Enzyme assay for mutant firefly luciferase

Enzymes and methods suitable for assaying ATP, and specific application for such assays are described and claimed. In particular, there is described a recombinant mutant luciferase having a mutation for example, in the amino-acid corresponding to amino acid residue number 245 in Photinus pyralis, is such that the K.sub.m for ATP of the luciferase is increased e.g. five-fold with respect to that of the corresponding non-mutated enzyme such that it is of the order of 500 .mu.m-1 mM. Also disclosed are luciferases having additional mutations conferring improved thermostability or altered wavelength of emitted light. Recombinant polynucleotides, vectors and host cells are also disclosed, as are methods of assaying the amount of ATP in a material (e.g. cells) optionally in real-time. Also disclosed are test-kits for in vitro assays.

TECHNICAL FIELD
 The present invention relates broadly to enzymes and methods suitable for
 assaying ATP. It further relates to specific applications for such assays.
 BACKGROUND ART
 Intracellular ATP concentrations can vary 10-fold or more depending upon a
 cell's state of health or developmental stage. It is of great value to be
 able to measure fluctuations in intracellular ATP levels as a means of
 investigating e.g. the effects of drugs, toxins, hormones, environmental
 agents or disease on cells.
 There is apparently at present no convenient method for analysing the
 concentration of ATP in vivo. For instance, in Dementieva et al (1996)
 Biochemistry (Moscow) Vol 61, No. 7., the intracellular concentration of
 ATP was measured in E. coli by calculating the total amount of ATP present
 using a recombinant luciferase, and dividing by an estimated total cell
 volume.
 Such an indirect approach can at best produce only an estimate of the
 actual ATP concentration.
 The measurement of ATP concentration in cells has also been performed using
 an in vitro coupled assay, such as that disclosed in the Sigma Diagnostic
 Kit Catalog No. 366, in which Phosphoglycerate kinase is used to convert
 3-phosphoglycerate to 1,3 diphosphoglycerate in an [ATP]-dependent
 fashion. The 1,3 diphosphoglycerate is then converted to
 glyceraldehyde-3-P concommitantly with conversion of NADH to NAD, which
 can be monitored spectroscopically. The assay has a dynamic range up to 1
 mM; the expected range is 380-620 .mu.m when used with blood cells.
 However it can be seen that, as with all coupled assays, the test is
 inevitably cumbersome to perform. Additionally it could not readily be
 adapted for in vivo use. It would thus be a contribution to the art to
 provide materials and methods which overcome some of the drawbacks of the
 prior art.
 DISCLOSURE OF THE INVENTION
 In a first aspect of the invention there is provided a recombinant mutant
 luciferase having a mutation which is such that the K.sub.m for ATP of the
 luciferase is increased with respect to that of the corresponding
 non-mutated enzyme. Preferably the K.sub.m is at least double that of the
 non-mutated enzyme, and more preferably at least around five, ten, or
 twenty times higher than that of the non-mutated enzyme.
 Luciferases are, of course, already known in the art. In the presence of
 Mg.sup.2+, luciferase (originally obtained from fireflies) catalyzes the
 reaction of luciferin, ATP and O.sub.2 to form oxyluciferin, AMP,
 CO.sub.2, pyrophosphate and light. This basic property (luciferin and ATP
 to produce light) is hereinafter referred to as `luciferase activity`.
 The term `luciferase` as used in relation to the invention is intended to
 embrace all luciferases, or recombinant enzymes derived from luciferases
 which have luciferase activity. This explicitly includes recombinant
 mutant luciferases which have deletions, additions or substitutions to
 their amino acid structure provided that they retain luciferase activity.
 Such luciferases will typically have considerable homology (e.g. up to 70,
 80, 90, or 99%) with wild-type enzymes. However the crucial technical
 feature of the luciferases of the present invention which distinguishes
 them from those of the prior art is that they have a mutation which causes
 an increase in the K.sub.m for ATP of the luciferase as compared with that
 measured for a corresponding enzyme which differs only in it that it lacks
 that same mutation.
 This increase K.sub.m may be measured by the person of ordinary skill in
 the art by conventional enzyme assays, as described in more detail in the
 Examples below.
