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CA2360585A1 - Protease - Google Patents

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Publication number
CA2360585A1
CA2360585A1 CA002360585A CA2360585A CA2360585A1 CA 2360585 A1 CA2360585 A1 CA 2360585A1 CA 002360585 A CA002360585 A CA 002360585A CA 2360585 A CA2360585 A CA 2360585A CA 2360585 A1 CA2360585 A1 CA 2360585A1
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CA
Canada
Prior art keywords
leu
ser
ala
val
gly
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
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CA002360585A
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French (fr)
Inventor
Kay Hofmann
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Memorec Biotec GmbH
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Individual
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Publication date
Priority claimed from DE19902550A external-priority patent/DE19902550A1/en
Application filed by Individual filed Critical Individual
Publication of CA2360585A1 publication Critical patent/CA2360585A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6478—Aspartic endopeptidases (3.4.23)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • C12Q1/37—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving peptidase or proteinase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Genetics & Genomics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • General Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Microbiology (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Immunology (AREA)
  • Analytical Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Catalysts (AREA)
  • Peptides Or Proteins (AREA)

Abstract

The invention relates to protease with two aspartate radicals in a catalytically active structure, a first aspartate radical being in a sequence X1GX2GD and a second aspartate radical being in a sequence X3X4DX5, X1, X2, X3 and X5 being selected independently of each other from the following: Ala, Val, Leu, Met and Ile; and X4 being an aromatic amino acid. The sequences X1GX2GD and X3X4DX5 lie in a transmembrane region.

Description

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.
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.

(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 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.
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 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.

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 Leu Leu Leu Ala Ala Gln Val Ala Cys Glu Tyr Gly Met Val His Val Val Ser Gln Ala Gly Gly Pro Glu Gly Lys Asp Tyr Cys Ile Leu Tyr f Asn Pro Gln Trp Ala His Leu Pro His Asp Leu Ser Lys Ala Ser Phe Leu Gln Leu Arg Asn Trp Thr Ala Ser Leu Leu Cys Ser Ala Ala Asp Leu Pro Ala Arg Gly Phe Ser Asn Gln Ile Pro Leu Val Ala Arg Gly Asn Cys Thr Phe Tyr Glu Lys Val Arg Leu Ala Gln Gly Ser Gly Ala Arg Gly Leu Leu Ile Val Ser Arg Glu Arg Leu Val Pro Pro Gly Gly Asn Lys Thr Gln Tyr Asp Glu Ile Gly Ile Pro Val Ala Leu Leu Ser Tyr LysAsp Asp ArgPhe Met Ile Gly Leu Phe Arg Thr Thr Val Arg Ala AlaLeu TyrAlaPro LysGlu ValLeuAsp MetVal Pro Tyr Asn Ile IlePhe IleMetAla ValGlyThr ValAlaIleGly TyrTrp Gly Ala GlySer ArgAspVal LysLysArg TyrMetLysHis LysArgAsp Asp GlyPro GluLysGln GluAspGlu AlaValAspVal ThrProVal 210 215 2.20 Met ThrCys ValPheVal ValMetCys CysSerMetLeu ValLeuLeu f.,w', Tyr TyrPhe TyrAspLeu LeuValTyr ValValle Gly IlePheCys I

Leu AlaSer AlaThrGly LeuTyrSer CysLeuAlaPro CysValArg Arg LeuPro PheGlyLys CysArgIle ProAsnAsnSer LeuProTyr Phe HisLys ArgProGln AlaArgMet LeuLeuLeuAla LeuPheCys Val AlaVal SerValVal TrpGlyVal PheArgAsnGlu AspGlnTrp Ala TrpVal LeuGlnAsp AlaLeuGly IleAlaPheCys LeuTyrMet Leu LysThr IleArgLeu ProThrPhe Lys CysThr LeuLeuLeu Ala .:. .

Leu Val Leu PheLeuTyr IlePhe Phe PheIle ThrProPhe Asp Val Leu Thr Lys Ser Gly Ser Ser Ile Met Val Glu Val Ala Thr Gly Pro Ser Asp Ser~Ala Thr Arg Glu Lys Leu Pro Met Val Leu Lys Val Pro Arg Leu Asn Ser Ser Pro Leu Ala Leu Cys Asp Arg Pro Phe Ser Leu Leu Gly Phe Gly Asp Ile Leu Val Pro Gly Leu Leu Val Ala Tyr Cys His Arg Phe Asp Ile Gln Val Gln Ser Ser Arg Val Tyr Phe Val Ala CysThrIle AlaTyrGly ValGlyLeu LeuValThr PheValAla Leu AlaLeuMet GlnArgGly GlnProAla LeuLeuTyr LeuValPro Cys ThrLeuVal ThrSerCys AlaValAla LeuTrpArg ArgGluLeu Gly ValPheTrp ThrGlySer GlyPheAla LysValLeu ProProSer Pro TrpAlaPro AlaProAla AspGlyPro GlnProPro LysAspSer Ala ThrProLeu SerProGln ProProSer GluGluPro AlaThrSer Pro Trp Pro Ala Glu Gln Ser Pro Lys Ser Arg Thr Ser Glu Glu Met Gly Ala Gly Ala Pro Met Arg Glu Pro Gly Ser Pro Ala Glu Ser Glu Gly Arg Asp Gln Ala Gln Pro Ser Pro Val Thr Gln Pro Gly Ala Sex Ala <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 Gly Phe Leu Leu Gln Leu Thr Ala Ala Gln Glu Ala Ile Leu His Ala SerGly GlyThrThr LysAspTyr CysMetLeu TyrAsnPro Tyr Asn TrpThrAla LeuProSer ThrLeuGlu AsnAlaThr SerI1eSer Leu MetAsnLeu ThrSerThr ProLeuCys AsnLeuSer AspIlePro Pro ValGlyIle LysSerLys AlaValVal ValProTrp GlySerCys His PheLeuGlu LysAlaArg IleAlaGln LysGlyGly AlaGluAla Met LeuValVal AsnAsnSer ValLeuPhe ProProSer GlyAsnArg Ser ' CA 02360585 2001-07-23 Glu PheProAsp ValLys IleLeuIle AlaPheIle SerTyrLysAsp Phe ArgAspMet AsnGln ThrLeuGly AspAsnIle ThrValLysMet Tyr SerProSer TrpPro AsnPheAsp TyrThrMet ValValIlePhe Val IleAlaVal PheThr ValAlaLeu GlyGlyTyr TrpSerGlyLeu Val GluLeuGlu AsnLeu LysAlaVal ThrThrGlu AspArgGluMet Arg LysLysLys GluGlu TyrLeuThr PheSerPro LeuThrValVal Ile PheValVal IleCys CysValMet MetValLeu LeuTyrPhePhe Tyr Lys Trp Leu Val Tyr Val Met Ile Ala Ile Phe Cys Ile Ala Ser Ala MetSerLeu TyrAsnCysLeu AlaAlaLeu IleHisLys I.lePro 260 265 270 , Tyr GlyGlnCys ThrIleAlaCys ArgGlyLys AsnMetGlu ValArg Leu IlePheLeu SerGlyLeuCys IleAlaVal AlaValVal TrpAla Val PheArgAsn GluAspArgTrp AlaTrpIle LeuGlnAsp IleLeu Gly IleAlaPhe CysLeuAsnLeu IleLysThr LeuLysLeu ProAsn Phe LysSerCys ValIleLeuLeu GlyLeuLeu LeuLeuTyr AspVal Phe Phe Val Phe Ile Thr Pro Phe Ile Thr Lys Asn Gly Glu Ser Ile Met Val Glu Leu Ala Ala Gly Pro Phe Gly Asn Asn Glu Lys Leu Pro Val Val Ile Arg Val Pro Lys Leu Ile Tyr Phe Ser Val Met Ser Val Cys Leu Met Pro Val Ser Ile Leu Gly Phe Gly Asp Ile Ile Val Pro Gly Leu Leu Ile Ala Tyr Cys Arg Arg Phe Asp Val Gln Thr Gly Ser Ser Tyr Ile TyrTyr ValSerSer Thr Ala AlaIle Val Tyr Gly Met Ile Leu Thr PheVal ValLeuVal Leu LysLys GlyGlnPro Met Ala Leu Leu Tyr LeuVal ProCysThr LeuIleThrAla SerValVal Ala Trp Arg Arg LysGlu MetLysLys PheTrpLysGly AsnSerTyr Gln Met Met Asp HisLeu AspCysAla ThrAsnGluGlu AsnProVal Ile Ser Gly Glu GlnIle ValGlnGln <210> 3 <211> 377 <212> PRT

