SerArgVal SerAsp GlnGln
Ala
115 120 125
CysSer ThrThrLeu AlaProGln AspProArg GlnPro LeuAla
Asp
130 135 140
AspLeu IleProVal AlaMetLeu HisTyrAla AspMet LeuAsp
Thr
145 150 155 160
IleLeu HisThrArg GlyGluAla ValValArg ValAla MetTyr
Ser
165 170 175
AlaPro GluProIle IleAspTyr AsnMetLeu ValIle PheIle
Pro
180 185 190
CA 02360585 2001-07-23
WO 00/43505 PCT/EP00/00390
- 20 -
Leu ValGly Ala Gly Ala
Ala Thr Gly Gly
Val Tyr Leu
Ala Trp Thr
195 200 205
Glu AsnArgLeu Gln Arg Arg Arg Gly Ser
Ala Arg Ala Arg Gly
Gly
210 215 220
GlyGly HisHisGln LeuGlnGlu AlaAlaAla AlaGluGly Gln
Ala
225 230 235 240
LysGlu AspAsnG1u AspIlePro ValAspPhe ThrProAla MetThr
245 250 255
GlyVal ValValThr LeuSerCys SerLeuMet LeuLeuLeu TyrPhe
260 265 270
PheTyr AspHisPhe ValTyrVal ThrIleGly IlePheGly LeuGly
275 280 285
AlaGly IleGlyLeu TyrSerCys LeuSerPro LeuValCys HisLeu
290 295 300
SerLeu ArgGlnTyr GlnArgPro ProHisSer LeuTrpAla SerLeu
305 310 315 320
ProLeu ProLeuLeu LeuLeuAla SerLeuCys AlaThrVal IleIle
325 330 335
PheTrp ValAlaTyr ArgAsnGlu AspArgTrp AlaTrpLeu LeuGln
340 345 350
AspThr LeuGlyIle SerTyrCys LeuPheVal LeuHisArg ValArg
355 360 365
LeuPro ThrLeuLys AsnCysSer SerPheLeu LeuAlaLeu LeuAla
370 375 380
PheAsp ValPhePhe ValPheVal ThrProPhe PheThrLys ThrGly
385 390 395 400
GluSer IleMetAla GlnValAla LeuGlyPro AlaGluSer SerSer
405 410 415
HisGlu ArgLeuPro MetValLeu LysValPro ArgLeuArg ValSer
420 425 430
AlaLeu ThrLeuCys SerGlnPro PheSerIle LeuGlyPhe GlyAsp
435 440 445
IleVal ValProGly PheLeuVal TyrCys CysArgPhe AspVal
Ala
450 455 460
GlnVal CysSerArg GlnIleTyr ValAla CysThrVal AlaTyr
Phe
465 470 475 480
AlaVal LeuLeu ValThrPhe Ala Val Met Gln
Gly Met Met Leu Met
485 490 495
CA 02360585 2001-07-23
WO 00/43505 PCT/EP00/00390
- 21 -
Gly Gln Pro Ala Leu Leu Tyr Leu Val Ser Ser Thr Leu Leu Thr Ser
500 505 510
Leu Ala Val Ala Ala Cys Arg Gln Glu Leu Ser Leu Phe Trp Thr Gly
515 520 525
Gln Gly Arg Ala Lys Met Cys Gly Leu Gly Cys Ala Pro Ser Ala Gly
530 535 540
Ser Arg Gln Lys Gln Glu Gly Ala Ala Asp Ala His Thr Ala Ser Thr
545 550 555 560
Leu Glu Arg Gly Thr Ser Arg Gly Ala Gly Asp Leu Asp Ser Asn Pro
565 570 575
Gly Glu Asp Thr Thr Glu Ile Val Thr Ile Ser Glu Asn Glu Ala Thr
580 585 590
Asn Pro Glu Asp Arg Ser Asp Ser Ser Glu Gly Trp Ser Asp Ala His
595 600 605
Leu Asp Pro Asn Glu Leu Pro Phe Ile Pro Pro Gly Ala Ser Glu Glu
610 615 620
Leu Met Pro Leu Met Pro Met Ala Met Leu Ile Pro Leu Met Pro Leu
625 630 635 640
Met Pro Pro Pro Ser Glu Leu Gly His Val His Ala Gln Ala Gln Ala
645 650 655
His Glu Thr Gly Leu Pro Trp Ala Gly Leu His Lys Arg Lys Gly Leu
660 665 670