 It should be noted that in the prior art, luciferase has sometimes been
 used as a marker for gene expression (in vivo) where its production in a
 cell is linked to a particular genetic control element. Luciferin is added
 exogenously and intracellular ATP concentrations, under almost all
 conditions, will be such that the enzyme is saturated. Thus the switching
 on of gene expression is signalled by light that is emitted in a
 quantitative manner according to the amount of active luciferase that is
 generated.
 However it should be stressed that in the previously known systems it is
 generally the concentration of luciferase which is measured; this
 concentration is then correlated with a different event e.g. the
 efficiency of a promoter. Indeed it has, on occasions, been an object of
 the prior art teaching on luciferases to reduce the K.sub.m for ATP see
 e.g. WO 96/22376) which ensures that changes in the ambient [ATP] does not
 interfere with the assay.
 Similarly the assay disclosed by Dementieva et al (1996) discussed above
 requires that all of the ATP be efficiently converted to light so that the
 total ATP present can be calculated. This approach requires a low K.sub.m
 luciferase so that the enzyme operates at near maximal velocity until all
 the ATP is hydrolysed.
 By making available luciferases which have an increased K.sub.m compared
 with those already known in the art, the present inventors have for the
 first time opened up the possibility of using these enzymes to measure
 steady state ATP concentrations over range which was previously
 unsuitable. This is because, generally speaking, the relationship between
 enzyme velocity (V, as measured by light intensity) and substrate
 concentration (of ATP, where luciferin is in excess) is as follows:
 V=V.sub.m. [ATP]/K.sub.m +[ATP]
 It can therefore be seen that only when the K.sub.m is greater than (or of
 a similar order as) the ambient [ATP] will there be a degree of
 proportionality between changes in [ATP] and changes in light intensity.
 Where the K.sub.m is much less than the ambient [ATP], any changes in
 [ATP] will not tangibly effect the measured light intensity. Clearly the
 more sensitive the light detection is, the smaller the measurable changes
 in `V` can be, and the smaller the K.sub.m can be with respect to the
 [ATP] range being assessed.
 For certain applications, e.g. in vivo measurements, it may be advantageous
 to have a luciferase wherein the K.sub.m is of the order of between 400
 .mu.m to 1.4 mM e.g. 500 .mu.m, 600 .mu.m, 1 mM etc. However, as can be
 appreciated from the discussion above, the main criterion is that the
 K.sub.m is not much less than the expected [ATP] range to be assessed, and
 the phrase `of the order of` should be construed accordingly.
 A particular expected [ATP] range which is important for physiological
 assays of blood cells is between 300 .mu.m and 1 mM, or more particularly
 380 .mu.m and 620 .mu.m, (cf. Sigma Diagnostic Kit, Catalog No. 366
 discussed above). For other mammalian cells such as hepatocytes, the [ATP]
 range is 2.5 mM-6 mM (see Dementieva et al (1996) discussed above. Use of
 the recombinant luciferases of the present invention for continuous assays
 in these ranges is particularly envisaged.
 The disclosure of the present application makes such high K.sub.m
 luciferases available for the first time. The prior art disclosures reveal
 only luciferases having a K.sub.m of between 60 .mu.m and 150 .mu.m, which
 would be saturated in these ranges.
 It is also advantageous, as with all enzymes used in assays, that the
 mutant enzyme retains sufficient activity (i.e. a high maximum turnover
 number, giving a high V.sub.m) such that practical concentrations of
 enzyme can give detectable results.
 Preferably the activity for ATP of the mutant is at least 5-100% of that of
 the corresponding wild-type; however reduced-activity as a result of the
 high K.sub.m mutation can, if necessary, be compensated for by using more
 enzyme or more sensitive detection if required.
 In one embodiment of the first aspect there is disclosed a luciferase
 wherein the amino-acid corresponding to amino acid residue number 245 in
 Photinus pyralis has been substituted with respect to the corresponding
 wild-type amino acid residue such that the K.sub.m for ATP is increased
 with respect to that of the corresponding non-mutated enzyme.