<213> Homo Sapiens <400> 3 Met Asp Ser AlaLeu SerAspPro HisAsnGlySer AlaGluAla Gly Gly Pro Thr AsnSer ThrThrArg ProProSerThr ProGluGly Ile Ala Leu Ala TyrGly SerLeuLeu LeuMetAlaLeu LeuProIle Phe Phe Gly Ala LeuArg SerValArg AlaArgGly Lys Ala Ser Cys Asn Asp Met Pro GluThr IleThrSer AspAlaAla Pro Ile Arg Arg Phe Ile Ala Ser Cys Thr Leu Leu Gly Leu Tyr Leu Phe Phe Lys Ile Phe Ser Gln Glu Tyr Ile Asn Leu Leu Leu Ser Met Tyr Phe Phe Val Leu Gly Ile Leu Ala Leu Ser His Thr Ile Ser Pro Phe Met Asn Lys Phe Phe Pro Ala Ser Phe Pro Asn Arg Gln Tyr Gln Leu Leu Phe Thr Gln Gly Ser Gly Glu Asn Lys Glu Glu Ile Ile Asn Tyr Glu Phe Asp Thr Lys Asp Leu Val Cys Leu Gly Leu Ser Ser Ile Val Gly Val Trp Tyr LeuLeu ArgLysHisTrp IleAlaAsn AsnLeu PheGlyLeu AlaPhe SerLeu AsnGlyValGlu LeuLeuHis LeuAsn AsnValSer ThrGly CysIle LeuLeuGlyGly LeuPheIle TyrAsp ValPheTrp ValPhe GlyThr AsnValMetVal ThrValAla LysSer PheGluAla ProIle LysLeu ValPheProGln AspLeuLeu GluLys GlyLeuGlu AlaAsn AsnPhe AlaMetLeuGly LeuGlyAsp ValVal IleProGly IlePhe Ile Ala Leu Leu Leu Arg Phe Asp Ile Ser Leu Lys Lys Asn Thr His Thr TyrPheTyr ThrSerPheAla AlaTyrIle PheGlyLeu GlyLeu Thr IlePheIle MetHisIlePhe LysHisAla GlnProAla LeuLeu 305 310 315 ,320 Tyr LeuValPro AlaCysIleGly PheProVal LeuValAla LeuAla Lys GlyGluVal ThrGluMetPhe SerTyrGlu GluSerAsn ProLys Asp ProAlaAla ValThrGluSer LysGluGly ThrGluAla SerAla Ser LysGlyLeu GluLysLysGlu Lys <210> 4 <211> 384 <212> PRT