Lys Val Arg Lys Ser Met Ser Thr Gln Ala Pro Leu
675 680
<210> 20
<211> 2052
<212> DNA
<213> Homo Sapiens
<400> 20
atggcgtgcc tgggcttcct cctccccgtg ggcttcctcc tcctcatcag caccgtggcc 60
gggggaaagt acggcgtggc ccacgtggtg tcggagaatt ggagcaagga ctactgtatc 120
ctgttcagct ccgactacat caccctcccc cgggacctgc accacgcccc actcctgccc 180
ctgtatgatg gcaccaaggc accctggtgc ccgggtgagg attcccccca ccaggcccag 240
ctccgctccc ccagccagcg gcccctccgc cagaccactg ccatggtcat gaggggtaac 300
tgcagcttcc acacgaaagg ctggctggct cagggccaag gtgcccacgg gctgctcatc 360
gtgagccggg tcagtgacca acagtgctca gacaccaccc tggcacccca ggatccccgc 420
cagcccctgg cagacctcac catccctgtg gctatgctcc actatgctga catgctggac 480
atcctcagcc acactcgtgg ggaggccgtc gtccgcgtgg ccatgtacgc acccccagag 540
cccatcatcg actacaacat gctggtcatc ttcatcctgg ctgtgggcac agtggctgca 600
ggcggctact gggccggcct gaccgaagcc aaccggctac agcggcgccg tgcccgaaga 660
ggaggggggt ctggtggtca ccatcagctg caggaagctg cagcagctga gggagcccag 720
aaggaagata atgaggacat cccagtggac ttcacgccgg ccatgacagg cgtggtggtc 780
accctgtcct gctcgctcat gctgctgctc tacttcttct atgaccactt tgtctatgtc 840
accattggga tctttggcct gggtgctggc attggcctct acagctgcct gtcacccctg 900
CA 02360585 2001-07-23
WO 00/43505 PCT/EP00/00390
- 22 -
gtgtgccacc tgtccctgcg gcaataccag aggcctccgc acagcctctg ggcctctctg 960
ccgctgcctc tgctgctgct ggcgagcctg tgcgcaaccg tgatcatctt ctgggtggcc 1020
taccgcaatg aggaccgctg ggcgtggctc ctgcaggaca cactgggcat ttcctactgc 1080
ctgttcgtcc tgcaccgtgt gcggctgccc actctcaaga actgctcctc cttcctgctg 1140
gccctgctgg cctttgatgt cttctttgtc ttcgtcaccc ccttcttcac caaaaccggt 1200
gagagcatca tggcgcaggt tgccttgggc cctgcagagt cttcaagcca tgagaggctg 1260
cccatggtac tcaaagtgcc ccggctaaga gtctccgcct tgaccctgtg cagccagccc 1320
ttctccatcc ttggcttcgg tgacattgtg gtccccggct tcctggttgc ttactgttgc 1380
cgctttgatg tgcaagtctg ctcccgtcag atctacttcg tggcctgcac cgtggcctat 1440
gctgtgggcc tgctggtcac attcatggcc atggtcctca tgcagatggg ccaacctgcc 1500
ttgctctacc tagtgtccag caccctgctc accagcctgg ctgtggctgc ctgccgccaa 1560
gagctcagcc tcttctggac tggccagggc agagctaaga tgtgtgggct cggctgtgcc 1620
ccttcggctg gctctaggca gaagcaggag ggcgcagcag atgcccacac agccagcaca 1680
cttgagagag gcaccagccg aggagcaggg gacttagaca gcaaccctgg agaagacacc 1740
actgagattg tcaccatatc tgagaatgaa gccaccaatc cagaggaccg cagtgatagc 1800
tccgagggct ggagtgacgc ccacttggat cctaatgagc tgcccttcat cccccctggg 1860
gcctcggagg agctgatgcc actgatgcca atggccatgc tgatcccact catgcccctg 1920
atgcccccgc cctcagagct gggccatgtc catgcccagg cccaggccca cgagactggc 1980
ctgccctggg cgggactcca caagaggaag ggtttgaaag taagaaagag catgtcgacc 2040
caggctccct tg 2052