 It should be noted that the sequences of a number of luciferases from
 different sources have already been published in the literature see e.g.
 WO 95/25798 for P pyralis (SEQ ID NOs:1, and 21); EP 0 524 448 for Luciola
 cruciata (SEQ ID NOs:13 and 14) and Luciola lateralis (SEQ ID NOs:15 and
 16). Other known luc genes include Luciola mingrelica (SEQ ID NOs:17 and
 18), and Lampyris noctiluca (SEQ ID NOs:19 and 20) (see Newby et al (1996)
 Biochemical J 313: 761-767.)
 Whether an amino-acid in a luciferase `corresponds` to number 245 in P
 pyralis (which is His in the wild-type, non-mutated enzyme) can be
 established by the person of ordinary skill in the art without difficulty
 as follows: the sequence of the luciferase is established (either from the
 literature or by sequencing); the sequence is aligned with P pyralis, for
 instance using commercially available software (e.g. "Bestfit" from the
 University of Wisconsin Genetics Computer Group; see Devereux et al (1984)
 Nucleic Acid Research 12: 387-395) or manually such as to demonstrate
 maximal homology and align conserved amino acids; the amino acid
 corresponding to number 245 in P pyralis is identified. An example of this
 is shown below using L cruciata--the corresponding acid in that case is
 number 247.
 Once identified a mutant can be prepared e.g. by site directed mutagenesis
 by methods commonly used in the art and exemplified below.
 Preferably corresponding amino-acid is substituted for an uncharged amino
 acid, for instance nonpolar (e.g. Ala) or uncharged polar (e.g. Asn, or
 Gln):

EXAMPLES
 EXAMPLE 1
 Production of Recombinant High K.sub.m Mutant Luciferase
 Except where otherwise stated, the methods employed were as those used by
 White et al (1996) Biochemical Journal 319: 342-350, which is concerned
 with thermostable mutants.
 STARTING MATERIALS: Mutants were generated by site directed mutagenesis of
 the plasmid pPW601a (FIG. 1) comprising the luciferase gene, luc, from P
 pyralis. The wild type luc gene from P pyralis is shown at Seq ID No. 1.
 Plasmid pPW601a was created by cloning the luc gene BamHI/SstI fragment
 from pGEM-luc (available from Promega) into pDR540 (available from
 Pharmacia). The unique XhoI site in the polylinker of the plasmid was
 removed to simplify the following procedures.
 SITE DIRECTED MUTAGENESIS: Three mutagenic oligonucleotides were used to
 create the mutations H245A, N and Q (Ala, Asn, or Gln--see Seq ID Nos. 2,
 3 & 4). The equivalent wild-type sequence is shown at Seq ID No. 5. The
 oligonucleotides also introduced a silent mutation which destroys a unique
 Xmn I site in the luc gene--this did not result in an amino acid
 substitution but facilitated mutant selection. The mutagenesis was carried
 out in accordance with the kit instructions of kit supplied by Clontech
 laboratories Inc, Palo Alto, Calif. USA.
 The amino acid sequence of H245Q is shown in Seq. ID No. 6.
 ISOLATION OF PLASMID DNA & TRANSFORMATION: this was carried out by the
 method of Brinboim & Doly (1979) Nucleic Acids Research 7: 1513.
 CELL CULTURE AND EXTRACTION: E. coli JM109 transformants were grown to an
 OD.sub.600 =1.0. Aliquots of cells expressing mutant luciferases from
 plasmid pPW601a, were subjected to lysis as described in the Promega
 technical bulletin and the lysed extracts were then stored on ice prior to
 assay.
 ASSAY OF Km OF MUTANT LUCIFERASES: luciferase assays were performed at
 21.degree. C. using 100 .mu.l of assay buffer (20 mM Tricine pH 7.8
 containing 2.0 mM MgSO.sub.4, 0.1 mM EDTA, 33 mM dithiotheitol, 470 .mu.M
 D-luciferin and ATP in the concentration range 6.25-800 .mu.M). Each assay
 contained 5-10 .mu.l of crude cell extract.