<213> Homosapiens <400> 4 Met Ala GlnThrTyr SerTrpAla TyrSerLeu ValAspSer Ser Glu Gln Val ThrPheLeu IleSerIle LeuLeuIle ValTyrGly Ser Ser Phe Arg LeuAsnMet AspPheGlu AsnGlnAsp LysG1uLys Asp Ser Ser Asn SerSerGly SerPheAsn GlyAsnSer ThrAsnAsn Ser Ser _ 7 _ Ile Gln Thr Ile Asp Ser Thr Gln Ala Leu Phe Leu Pro Ile Gly Ala Ser Val Ser Leu Leu Val Met Phe Phe Phe Phe Asp Ser Val Gln Val Val Phe Thr Ile Cys Thr Ala Val Leu Ala Thr Ile Ala Phe Ala Phe Leu Leu Leu Pro Met Cys Gln Tyr Leu Thr Arg Pro Cys Ser Pro Gln Asn Lys Ile Ser Phe Gly Cys Cys Gly Arg Phe Thr Ala Ala Glu Leu Leu Ser Phe Ser Leu Ser Val Met Leu Val Leu Ile Trp Val Leu Thr Gly His Trp Leu Leu Met Asp Ala Leu Ala Met Gly Leu Cys Val Ala Met Ile Ala Phe Val Arg Leu Pro Ser Leu Lys Val. Ser Cys Leu Leu 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 Asp Asn Pro Leu Asp Val Leu Ser Arg Lys Leu His Leu Gly Pro Asn Val Gly Arg Asp Val Pro Arg Leu Ser Leu Pro Gly Lys Leu Val Phe Pro Ser Ser Thr Gly Ser His Phe Ser Met Leu Gly Ile Gly Asp Ile Val Met Pro Gly Leu Leu Leu Cys Phe Val Leu Arg Tyr Asp Asn Tyr Lys Lys Gln Ala Ser Gly Asp Ser Cys Gly Ala Pro Gly Pro Ala Asn Ile Ser Gly Arg Met Gln Lys Val Ser Tyr Phe His Cys Thr Leu Ile Gly Tyr Phe Val Gly Leu Leu Thr Ala Thr Val Ala Ser Arg Ile His Arg Ala Ala Gln Pro Ala Leu Leu Tyr Leu Val Pro Phe Thr Leu Leu Pro Leu Leu Thr Met Ala Tyr Leu Lys Gly Asp Leu Arg Arg Met Trp Ser Glu Pro Phe His Ser Lys Ser Ser Ser Ser Arg Phe Leu Glu Val <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 Cys Arg Arg Phe Asp Val Gln Thr Gly Ser Ser Ile Tyr Tyr Ile Ser Ser Thr Ile Ala Tyr Ala Val Gly Met Ile Ile Thr Phe Val Val Leu Met Val Met Lys Thr Gly Gln Pro Ala Leu Leu Tyr Leu Val Pro Cys Thr Leu Ile Thr Val Ser Val Val Ala Trp Ser Arg Lys Glu Met Lys Lys Phe Trp Lys Gly Ser Ser Tyr Gln Val Met Asp His Leu AspITyr Ser Thr Asn Glu Glu Asn Pro Val Thr Thr Asp Glu Gln Ile Val Gln 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 Thr Pro Ala Asn Gly Thr Thr Arg Pro Pro Ser Thr Pro Glu Gly Ile Ala Leu Ala Tyr Gly Ser Leu Leu Leu Met Ala Leu Leu Pro Ile Phe Phe Gly Ala Leu Pro Ser Val Arg Cys Ala Arg Gly Lys Ser Ser Ser Asp Met Pro Glu Thr Ile Thr Ser Arg Asp Ala Ala Arg Phe Pro Ile Ile Ala Ser Cys Thr Leu Leu Gly Leu Tyr Leu Phe Phe Lys Ile Phe ' CA 02360585 2001-07-23 _ g _ Ser Gln Glu Tyr Ile Asn Leu Leu Leu Ser Met Tyr Phe Phe Val Leu Gly Ile Leu Ala Leu Ser His Thr Ile Ser Pro Phe Met Asn Lys Phe Phe Pro Ala Asn Phe Pro Asn Arg Gln Tyr Gln Leu Leu Phe Thr Gln Gly Ser Gly Glu Asn Lys Glu Glu Ile Ile Asn Tyr Glu Phe Asp Thr Lys Asp Leu Val Cys Leu Gly Leu Ser Ser Val Val Gly Val Trp Tyr Leu Leu Arg Lys His Trp Ile Ala Asn Asn Leu Phe Gly Leu Ala Phe Ser Leu Asn Gly Val Glu Leu Leu His Leu Asn Asn Val Ser Thr Gly Cys Ile Leu Leu Gly Gly Leu Phe Ile Tyr Asp Ile Phe Trp Val Phe 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 Asn Phe Ala Met Leu Gly Leu Gly Asp Ile Val Ile Pro Gly Ile Phe Ile Ala Leu Leu Leu Arg Phe Asp Ile Ser Leu Lys Lys Asn Thr His Thr Tyr Phe Tyr Thr Ser Phe Ala Ala Tyr Ile Phe Gly Leu Gly Leu f; ..
Thr Ile Phe Ile Met His Ile Phe Lys His Ala Gln Pro Ala Leu Leu Tyr Leu Val Pro Ala Cys Ile Gly Phe Pro Val Leu Val Ala Leu Ala Lys Gly Glu Val Ala Glu Met Phe Ser Tyr Glu Glu Ser Asn Pro Lys Asp Pro Ala Ala Val Thr Glu Ser Lys Glu Glu Ser Thr Glu Ala Ser Ala Ser Lys Arg Leu Glu Lys Lys Glu Lys <210> 7 <211> 257 <212> PRT
<213> Mus musculus <400> 7 Gln Asn Lys Ile Ser Phe Gly Cys Cys Gly Arg Phe Thr Ala Ala Glu Leu Leu Ser Phe Tyr Leu Ser Val Met Leu Val Leu Ile Trp Val Leu Thr Gly His Trp Leu Leu Met Asp Ala Leu Ala Met Gly Leu Cys Val Ala Met Ile Ala Phe Val Arg Leu Pro Ser Leu Lys Val Ser Cys Leu Leu Leu Ser Gly Leu Leu Ile Tyr Asp Val Phe Trp Val Phe Phe Ser Ala Tyr Ile Phe Asn Ser Asn Val Met Val Lys Val Ala Thr Gln Pro Ala Asp Asn Pro Leu Asp Val Leu Ser Arg Lys Leu His Leu Gly Pro Asn Val Gly Arg Asp Val Pro Arg Leu Ser Leu Pro Gly Lys Leu Val Phe Pro Ser Ser Thr Gly Ser His Phe Ser Met Leu Gly Tle Gly~Asp Ile Val Met Pro Gly Leu Leu Leu Cys Phe Val Leu Arg Tyr Asp Asn Tyr Lys Lys Gln Ala Ser Gly Asp Ser Cys Gly Ala Pro Gly Xaa Ala Asn Ile Ser Gly Arg Met Gln Lys Val Ser Tyr Phe His Cys Thr Leu Ile Gly Tyr Phe Val Gly Leu Leu Thr Ala Thr Val Ala Ser Arg Val His Arg Ala Ala Gln Pro Ala Leu Leu Tyr Leu Val Pro Phe Thr Leu Leu Pro Leu Leu Thr Met Ala Tyr Leu Lys Gly Asp Leu Arg Arg Met Trp Ser Glu Pro Phe His Ser Lys Ser Ser Ser Ser Arg Phe Leu Glu 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 <400> 8 Met Asp Lys Tyr Leu Asn Ser Phe Val Asp His Leu Ser Glu Trp Ser Ser Arg Ala Phe Arg Asn Asn Ser Ser Ser Ala Asn Gln Ser Ala Ser 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 Val Ala His Lys Ile Thr His Leu Val Glu Ser His Ser Leu Val Phe Asn Tyr Ala Thr Leu Val Leu Ile Ala Ser Ala Leu Val Val Ile Gly Ser Phe Thr Ser Ile Ser Ser Ile Pro Phe Thr Ala Leu Pro Pro Thr Arg Glu His Ser Leu Phe Asp Pro Thr Asp Phe Asp Val Asp His Asp Cys His Val Ile Tyr Arg Glu Asn Asp Glu Asp Lys Lys Lys Lys,Lys Lys Ser Lys Arg Phe Phe Asp Met Met Asp Glu Lys His Ala Ile Ile Leu Pro Leu Thr Ser Gly Cys Thr Leu Leu Ala Leu Tyr Phe Val Ile Lys Lys Leu His Leu Asn Trp Leu Lys Tyr Val Val Lys Ile Leu Asn 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 Asn Pro Leu Val Val Leu Pro Arg Tyr Arg Val Thr Ile Ala Asp Asp Asn Glu Asp Leu Asn Lys Ile Gly Gly Phe Val Thr Asn Leu Asn Tyr Lys Asp Gly Leu Thr Asn Ser Val Val His Lys Lys Thr Leu Asp Glu Ile Glu Lys Asp His Trp Met Lys His Phe Tyr Arg Arg Glu Leu Val Glu Pro Lys Asp Ile Lys Ser Lys Arg Gln Ile Ser Asn Met Tyr Leu Asn Ser Ala Leu Ile Val Ser Phe Val Leu Ser Ile Val Ser Thr Val Tyr Phe Tyr Leu Ser Pro Asn Asp Trp Leu Ile Ser Asn Ala Val Ser Met Asn Met Ala Ile Trp Ser Ile Ala Gln Leu Lys Leu Lys Asn Leu Lys Ser Gly Ala Leu Ile Leu Ile Ala Leu Phe Phe Tyr Asp Ile Cys Phe Val Phe Gly Thr Asp Val Met Val Thr Val Ala Thr Asn Leu Asp Ile Pro Val Lys Leu Ser Leu Pro Val Lys Phe Asn Thr Ala Gln Asn r'"<%y; Asn Phe Asn Phe Ser Ile Leu Gly Leu Gly Asp Ile Ala Leu Pro Gly Met Phe Ile Ala Met Cys Tyr Lys Tyr Asp Ile Trp Lys Trp His Leu Asp His Asp Asp Thr Glu Phe His Phe Leu Asn Trp Ser Tyr Val Gly Lys Tyr Phe Ile Thr Ala Met Val Ser Tyr Val Ala Ser Leu Val Ser Ala Met Val Ser Leu Ser Ile Phe Asn Thr Ala Gln Pro Ala Leu Leu Tyr Ile Val Pro Ser Leu Leu Ile Ser Thr Ile Leu Val Ala Cys Trp Asn Lys Asp Phe Lys Gln Phe Trp Asn Phe Gln Tyr Asp Thr Ile Glu r.
a, Val Asp Lys Ser Leu Lys Lys Ala Ile Glu Lys Lys Glu Asn Ser Ile Thr Tyr Ser Thr Phe Ile Leu Ser Glu Tyr Tyr Asn Asp Ala Asp Lys Tyr Ala Leu Leu Gly Asp Asp Val Asn Glu Asn Phe Asp Asp Asp Glu Glu Phe Val Gln Glu Glu Asp Leu Ser Asp Ser Ser Glu Glu.Glu Leu Ser Glu Glu Asp Leu Leu Asp Asp Glu Ser Ser <210> 9 <211> 1776 <212> DNA

<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 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 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 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 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 Gly Phe Leu Leu Gln Leu Thr Ala Ala Gln Glu Ala Ile Leu His Ala Ser Gly Asn Gly Thr Thr Lys Asp Tyr Cys Met Leu Tyr Asn Pro Tyr Trp Thr Ala Leu Pro Ser Thr Leu Glu Asn Ala Thr Ser Ile Ser Leu Met Asn Leu Thr Ser Thr Pro Leu Cys Asn Leu Ser Asp Ile Pro Pro Val Gly Ile Lys Ser Lys Ala Val Val Val Pro Trp Gly Ser Cys His Phe Leu Glu Lys Ala Arg Ile Ala Gln Lys Gly Gly Ala Glu Ala Met Leu Val Val Asn Asn Ser Val Leu Phe Pro Pro Ser Gly Asn Arg Ser Glu Phe Pro Asp Val Lys Ile Leu Ile Ala Phe Ile Ser Tyr Lys Asp - 1$ -Phe Arg Asp Met Asn Gln Thr Leu Gly Asp Asn Ile Thr Val Lys Met Tyr Ser Pro Ser Trp Pro Asn Tyr Asp Tyr Thr Met Val Gly Ile Phe Gly IleAla ValPheThr GlyAlaLeu SerGlyTyr TrpSerGlyLeu Val GluLeu GluAsnLeu LysAlaVal ThrThrGlu AspArgGluMet Arg LysLys LysGluGlu TyrLeuThr PheSerPro LeuThrValVal Ile PheVal ValIleCys CysValMet MetValLeu LeuTyrPhePhe ( Tyr LysTrp LeuValTyr ValMetIle AlaIlePhe CysIleAlaSer Ala MetSer LeuTyrAsn CysLeuAla AlaLeuIle HisLysIlePro 260 265 27p Tyr GlyGln CysThrIle AlaCysArg GlyLysAsn MetGluValArg 275 280 285 , Leu IlePhe LeuSerGly LeuCysIle AlaValAla ValValTrpAla Val PheArg AsnGluAsp ArgTrpAla TrpIleLeu GlnAspIleLeu Gly IleAla PheCysLeu AsnLeuIle LysThrLeu LysLeuProAsn Phe LysSer CysValIle LeuLeuGly LeuLeuLeu LeuTyrAspVal Phe Phe Val Phe Ile Thr Pro Phe Ile Thr Lys Asn Gly Glu Ser Ile Met Val Glu Leu Ala Ala Gly Pro Phe Gly Asn Asn Glu Lys Leu Pro Val Val Ile Arg Val Pro Lys Leu Ile Tyr Phe Ser Val Met Ser Val Cys Leu Met Pro Val Ser Ile Leu Gly Phe Gly Asp Ile Ile Val Pro Gly Leu Leu Ile Ala Tyr Cys Arg Arg Phe Asp Val Gln Thr Gly Ser Ser Tyr Ile Tyr Tyr Val Ser Ser Thr Val Ala Tyr Ala Ile Gly Met ' CA 02360585 2001-07-23 IleLeuThr-PheValValLeu ValLeuMet LysLysGly GlnProAla LeuLeuTyrLeu ValProCys ThrLeuIle ThrAlaSer ValValAla TrpArgArgLys GluMetLys LysPheTrp LysGlyAsn SerTyrGln MetMetAspHis LeuAspCys AlaThrAsn GluGluAsn ProValIle SerGlyGluGln IleValGln Gln <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 Ser Thr Val Ala Gly Gly Lys Tyr Gly Val Ala His Val Val Ser.Glu Asn Trp Ser Lys Asp Tyr Cys Ile Leu Phe Ser Ser Asp Tyr Ile Thr Leu Pro Arg Asp Leu His His Ala Pro Leu Leu Pro Leu Tyr Asp Gly Thr Lys Ala Pro Trp Cys Pro Gly Glu Asp Ser Pro His Gln Ala Gln 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 Gln Gly Ala His Gly Leu Leu Ile Val Ser Arg Val Ser Asp Gln Gln Cys Ser Asp Thr Thr Leu Ala Pro Gln Asp Pro Arg Gln Pro Leu Ala Asp Leu Thr Ile Pro Val Ala Met Leu His Tyr Ala Asp Met Leu Asp Ile Leu Ser His Thr Arg Gly Glu Ala Val Val Arg Val Ala Met Tyr Ala Pro Pro Glu Pro Ile Ile Asp Tyr Asn Met Leu Val Ile Phe Ile Leu Ala Val Gly Thr Val Ala Ala Gly Gly Tyr Trp Ala Gly Leu Thr Glu Ala Asn Arg Leu Gln Arg Arg Arg Ala Arg Arg Gly Gly Gly Ser Gly Gly His His Gln Leu Gln Glu Ala Ala Ala Ala Glu Gly Ala Gln Lys Glu Asp Asn Glu Asp Ile Pro Val Asp Phe Thr Pro Ala Met Thr Gly Val Val Val Thr Leu Ser Cys Ser Leu Met Leu Leu Leu Tyr Phe Phe Tyr Asp His Phe Val Tyr Val Thr Ile Gly Ile Phe Gly Leu Gly Ala Gly Ile Gly Leu Tyr Ser Cys Leu Ser Pro Leu Val Cys His Leu Ser Leu Arg Gln Tyr Gln Arg Pro Pro His Ser Leu Trp Ala Ser Leu 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 Asp Thr Leu Gly Ile Ser Tyr Cys Leu Phe Val Leu His Arg Val Arg Leu Pro Thr Leu Lys Asn Cys Ser Ser Phe Leu Leu Ala Leu Leu Ala Phe Asp Val Phe Phe Val Phe Val Thr Pro Phe Phe Thr Lys Thr Gly w Glu Ser Ile Met Ala Gln Val Ala Leu Gly Pro Ala Glu Ser Ser Ser His Glu Arg Leu Pro Met Val Leu Lys Val Pro Arg Leu Arg Val Ser Ala Leu Thr Leu Cys Ser Gln Pro Phe Ser Ile Leu Gly Phe Gly Asp Ile Val Val Pro Gly Phe Leu Val Ala Tyr Cys Cys Arg Phe Asp Val Gln Val Cys Ser Arg Gln.Ile Tyr Phe Val Ala Cys Thr Val Ala Tyr Ala Val Gly Leu Leu Val Thr Phe Met Ala Met Val Leu Met Gln Met GlyGlnPro AlaLeuLeu TyrLeuValSer SerThrLeu LeuThr Ser LeuAlaVal AlaAlaCys ArgGlnGluLeu SerLeuPhe TrpThr Gly GlnGlyArg AlaLysMet CysGlyLeuGly CysAlaPro SerAla Gly SerArgGln LysGlnGlu GlyAlaAlaAsp AlaHisThr AlaSer Thr LeuGluArg GlyThrSer ArgGlyAlaGly AspLeuAsp SerAsn Pro GlyGluAsp ThrThrGlu IleValThrIle SerGluAsn GluAla Thr t~, . Asn Pro Glu Asp Arg Ser Asp Ser Ser Glu Gly Trp Ser Asp Ala His Leu Asp Pro Asn Glu Leu Pro Phe Ile Pro Pro Gly Ala Ser Glu Glu Leu Met Pro Leu Met Pro Met Ala Met Leu Ile Pro Leu Met Pro Leu Met Pro Pro Pro Ser Glu Leu Gly His Val His Ala Gln Ala Gln Ala His Glu Thr Gly Leu Pro Trp Ala Gly Leu His Lys Arg Lys Gly Leu Lys Val Arg Lys Ser Met Ser Thr Gln Ala Pro Leu <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 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 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 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 Leu Leu Leu Ala Ala Gln Val Ala Cys Glu Tyr Gly Met Val His Val Val Ser Gln Ala Gly Gly Pro Glu Gly Lys Asp Tyr Cys Ile Leu Tyr Asn Pro Gln Trp Ala His Leu Pro His Asp Leu Ser Lys Ala Ser Phe Leu Gln Leu Arg Asn Trp Thr Ala Ser Leu Leu Cys