 The plots of V against [ATP] and 1/V against 1/ [ATP] for mutant H245A are
 shown in FIG. 2. Such plots kan be used to determine the K.sub.m.
 The results of each mutation and the recombinant Wild Type are shown in
 Table 1:
 TABLE 1
 Luciferase K.sub.m MgATP (.mu.M)
 r Wild Type 66
 H245A 442
 H245N 623
 H245Q 1340
 A21SL* 65
 *A215L is a thermostable mutant in which amino acid 215 is substituted with
 lysine (see WO 96/22376 - SECRETARY OF STATE FOR DEFENCE).
 ASSAY OF THERMOSTABILITY OF MUTANT LUCIFERASES: the thermostability of
 H245N & H245Q was also tested, as compared with mutant A215L and the
 wild-type. Lysed crude extracts of cells containing luciferase activity
 were incubated at 37.degree. C. for set time periods. The thermostability
 of the mutant H245A was found to be very similar to that of the
 recombinant wild-type. The results are shown in Table 2:
 TABLE 2
 Remaining activity %
 Enzyme 0 2 4 8 minutes
 r Wild 100 64.8 36.6 26.6
 Type
 A215L 100 101 88 84
 H245N 100 96 61 46
 H245Q 100 103 78.6 51.5
 PURIFICATION: luciferases, e.g. incorporating the H245Q mutation, may be
 purified as described in White et al (1996) [supra]. Briefly, the cell
 lysates are centrifuged at 30000 g for 30 mins and the supernatant is
 fractionated with ammonium sulphate (30-55%). This fraction is resuspended
 and desalted. The desalted material was passed through a hydroxyapatite
 column and eluted with 10-200 mM sodium phosphate containing
 dithiothreitol. The luciferase containing eluant is dialysed and applied
 to a Mono Q anion-exchange column. The enzyme can be eluted with 0 to 500
 mM NaCl.
 EXAMPLE 2
 Identification of Corresponding High K.sub.M Mutants
 FIG. 3. shows a sequence comparison of one region of P pyralis and the
 corresponding region of L cruciata as describe din Example 2. In this case
 it can be seen that amino acid 245 corresponds to 247.
 EXAMPLE 3
 Expression of Mutant Luciferase in Mammals
 This can be achieved by methods analogous to those disclosed by Liu et al
 (1997) Nature Biotechnology 15: 167-173. In this method cationic liposomes
 are used to deliver plasmid DNA containing luciferase a gene to mice.
 EXAMPLE 4
 An in Vivo ATP Assay in Mammals
 This can be carried out by methods analogous to those used by Contag et al
 (1995) Molecular Microbiology 18(4): 593-603. In this method luciferase
 expression in S typhimurium in mice is monitored using a CCD camera.
 EXAMPLE 5
 A Kit for an in Vitro ATP Assay
 This may be provided as follows: luciferase H245Q; buffer; or dry materials
 for preparing a buffer; ATP for standards; luciferin; and instructions for
 carrying out an ATP assay.
 EXAMPLE 6
 Assay for Determining Cell Behaviour
 Using a luciferase assay as described in Example 1, a plot of the photon
 count versus the ATP concentration was prepared for the H245N mutant. The
 results are shown in FIG. 4.
 In order to demonstrate how the enzyme of the invention can be used in
 studying cellular behaviour, a sample of recombinant E.coli cells which
 expressed the H245N mutant luciferase were rendered dormant by exhaustion
 of nutrients. The cells were charged with luciferin by 10 minutes
 immersion in p.H. 5.0 citrate buffer containing 1 mM luciferin. They were
 then centrifugally washed, resuspended in 1 ml Nutrient Broth and the
 luminescence monitored. The results are shown in FIG. 5.
 Using the mutant luciferase of the invention, the revival and growth of
 functional cells could be monitored.