Ser Ala Ala Asp Leu Pro Ala Arg Gly Phe Ser Asn Gln Ile Pro Leu Val Ala Arg Gly Asn Cys Thr Phe Tyr Glu Lys Val Arg Leu Ala Gln Gly Ser Gly Ala Arg Gly Leu Leu Ile Val Ser Arg Glu Arg Leu Val Pro Pro Gly Gly Asn Lys Thr Gln Tyr Asp Glu Ile Gly Ile Pro Val Ala Leu Leu Ser Tyr Asp Lys Met Leu Asp Ile Phe Thr Arg Phe Gly Arg Thr Val Arg Ala Leu Glu Val Ala Tyr Pro Ala Val Pro Leu Lys Asp Tyr Asn Met IleIle PheIleMet Ala Gly Ala Ile Trp Val Thr Gly Val Gly Tyr AlaGly SerArgAsp ValLysLys Arg LysHisLys ArgAsp Tyr Met AspGly ProGluLys GlnGluAsp GluAlaVal AspValThr ProVal MetThr CysValPhe ValValMet CysCysSer MetLeuVal LeuLeu TyrTyr PheTyrAsp LeuLeuVal TyrValVal IleGlyIle PheCys LeuAla SerAlaThr GlyLeuTyr SerCysLeu AlaProCys ValArg ArgLeu ProPheGly LysCysArg IleProAsn AsnSerLeu ProTyr PheHis LysArgPro GlnAlaArg MetLeuLeu LeuAlaLeu PheCys ValAla ValSerVal ValTrpGly ValPheArg AsnGluAsp GlnTrp AlaTrp ValLeuGln AspAlaLeu GlyIleAla PheCysLeu TyrMet LeuLys ThrIleArg LeuProThr PheLysAla CysThrLeu LeuLeu LeuVal LeuPheLeu TyrAspIle PhePheVal PheIleThr ProPhe LeuThr LysSerGly SerSerIle MetValGlu ValAlaThr GlyPro SerAsp SerAlaThr ArgGluLys LeuProMet ValLeuLys ValPro ArgLeu SerSer ProLeu LeuCysAsp ArgProPhe Ser Asn Ala Leu LeuGly PheGlyAsp IleLeu ProGlyLeu LeuVal Tyr Val Ala Cys His Ile GlnVal SerSerArg Tyr Arg Gln Val Phe Phe Val Asp Ala Cys ThrIleAla TyrGlyVal GlyLeuLeu ValThrPhe ValAlaLeu Ala LeuMetGln ArgGlyGln ProAlaLeu LeuTyrLeu ValProCys Thr LeuValThr SerCysAla ValAlaLeu TrpArgArg GluLeuGly Val PheTrpThr GlySerGly PheAlaLys ValLeuPro ProSerPro Trp AlaProAla ProAlaAsp GlyProGln ProProLys AspSerAla Thr ProLeuSer ProGlnPro ProSerGlu GluProAla ThrSerPro Trp ProAlaGlu GlnSerPro LysSerArg ThrSerGlu GluMetGly Ala GlyAlaPro MetArgGlu ProGlySer ProAlaGlu SerGluGly Arg AspGlnAla GlnProSer ProValThr GlnProGly AlaSerAla <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 Gly Phe Leu Leu Gln Leu Thr Ala Ala Gln Glu Ala Ile Leu His Ala Ser Gly Asn Gly Thr Thr Lys Asp Tyr Cys Met Leu Tyr Asn Pro Tyr Trp Thr Ala Leu Pro Ser Thr Leu Glu Asn Ala Thr Ser Ile Ser Leu Met Asn Leu Thr Ser Thr Pro Leu Cys Asn Leu Ser Asp Ile Pro Pro Val Gly Ile Lys Ser Lys Ala Val Val Val Pro Trp Gly Ser Cys His Phe Leu Glu Lys Ala Arg Ile Ala Gln Lys Gly Gly Ala Glu Ala Met Leu Val Val Asn Asn Ser Val Leu Phe Pro Pro Ser Gly Asn Arg Ser Glu Pro Phe Asp Val Lys Ile Leu Ile Ala Phe Ile Ser Tyr Lys Asp Phe Asp Asn Leu Arg Met Gln Gly Thr Asp Asn Ile Thr Val Lys Met Tyr SerPro TrpPro PheAsp Val Ser Asn Tyr Ile Thr Phe Met Val Val IleAlaVal PheThrVal AlaLeu Trp Gly Ser Gly Gly Tyr Leu Val GluLeuGlu AsnLeuLys AlaValThr Asp Met Thr Arg Glu Glu Arg LysLysLys GluGluTyr LeuThrPhe ProLeu Thr Val Ser Val Ile PheValVal IleCysCys ValMetMet LeuLeu Tyr Phe Val Phe Tyr LysTrpLeu ValTyrVal MetIleAla PheCys Ile Ser Ile Ala Ala MetSerLeu TyrAsnCys LeuAlaAla IleHis Lys Pro Leu Ile Tyr GlyGlnCys ThrIleAla CysArgGly AsnMet Glu Arg Lys Val Leu IlePheLeu SerGlyLeu CysIleAla AlaVal Val Ala Val Trp Val PheArgAsn GluAspArg TrpAlaTrp LeuGln Asp Leu Ile Ile Gly IleAlaPhe CysLeuAsn LeuIleLys LeuLys Leu Asn Thr Pro Phe LysSerCys ValIleLeu LeuGlyLeu LeuLeu Tyr Val Leu Asp Phe PheValPhe IleThrPro PheIleThr AsnGly Glu Ile Lys Ser Met ValGluLeu AlaAlaGly ProPheGly AsnGlu Lys Pro Asn Leu Val ValIleArg ValProLys LeuIleTyr SerVal Met Val Phe Ser Cys Leu Pro ValSerIle GlyPhe AspIle Ile Pro Met Leu Gly Val Gly Leu Ile TyrCys Phe ValGln Thr Ser Leu Ala Arg Asp Gly Arg Ser Tyr Ile Tyr Tyr Val Ser Ser Thr Val Ala Tyr Ala Ile Gly Met Ile Leu Thr Phe Val Val Leu Val Leu Met Lys Lys Gly Gln Pro Ala Leu Leu Tyr Leu Val Pro Cys Thr Leu Ile Thr Ala Ser Val Val Ala Trp Arg Arg Lys Glu Met Lys Lys Phe Trp Lys Gly Asn Ser Tyr Gln Met Met Asp His Leu Asp Cys Ala Thr Asn Glu Glu Asn Pro Val Ile Ser Gly Glu Gln Ile Val Gln Gln <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 Gly Pro Thr Asn Ser Thr Thr Arg Pro Pro Ser Thr Pro Glu Gly Ile Ala Leu Ala Tyr Gly Ser Leu Leu Leu Met Ala Leu Leu Pro Ile Phe Phe Gly Ala Leu Arg Ser Val Arg Cys Ala Arg Gly Lys Asn Ala Ser Asp Met Pro Glu Thr Ile Thr Ser Arg Asp Ala Ala Arg Phe Pro Ile Ile Ala Ser Cys Thr Leu Leu Gly Leu Tyr Leu Phe Phe Lys Ile Phe Ser Gln Glu Tyr Ile Asn Leu Leu Leu Ser Met Tyr Phe Phe Val Leu Gly Ile Leu Ala Leu Ser His Thr Ile Ser Pro Phe Met Asn Lys Phe Phe Pro Ala Ser Phe Pro Asn Arg Gln Tyr Gln Leu Leu Phe Thr Gln Gly Ser Gly Glu Asn Lys Glu Glu Ile Ile Asn Tyr Glu Phe Asp Thr Lys Asp Leu Val Cys Leu Gly Leu Ser Ser Ile Val Gly Val Trp Tyr LeuLeuArg LysHisTrp IleAla AsnAsnLeu PheGlyLeu AlaPhe SerLeuAsn GlyValGlu LeuLeu HisLeuAsn AsnValSer ThrGly CysIleLeu LeuGlyGly LeuPhe IleTyrAsp ValPheTrp ValPhe GlyThrAsn ValMetVal ThrVal AlaLysSer PheGluAla ProIle LysLeuVal PheProGln AspLeu LeuGluLys GlyLeuGlu AlaAsn AsnPheAla MetLeuGly LeuGly AspValVal IleProGly IlePhe IleAlaLeu LeuLeuArg PheAsp IleSerLeu LysLysAsn ThrHis ThrTyrPhe TyrThrSer PheAla AlaTyrIle PheGlyLeu GlyLeu ThrIlePhe IleMetHis IlePhe LysHisAla GlnProAla LeuLeu TyrLeuVal ProAlaCys IleGly PheProVal LeuValAla LeuAla LysGlyGlu ValThrGlu MetPhe SerTyrGlu GluSerAsn ProLys AspProAla AlaValThr GluSer LysGluGly ThrGluAla SerAla SerLysGly LeuGluLys LysGlu Lys <210>