 SEQUENCE LISTING
 (1) GENERAL INFORMATION:
 (iii) NUMBER OF SEQUENCES: 21
 (2) INFORMATION FOR SEQ ID NO: 1:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 1722 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: unknown
 (ii) MOLECULE TYPE: DNA (genomic)
 (iii) HYPOTHETICAL: NO
 (iv) ANTI-SENSE: NO
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: Photinus pyralis
 (ix) FEATURE:
 (A) NAME/KEY: CDS
 (B) LOCATION: 4..1653
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1
 CAAATGGAAG ACGCCAAAAA CATAAAGAAA GGCCCGGCGC CATTCTATCC TCTAGAGGAT 60
 GGAACCGCTG GAGAGCAACT GCATAAGGCT ATGAAGAGAT ACGCCCTGGT TCCTGGAACA 120
 ATTGCTTTTA CAGATGCACA TATCGAGGTG AACATCACGT ACGCGGAATA CTTCGAAATG 180
 TCCGTTCGGT TGGCAGAAGC TATGAAACGA TATGGGCTGA ATACAAATCA CAGAATCGTC 240
 GTATGCAGTG AAAACTCTCT TCAATTCTTT ATGCCGGTGT TGGGCGCGTT ATTTATCGGA 300
 GTTGCAGTTG CGCCCGCGAA CGACATTTAT AATGAACGTG AATTGCTCAA CAGTATGAAC 360
 ATTTCGCAGC CTACCGTAGT GTTTGTTTCC AAAAAGGGGT TGCAAAAAAT TTTGAACGTG 420
 CAAAAAAAAT TACCAATAAT CCAGAAAATT ATTATCATGG ATTCTAAAAC GGATTACCAG 480
 GGATTTCAGT CGATGTACAC GTTCGTCACA TCTCATCTAC CTCCCGGTTT TAATGAATAC 540
 GATTTTGTAC CAGAGTCCTT TGATCGTGAC AAAACAATTG CACTGATAAT GAATTCCTCT 600
 GGATCTACTG GGTTACCTAA GGGTGTGGCC CTTCCGCATA GAACTGCCTG CGTCAGATTC 660
 TCGCATGCCA GAGATCCTAT TTTTGGCAAT CAAATCATTC CGGATACTGC GATTTTAAGT 720
 GTTGTTCCAT TCCATCACGG TTTTGGAATG TTTACTACAC TCGGATATTT GATATGTGGA 780
 TTTCGAGTCG TCTTAATGTA TAGATTTGAA GAAGAGCTGT TTTTACGATC CCTTCAGGAT 840
 TACAAAATTC AAAGTGCGTT GCTAGTACCA ACCCTATTTT CATTCTTCGC CAAAAGCACT 900
 CTGATTGACA AATACGATTT ATCTAATTTA CACGAAATTG CTTCTGGGGG CGCACCTCTT 960
 TCGAAAGAAG TCGGGGAAGC GGTTGCAAAA CGCTTCCATC TTCCAGGGAT ACGACAAGGA 1020
 TATGGGCTCA CTGAGACTAC ATCAGCTATT CTGATTACAC CCGAGGGGGA TGATAAACCG 1080
 GGCGCGGTCG GTAAAGTTGT TCCATTTTTT GAAGCGAAGG TTGTGGATCT GGATACCGGG 1140
 AAAACGCTGG GCGTTAATCA GAGAGGCGAA TTATGTGTCA GAGGACCTAT GATTATGTCC 1200
 GGTTATGTAA ACAATCCGGA AGCGACCAAC GCCTTGATTG ACAAGGATGG ATGGCTACAT 1260
 TCTGGAGACA TAGCTTACTG GGACGAAGAC GAACACTTCT TCATAGTTGA CCGCTTGAAG 1320
 TCTTTAATTA AATACAAAGG ATATCAGGTG GCCCCCGCTG AATTGGAATC GATATTGTTA 1380
 CAACACCCCA ACATCTTCGA CGCGGGCGTG GCAGGTCTTC CCGACGATGA CGCCGGTGAA 1440
 CTTCCCGCCG CCGTTGTTGT TTTGGAGCAC GGAAAGACGA TGACGGAAAA AGAGATCGTG 1500
 GATTACGTCG CCAGTCAAGT AACAACCGCG AAAAAGTTGC GCGGAGGAGT TGTGTTTGTG 1560
 GACGAAGTAC CGAAAGGTCT TACCGGAAAA CTCGACGCAA GAAAAATCAG AGAGATCCTC 1620
 ATAAAGGCCA AGAAGGGCGG AAAGTCCAAA TTGTAAAATG TAACTGTATT CAGCGATGAC 1680
 GAAATTCTTA GCTATTGTAA TCCTCCGAGG CCTCGAGGTC GA 1722
 (2) INFORMATION FOR SEQ ID NO: 2:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 35 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2
 GTTGTTCCAT TCCATGCCGG TTTCGGAATG TTTAC 35
 (2) INFORMATION FOR SEQ ID NO: 3:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 35 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3
 GTTGTTCCAT TCCATCAGGG TTTCGGAATG TTTAC 35
 (2) INFORMATION FOR SEQ ID NO: 4:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 35 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4
 GTTGTTCCAT TCCATAACGG TTTCGGAATG TTTAC 35
 (2) INFORMATION FOR SEQ ID NO: 5:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 35 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 5
 GTTGTTCCAT TCCATCACGG TTTTGGAATG TTTAC 35
 (2) INFORMATION FOR SEQ ID NO: 6:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 550 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: unknown
 (ii) MOLECULE TYPE: protein
 (iii) HYPOTHETICAL: NO
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: Photinus pyralis
 (ix) FEATURE:
 (A) NAME/KEY: Modified-site
 (B) LOCATION: 245
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 6
 Met Glu Asp Ala Lys Asn Ile Lys Lys Gly Pro Ala Pro Phe Tyr Pro
 1 5 10 15
 Leu Glu Asp Gly Thr Ala Gly Glu Gln Leu His Lys Ala Met Lys Arg
 20 25 30
 Tyr Ala Leu Val Pro Gly Thr Ile Ala Phe Thr Asp Ala His Ile Glu
 35 40 45
 Val Asn Ile Thr Tyr Ala Glu Tyr Phe Glu Met Ser Val Arg Leu Ala
 50 55 60
 Glu Ala Met Lys Arg Tyr Gly Leu Asn Thr Asn His Arg Ile Val Val
 65 70 75 80
 Cys Ser Glu Asn Ser Leu Gln Phe Phe Met Pro Val Leu Gly Ala Leu
 85 90 95
 Phe Ile Gly Val Ala Val Ala Pro Ala Asn Asp Ile Tyr Asn Glu Arg
 100 105 110
 Glu Leu Leu Asn Ser Met Asn Ile Ser Gln Pro Thr Val Val Phe Val
 115 120 125
 Ser Lys Lys Gly Leu Gln Lys Ile Leu Asn Val Gln Lys Lys Leu Pro
 130 135 140
 Ile Ile Gln Lys Ile Ile Ile Met Asp Ser Lys Thr Asp Tyr Gln Gly
 145 150 155 160
 Phe Gln Ser Met Tyr Thr Phe Val Thr Ser His Leu Pro Pro Gly Phe
 165 170 175
 Asn Glu Tyr Asp Phe Val Pro Glu Ser Phe Asp Arg Asp Lys Thr Ile
 180 185 190
 Ala Leu Ile Met Asn Ser Ser Gly Ser Thr Gly Leu Pro Lys Gly Val
 195 200 205
 Ala Leu Pro His Arg Thr Ala Cys Val Arg Phe Ser His Ala Arg Asp
 210 215 220
 Pro Ile Phe Gly Asn Gln Ile Ile Pro Asp Thr Ala Ile Leu Ser Val
 225 230 235 240
 Val Pro Phe His Gln Gly Phe Gly Met Phe Thr Thr Leu Gly Tyr Leu
 245 250 255
 Ile Cys Gly Phe Arg Val Val Leu Met Tyr Arg Phe Glu Glu Glu Leu
 260 265 270
 Phe Leu Arg Ser Leu Gln Asp Tyr Lys Ile Gln Ser Ala Leu Leu Val
 275 280 285
 Pro Thr Leu Phe Ser Phe Phe Ala Lys Ser Thr Leu Ile Asp Lys Tyr
 290 295 300
 Asp Leu Ser Asn Leu His Glu Ile Ala Ser Gly Gly Ala Pro Leu Ser
 305 310 315 320