<211>

<212>
PRT

<213> Sapiens Homo <400>

Met Ala Gln ThrTyr SerTrpAla Tyr Leu ValAspSer Ser Glu Ser Gln Val Thr PheLeu IleSerIle Leu Ile ValTyrGly Ser Ser Leu Phe Arg Leu AsnMet AspPheGlu Asn Asp LysGluLys Asp Ser Gln Ser Asn Ser SerGly SerPheAsn Gly Ser ThrAsnAsn Ser Ser Asn Ile Gln Thr Ile Asp Ser Thr Gln Ala Leu Phe Leu Pro Ile Gly Ala Ser Val Ser Leu Leu Val Met Phe Phe Phe Phe Asp Ser Val Gln Val Val Phe Thr Ile Cys Thr Ala Val Leu Ala Thr Ile Ala Phe Ala Phe Leu Leu Leu Pro Met Cys Gln Tyr Leu Thr Arg Pro Cys Ser Pro Gln Asn Lys Ile Ser Phe Gly Cys Cys Gly Arg Phe Thr Ala Ala Glu Leu Leu Ser Phe Ser Leu Ser Val Met Leu Val Leu Ile Trp Val Leu Thr Gly His Trp Leu Leu Met Asp Ala Leu Ala Met Gly Leu Cys Val Ala Met Ile Ala Phe Val Arg Leu Pro Ser Leu Lys Val Ser Cys Leu Leu Leu Ser Gly Leu Leu Ile Tyr Asp Val Phe Trp Val Phe Phe Ser Ala Tyr Ile Phe Asn Ser Asn Val Met Val Lys Val Ala Thr Gln Pro Ala Asp Asn Pro Leu Asp Val Leu Ser Arg Lys Leu His Leu Gly Pro Asn Val Gly Arg Asp Val Pro Arg Leu Ser Leu Pro Gly Lys Leu Val Phe Pro Ser Ser Thr Gly Ser His Phe Ser Met Leu Gly Ile Gly Asp Ile Val Met Pro Gly Leu Leu Leu Cys Phe Val Leu Arg Tyr Asp Asn Tyr Lys Lys Gln Ala Ser Gly Asp Ser Cys Gly Ala Pro Gly Pro Ala Asn Ile Ser Gly Arg Met Gln Lys Val Ser Tyr Phe His Cys Thr Leu Ile Gly Tyr Phe Val Gly Leu Leu Thr Ala Thr Val Ala Ser Arg Ile His Arg Ala Ala Gln Pro Ala Leu Leu Tyr Leu Val Pro Phe Thr Leu Leu Pro Leu Leu Thr Met Ala Tyr Leu Lys Gly Asp Leu Arg Arg Met Trp _ g _ Ser Glu Pro Phe His Ser Lys Ser Ser Ser Ser Arg Phe Leu Glu Val <210>

<211> 13 <212> RT
P

<213> us lus M muscu <400>

Val GlyPhe GlyAspIle IleVal ProGlyLeu LeuIleAla Tyr Leu Cys ArgPhe AspValGln ThrGly SerSerIle TyrTyrIle Ser Arg Ser IleAla TyrAlaVal GlyMet IleIleThr PheValVal Leu Thr Met MetLys ThrGlyGln ProAla LeuLeuTyr LeuValPro Cys Val Thr IleThr ValSerVal ValAla TrpSerArg LysGluMet Lys Leu Lys TrpLys GlySerSer TyrGln ValMetAsp HisLeuAsp Tyr Phe Ser AsnGlu GluAsnPro ValThr ThrAspGlu GlnIleVal Gln Thr Gln <210>

<211>

<212>
PRT

<213> usculus Mus m <400>

Met Asp Ala ValSerAsp ProHisAsn GlySerAla GluAlaGly Ser Thr Pro Asn GlyThrThr ArgProPro SerThrPro GluGlyIle Ala Ala Leu Tyr GlySerLeu LeuLeuMet AlaLeuLeu ProIlePhe Ala Phe Gly Leu ProSerVal ArgCysAla ArgGlyLys SerSerSer Ala Asp Met Glu ThrIleThr SerArgAsp AlaAlaArg PheProIle Pro Ile Ala Cys ThrLeuLeu GlyLeuTyr LeuPhePhe LysIlePhe Ser - 9 _ Ser Gln Glu Tyr Ile Asn Leu Leu Leu Ser Met Tyr Phe Phe Val Leu Gly Ile Leu Ala Leu Ser His Thr Ile Ser Pro Phe Met Asn Lys Phe Phe Pro Ala Asn Phe Pro Asn Arg Gln Tyr Gln Leu Leu Phe Thr Gln Gly Ser Gly Glu Asn Lys Glu Glu Ile Ile Asn Tyr Glu Phe Asp Thr Lys Asp Leu Val Cys Leu Gly Leu Ser Ser Val Val Gly Val Trp Tyr Leu Leu Arg Lys His Trp Ile Ala Asn Asn Leu Phe Gly Leu Ala Phe Ser Leu Asn Gly Val Glu Leu Leu His Leu Asn Asn Val Ser Thr Gly Cys Ile Leu Leu Gly Gly Leu Phe Ile Tyr Asp Ile Phe Trp Val Phe Gly Thr Asn Val Met Val Thr Val Ala Lys Ser Phe Glu Ala Pro Ile Lys Leu Val Phe Pro Gln Asp Leu Leu Glu Lys Gly Leu Glu Ala Asp Asn Phe Ala Met Leu Gly Leu Gly Asp Ile Val Ile Pro Gly Ile Phe Ile Ala Leu Leu Leu Arg Phe Asp Ile Ser Leu Lys Lys Asn Thr His Thr Tyr Phe Tyr Thr Ser Phe Ala Ala Tyr Ile Phe Gly Leu Gly Leu Thr Ile Phe Ile Met His Ile Phe Lys His Ala Gln Pro Ala Leu Leu Tyr Leu Val Pro Ala Cys Ile Gly Phe Pro Val Leu Val Ala Leu Ala Lys Gly Glu Val Ala Glu Met Phe Ser Tyr Glu Glu Ser Asn Pro Lys Asp Pro Ala Ala Val Thr Glu Ser Lys Glu Glu Ser Thr Glu Ala Ser Ala Ser Lys Arg Leu Glu Lys Lys Glu Lys <210> 7 <211> 257 <212> PRT
<213> Mus musculus <400> 7 Gln Asn Lys Ile Ser Phe Gly Cys Cys Gly Arg Phe Thr Ala Ala Glu Leu Leu Ser Phe Tyr Leu Ser Val Met Leu Val Leu Ile Trp Val Leu Thr Gly His Trp Leu Leu Met Asp Ala Leu Ala Met Gly Leu Cys Val Ala Met Ile Ala Phe Val Arg Leu Pro Ser Leu Lys Val Ser Cys Leu Leu Leu Ser Gly Leu Leu Ile Tyr Asp Val Phe Trp Val Phe Phe Ser Ala Tyr Ile Phe Asn Ser Asn Val Met Val Lys Val Ala Thr Gln Pro A1a Asp Asn Pro Leu Asp Val Leu Ser Arg Lys Leu His Leu Gly Pro Asn Val Gly Arg Asp Val Pro Arg Leu Ser Leu Pro Gly Lys Leu Val Phe Pro Ser Ser Thr Gly Ser His Phe Ser Met Leu Gly Ile Gly Asp Ile Val Met Pro Gly Leu Leu Leu Cys Phe Val Leu Arg Tyr Asp Asn Tyr Lys Lys Gln Ala Ser Gly Asp Ser Cys Gly Ala Pro Gly Xaa Ala Asn Ile Ser Gly Arg Met Gln Lys Val Ser Tyr Phe His Cys Thr Leu Ile Gly Tyr Phe Val Gly Leu Leu Thr Ala Thr Val Ala Ser Arg Val His Arg Ala Ala Gln Pro Ala Leu Leu Tyr Leu Val Pro Phe Thr Leu Leu Pro Leu Leu Thr Met Ala Tyr Leu Lys Gly Asp Leu Arg Arg Met Trp Ser Glu Pro Phe His Ser Lys Ser Ser Ser Ser Arg Phe Leu Glu Val <210> 8 <211> 587 <212> PRT
<213> Saccharomyces cerevisiae <400> 8 Met Asp Lys Tyr Leu Asn Ser Phe Val Asp His Leu Ser Glu Trp Ser Ser Arg Ala Phe Arg Asn Asn Ser Ser Ser Ala Asn Gln Ser Ala Ser Asn Lys Glu Leu Glu Gln Val Phe Glu Gln Ile Asn Ala Ile Val Glu Asn His Asn Asn Lys Leu Thr Thr Ala Phe Asp Lys Ile Ser Tyr Arg Val Ala His Lys Ile Thr His Leu Val Glu Ser His Ser Leu Val Phe Asn Tyr Ala Thr Leu Val Leu Ile Ala Ser Ala Leu Val Val Ile Gly Ser Phe Thr Ser Ile Ser Ser Ile Pro Phe Thr Ala Leu Pro Pro Thr Arg Glu His Ser Leu Phe Asp Pro Thr Asp Phe Asp Val Asp His Asp Cys His Val Ile Tyr Arg Glu Asn Asp Glu Asp Lys Lys Lys Lys Lys Lys Ser Lys Arg Phe Phe Asp Met Met Asp Glu Lys His Ala Ile Ile Leu Pro Leu Thr Ser Gly Cys Thr Leu Leu Ala Leu Tyr Phe Val Ile Lys Lys Leu His Leu Asn Trp Leu Lys Tyr Val Val Lys Ile Leu Asn Phe Asn Ile Thr Leu Leu Asn Ile Pro Ala Gly Thr Phe Val Tyr Ser Tyr Phe Leu Asn Ser Leu Phe Arg Asn Leu Ser His Leu Ala Ser Trp Asn Pro Leu Val Val Leu Pro Arg Tyr Arg Val Thr Ile Ala Asp Asp Asn Glu Asp Leu Asn Lys Ile Gly Gly Phe Val Thr Asn Leu Asn Tyr Lys Asp Gly Leu Thr Asn Ser Val Val His Lys Lys Thr Leu Asp Glu Ile Glu Lys Asp His Trp Met Lys His Phe Tyr Arg Arg Glu Leu Val Glu Pro Lys Asp Ile Lys Ser Lys Arg Gln Ile Ser Asn Met Tyr Leu Asn Ser Ala Leu Ile Val Ser Phe Val Leu Ser Ile Val Ser Thr Val Tyr Ser Asp Trp Phe Pro Leu Tyr Asn Ile Leu Ser Asn Ala Val Ser Met MetAlaIle Trp Ala LeuLys Asn Ser Gln Asn Ile Leu Leu Lys Lys Gly Leu Ile Ile Ala Phe TyrAsp Cys Ser Ala Leu Leu Phe Ile Phe PheGlyThr Asp Met ValThrValAla ThrAsn Asp Val Val Leu Ile ValLysLeu Ser Pro ValLysPheAsn ThrAla Asn Pro Leu Gln 385 390 , 395 400 Asn AsnPheSer Ile Gly LeuGlyAspIle AlaLeu Gly Phe Leu Pro Met IleAlaMet Cys Lys TyrAspIleTrp LysTrp Leu Phe Tyr His Asp AspAspThr Glu His PheLeuAsnTrp SerTyr Gly His Phe Val Lys PheIleThr Ala Val SerTyrValAla SerLeu Ser Tyr Met Val Ala ValSerLeu Ser Phe AsnThrAlaGln ProAla Leu Met Ile Leu Tyr ValProSer Leu Ile SerThrIleLeu ValAla Trp Ile Leu Cys Asn AspPheLys Gln Trp AsnPheGlnTyr AspThr Glu Lys Phe Ile Val LysSerLeu Lys Ala IleGluLysLys GluAsn Ile Asp Lys Ser Thr SerThrPhe Ile Ser GluTyrTyrAsn Asp Lys Tyr Leu Ala Asp Tyr LeuLeuGly Val GluAsnPhe Asp Glu Ala Asp Asn Asp Asp Asp Glu ValGln Leu AspSerSer Glu Leu Phe Glu Ser Glu Glu Glu Asp Ser GluAsp SerSer Glu Leu Leu Asp Asp Glu <210>