 Lys Glu Val Gly Glu Ala Val Ala Lys Arg Phe His Leu Pro Gly Ile
 325 330 335
 Arg Gln Gly Tyr Gly Leu Thr Glu Thr Thr Ser Ala Ile Leu Ile Thr
 340 345 350
 Pro Glu Gly Asp Asp Lys Pro Gly Ala Val Gly Lys Val Val Pro Phe
 355 360 365
 Phe Glu Ala Lys Val Val Asp Leu Asp Thr Gly Lys Thr Leu Gly Val
 370 375 380
 Asn Gln Arg Gly Glu Leu Cys Val Arg Gly Pro Met Ile Met Ser Gly
 385 390 395 400
 Tyr Val Asn Asn Pro Glu Ala Thr Asn Ala Leu Ile Asp Lys Asp Gly
 405 410 415
 Trp Leu His Ser Gly Asp Ile Ala Tyr Trp Asp Glu Asp Glu His Phe
 420 425 430
 Phe Ile Val Asp Arg Leu Lys Ser Leu Ile Lys Tyr Lys Gly Tyr Gln
 435 440 445
 Val Ala Pro Ala Glu Leu Glu Ser Ile Leu Leu Gln His Pro Asn Ile
 450 455 460
 Phe Asp Ala Gly Val Ala Gly Leu Pro Asp Asp Asp Ala Gly Glu Leu
 465 470 475 480
 Pro Ala Ala Val Val Val Leu Glu His Gly Lys Thr Met Thr Glu Lys
 485 490 495
 Glu Ile Val Asp Tyr Val Ala Ser Gln Val Thr Thr Ala Lys Lys Leu
 500 505 510
 Arg Gly Gly Val Val Phe Val Asp Glu Val Pro Lys Gly Leu Thr Gly
 515 520 525
 Lys Leu Asp Ala Arg Lys Ile Arg Glu Ile Leu Ile Lys Ala Lys Lys
 530 535 540
 Gly Gly Lys Ser Lys Leu
 545 550
 (2) INFORMATION FOR SEQ ID NO: 7:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 28 amino acids
 (B) TYPE: amino acid
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 7
 Ile Ile Pro Asp Thr Ala Ile Leu Ser Val Val Pro Phe His His Gly
 1 5 10 15
 Phe Gly Met Phe Thr Thr Leu Gly Tyr Leu Ile Cys
 20 25
 (2) INFORMATION FOR SEQ ID NO: 8:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 28 amino acids
 (B) TYPE: amino acid
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 8
 Val Ser Pro Gly Thr Ala Val Leu Thr Val Val Pro Phe His His Gly
 1 5 10 15
 Phe Gly Met Phe Thr Thr Leu Gly Tyr Leu Ile Cys
 20 25
 (2) INFORMATION FOR SEQ ID NO: 9:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 35 amino acids
 (B) TYPE: amino acid
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 9
 Ile Asp Lys Tyr Asp Leu Ser Asn Leu His Glu Ile Ala Ser Gly Gly
 1 5 10 15
 Ala Pro Leu Ser Lys Glu Val Gly Glu Ala Val Ala Lys Arg Phe His
 20 25 30
 Leu Pro Gly
 35
 (2) INFORMATION FOR SEQ ID NO: 10:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 35 amino acids
 (B) TYPE: amino acid
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 10
 Leu Asn Lys Tyr Asp Leu Ser Asn Leu Val Glu Ile Ala Ser Gly Gly
 1 5 10 15
 Ala Pro Leu Ser Lys Glu Val Gly Glu Ala Val Ala Arg Arg Phe His
 20 25 30
 Leu Pro Gly
 35
 (2) INFORMATION FOR SEQ ID NO: 11:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 40 amino acids
 (B) TYPE: amino acid
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 11