<211> 76 <212>
DNA

<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 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 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 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 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 Gly Phe Leu Leu Gln Leu Thr Ala Ala Gln Glu Ala Ile Leu His Ala Ser Gly Asn Gly Thr Thr Lys Asp Tyr Cys Met Leu Tyr Asn Pro Tyr Trp Thr Ala Leu Pro Ser Thr Leu Glu Asn Ala Thr Ser Ile Ser Leu Met Asn Leu Thr Ser Thr Pro Leu Cys Asn Leu Ser Asp Ile Pro Pro Val Gly Ile Lys Ser Lys Ala Val Val Val Pro Trp Gly Ser Cys His Phe Leu Glu Lys Ala Arg Ile Ala Gln Lys Gly Gly Ala Glu Ala Met Leu Val Val Asn Asn Ser Val Leu Phe Pro Pro Ser Gly Asn Arg Ser Glu Phe Pro Asp Val Lys Ile Leu Ile Ala Phe Ile Ser Tyr Lys Asp Phe Arg Asp Met Asn Gln Thr Leu Gly Asp Asn Ile Thr Val Lys Met Tyr Ser Pro Ser Trp Pro Asn Tyr Asp Tyr Thr Met Val Gly Ile Phe Gly Ile Ala Val Phe Thr Gly Ala Leu Ser Gly Tyr Trp Ser Gly Leu Val Glu Leu Glu Asn Leu Lys Ala Val Thr Thr Glu Asp Arg Glu Met Arg Lys Lys Lys Glu Glu Tyr Leu Thr Phe Ser Pro Leu Thr Val Val Ile Phe Val Val Ile Cys Cys Val Met Met Val Leu Leu Tyr Phe Phe Tyr Lys Trp Leu Val Tyr Val Met Ile Ala Ile Phe Cys Ile Ala Ser Ala Met Ser Leu Tyr Asn Cys Leu Ala Ala Leu Ile His Lys Ile Pro Tyr Gly Gln Cys Thr Ile Ala Cys Arg Gly Lys Asn Met Glu Val Arg Leu Ile Phe Leu Ser Gly Leu Cys Ile Ala Val Ala Val Val Trp Ala Val Phe Arg Asn Glu Asp Arg Trp Ala Trp Ile Leu Gln Asp Ile Leu Gly Ile Ala Phe Cys Leu Asn Leu Ile Lys Thr Leu Lys Leu Pro Asn Phe Lys Ser Cys Val Ile Leu Leu Gly Leu Leu Leu Leu Tyr Asp Val Phe Phe Val Phe Ile Thr Pro Phe Ile Thr Lys Asn Gly Glu Ser Ile Met Val Glu Leu Ala Ala Gly Pro Phe Gly Asn Asn Glu Lys Leu Pro Val Val Ile Arg Val Pro Lys Leu Ile Tyr Phe Ser Val Met Ser Val Cys Leu Met Pro Val Ser Ile Leu Gly Phe Gly Asp Ile Ile Val Pro Gly Leu Leu Ile Ala Tyr Cys Arg Arg Phe Asp Val Gln Thr Gly Ser Ser Tyr Ile Tyr Tyr Val Ser Ser Thr Val Ala Tyr Ala Ile Gly Met Ile Leu Thr Phe Val Val Leu Val Leu Met Lys Lys Gly Gln Pro Ala Leu Leu Tyr Leu Val Pro Cys Thr Leu Ile Thr Ala Ser Val Val Ala Trp Arg Arg Lys Glu Met Lys Lys Phe Trp Lys Gly Asn Ser Tyr Gln Met Met Asp His Leu Asp Cys Ala Thr Asn Glu Glu Asn Pro Val Ile Ser Gly Glu Gln Ile Val Gln Gln <210>

<211> 684 <212> PRT

<213> Homosapiens <400> 19 MetAla LeuGlyPhe LeuLeuPro ValGlyPhe LeuLeu LeuIle Cys SerThr AlaGlyGly LysTyrGly ValAlaHis ValVal SerGlu Val AsnTrp LysAspTyr CysIleLeu PheSerSer AspTyr IleThr Ser LeuPro AspLeuHis HisAlaPro LeuLeuPro LeuTyr AspGly Arg ThrLys ProTrpCys ProGlyGlu AspSerPro HisGln AlaGln Ala LeuArg ProSerGln ArgProLeu ArgGlnThr ThrAla MetVal Ser MetArg AsnCysSer PheHisThr LysGlyTrp LeuAla GlnGly Gly GlnGly HisGlyLeu LeuIleVal SerArgVal SerAsp GlnGln Ala CysSer ThrThrLeu AlaProGln AspProArg GlnPro LeuAla Asp AspLeu IleProVal AlaMetLeu HisTyrAla AspMet LeuAsp Thr IleLeu HisThrArg GlyGluAla ValValArg ValAla MetTyr Ser AlaPro GluProIle IleAspTyr AsnMetLeu ValIle PheIle Pro Leu ValGly Ala Gly Ala Ala Thr Gly Gly Val Tyr Leu Ala Trp Thr Glu AsnArgLeu Gln Arg Arg Arg Gly Ser Ala Arg Ala Arg Gly Gly GlyGly HisHisGln LeuGlnGlu AlaAlaAla AlaGluGly Gln Ala LysGlu AspAsnG1u AspIlePro ValAspPhe ThrProAla MetThr GlyVal ValValThr LeuSerCys SerLeuMet LeuLeuLeu TyrPhe PheTyr AspHisPhe ValTyrVal ThrIleGly IlePheGly LeuGly AlaGly IleGlyLeu TyrSerCys LeuSerPro LeuValCys HisLeu SerLeu ArgGlnTyr GlnArgPro ProHisSer LeuTrpAla SerLeu ProLeu ProLeuLeu LeuLeuAla SerLeuCys AlaThrVal IleIle PheTrp ValAlaTyr ArgAsnGlu AspArgTrp AlaTrpLeu LeuGln AspThr LeuGlyIle SerTyrCys LeuPheVal LeuHisArg ValArg LeuPro ThrLeuLys AsnCysSer SerPheLeu LeuAlaLeu LeuAla PheAsp ValPhePhe ValPheVal ThrProPhe PheThrLys ThrGly GluSer IleMetAla GlnValAla LeuGlyPro AlaGluSer SerSer HisGlu ArgLeuPro MetValLeu LysValPro ArgLeuArg ValSer AlaLeu ThrLeuCys SerGlnPro PheSerIle LeuGlyPhe GlyAsp IleVal ValProGly PheLeuVal TyrCys CysArgPhe AspVal Ala GlnVal CysSerArg GlnIleTyr ValAla CysThrVal AlaTyr Phe AlaVal LeuLeu ValThrPhe Ala Val Met Gln Gly Met Met Leu Met Gly Gln Pro Ala Leu Leu Tyr Leu Val Ser Ser Thr Leu Leu Thr Ser Leu Ala Val Ala Ala Cys Arg Gln Glu Leu Ser Leu Phe Trp Thr Gly Gln Gly Arg Ala Lys Met Cys Gly Leu Gly Cys Ala Pro Ser Ala Gly Ser Arg Gln Lys Gln Glu Gly Ala Ala Asp Ala His Thr Ala Ser Thr Leu Glu Arg Gly Thr Ser Arg Gly Ala Gly Asp Leu Asp Ser Asn Pro Gly Glu Asp Thr Thr Glu Ile Val Thr Ile Ser Glu Asn Glu Ala Thr Asn Pro Glu Asp Arg Ser Asp Ser Ser Glu Gly Trp Ser Asp Ala His Leu Asp Pro Asn Glu Leu Pro Phe Ile Pro Pro Gly Ala Ser Glu Glu Leu Met Pro Leu Met Pro Met Ala Met Leu Ile Pro Leu Met Pro Leu Met Pro Pro Pro Ser Glu Leu Gly His Val His Ala Gln Ala Gln Ala His Glu Thr Gly Leu Pro Trp Ala Gly Leu His Lys Arg Lys Gly Leu Lys Val Arg Lys Ser Met Ser Thr Gln Ala Pro Leu <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 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

Claims (4)

CLAIMS:
1. A protease having two aspartate residues in a catalytically active structure, wherein a first aspartate residue resides in an X1GX2GD motif and a second aspartate residue resides in an 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 X1GX2GD and X3X4DX5 reside in a transmem-brane region.
2. The protease according to claim 1, characterized by having the sequence PALX6YX7V, wherein X6 and X7 independently have the same meaning as X1 and preferably are Leu or Ile.
3. The protease according to any of claims 1 to 2, characterized by having one of the sequences SEQ ID Nos. 1 to 8 and 18, 19.

4. Nucleic acids coding for a protease according to at least one of claims 1 to 3, preferably having SEQ ID No. 9-17 or 20.

5. Inhibitors, characterized by inhibiting the expression or activity of the protease according to any of claims 1 to 3.

6. An antibody directed against proteases according to any of claims 1 to 3.

7. A method for the identification of inhibitors, characterized in that the activity of the proteases is measured according to any of claims 1 to 3 in the pres-ence of potential inhibitors.

8. A medicament or diagnostic agent containing a protease according to any of claims 1 to 3, a nucleic acid according to claim 4, an inhibitor according to claim 5, and/or an antibody according to claim 6.

9. Use of the medicament or diagnostic agent according to claim 8 for the diagnosis or treatment of diseases which are causally related with the cleav-age of the amyloid precursor protein, especially Alzheimer's disease.

10. Use of the medicament or diagnostic agent according to claim 8 for the diagnosis or treatment of diseases which are causally related with a dis-turbed degradation of hydrophobic signal peptides.

11. Use of the medicament or diagnostic agent according to claim 8 for the diagnosis or treatment of diseases which are causally related with the accu-mulation of unfolded proteins in the endoplasmic reticulum.

12. Use of the medicament according to claim 8 for influencing the presentation of hydrophobic peptides by histocompatibility complex molecules in condi-tions such as viral infection, cancer or rejection after transplantation.

13. A cell line, characterized by not expressing any protease according to at least one of claims 1 to 3 and/or not containing any nucleic acid according to
claim 4.
CA002360585A 1999-01-22 2000-01-19 Protease Abandoned CA2360585A1 (en)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
DE19902550A DE19902550A1 (en) 1999-01-22 1999-01-22 A novel aspartate protease, coding sequence, inhibitors and antibodies, useful for treatment and diagnosis of Alzheimer's disease
DE19902550.9 1999-01-22
DE19925946 1999-06-08
DE19925946.1 1999-06-08
DE19929115 1999-06-24
DE19929115.2 1999-06-24
PCT/EP2000/000390 WO2000043505A2 (en) 1999-01-22 2000-01-19 Protease with two aspartate radicals in the catalytically active structure

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CA2360585A1 true CA2360585A1 (en) 2000-07-27

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AU (1) AU2542100A (en)
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WO (1) WO2000043505A2 (en)

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US8609087B2 (en) 1999-07-12 2013-12-17 Trustees Of Dartmouth College Compounds and methods for identifying compounds which inhibit a new class of aspartyl proteases
US6887677B1 (en) 1999-07-12 2005-05-03 Trustees Of Dartmouth College Compounds and methods for identifying compounds which inhibit a new class of aspartyl proteases
GB0126782D0 (en) * 2001-11-07 2002-01-02 Medical Res Council Assay
RU2258531C1 (en) * 2004-04-20 2005-08-20 Рогаев Евгений Иванович Protein eliciting property of intramembrane aspartate protease, method for its preparing

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US5965397A (en) * 1997-01-31 1999-10-12 Genetics Institute, Inc. Secreted proteins and polynucleotides encoding them
WO1998040404A2 (en) * 1997-03-11 1998-09-17 Genetics Institute, Inc. Secreted proteins and polynucleotides encoding them
AU8404598A (en) * 1997-07-16 1999-02-10 Human Genome Sciences, Inc. 64 human secreted proteins
JPH11187882A (en) * 1997-12-26 1999-07-13 Ono Pharmaceut Co Ltd Novel polypeptide, its production, cdna coding for the same polypeptide, vector comprising the same cdna, host cell transformed by the same vector, antibody of the same polypeptide, and pharmaceutical composition containing the polypeptide of antibody
EP1056760A4 (en) * 1998-02-26 2003-03-05 Human Genome Sciences Inc 36 human secreted proteins
AU5928899A (en) * 1998-09-23 2000-04-10 Human Genome Sciences, Inc. 31 human secreted proteins

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WO2000043505A3 (en) 2001-11-29
EP1144603A3 (en) 2002-02-06

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