 Arg Phe His Leu Pro Gly Ile Arg Gln Gly Tyr Gly Leu Thr Glu Thr
 1 5 10 15
 Thr Ser Ala Ile Leu Ile Thr Pro Glu Gly Asp Asp Lys Pro Gly Ala
 20 25 30
 Val Gly Lys Val Val Pro Phe Phe
 35 40
 (2) INFORMATION FOR SEQ ID NO: 12:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 40 amino acids
 (B) TYPE: amino acid
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 12
 Arg Phe Asn Leu Pro Gly Val Arg Gln Gly Tyr Gly Leu Thr Glu Thr
 1 5 10 15
 Thr Ser Ala Ile Ile Ile Thr Pro Glu Gly Asp Asp Lys Pro Gly Ala
 20 25 30
 Ser Gly Lys Val Val Pro Leu Phe
 35 40
 (2) INFORMATION FOR SEQ ID NO: 13:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 1644 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (ix) FEATURE:
 (A) NAME/KEY: CDS
 (B) LOCATION: 1..1644
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 13
 ATG GAA AAC ATG GAA AAC GAT GAA AAT ATT GTA GTT GGA CCT AAA CCG 48
 Met Glu Asn Met Glu Asn Asp Glu Asn Ile Val Val Gly Pro Lys Pro
 1 5 10 15
 TTT TAC CCT ATC GAA GAG GGA TCT GCT GGA ACA CAA TTA CGC AAA TAC 96
 Phe Tyr Pro Ile Glu Glu Gly Ser Ala Gly Thr Gln Leu Arg Lys Tyr
 20 25 30
 ATG GAG CGA TAT GCA AAA CTT GGC GCA ATT GCT TTT ACA AAT GCA GTT 144
 Met Glu Arg Tyr Ala Lys Leu Gly Ala Ile Ala Phe Thr Asn Ala Val
 35 40 45
 ACT GGT GTT GAT TAT TCT TAC GCC GAA TAC TTG GAG AAA TCA TGT TGT 192
 Thr Gly Val Asp Tyr Ser Tyr Ala Glu Tyr Leu Glu Lys Ser Cys Cys
 50 55 60
 CTA GGA AAA GCT TTG CAA AAT TAT GGT TTG GTT GTT GAT GGC AGA ATT 240
 Leu Gly Lys Ala Leu Gln Asn Tyr Gly Leu Val Val Asp Gly Arg Ile
 65 70 75 80
 GCG TTA TGC AGT GAA AAC TGT GAA GAA TTT TTT ATT CCT GTA ATA GCC 288
 Ala Leu Cys Ser Glu Asn Cys Glu Glu Phe Phe Ile Pro Val Ile Ala
 85 90 95
 GGA CTG TTT ATA GGT GTA GGT GTT GCA CCC ACT AAT GAG ATT TAC ACT 336
 Gly Leu Phe Ile Gly Val Gly Val Ala Pro Thr Asn Glu Ile Tyr Thr
 100 105 110
 TTA CGT GAA CTG GTT CAC AGT TTA GGT ATC TCT AAA CCA ACA ATT GTA 384
 Leu Arg Glu Leu Val His Ser Leu Gly Ile Ser Lys Pro Thr Ile Val
 115 120 125
 TTT AGT TCT AAA AAA GGC TTA GAT AAA GTT ATA ACA GTA CAG AAA ACA 432
 Phe Ser Ser Lys Lys Gly Leu Asp Lys Val Ile Thr Val Gln Lys Thr
 130 135 140
 GTA ACT ACT ATT AAA ACC ATT GTT ATA CTA GAT AGC AAA GTT GAT TAT 480
 Val Thr Thr Ile Lys Thr Ile Val Ile Leu Asp Ser Lys Val Asp Tyr
 145 150 155 160
 CGA GGA TAT CAA TGT CTG GAC ACC TTT ATA AAA AGA AAC ACT CCA CCA 528
 Arg Gly Tyr Gln Cys Leu Asp Thr Phe Ile Lys Arg Asn Thr Pro Pro
 165 170 175
 GGT TTT CAA GCA TCC AGT TTC AAA ACT GTG GAA GTT GAC CGT AAA GAA 576
 Gly Phe Gln Ala Ser Ser Phe Lys Thr Val Glu Val Asp Arg Lys Glu
 180 185 190
 CAA GTT GCT CTT ATA ATG AAC TCT TCG GGT TCT ACC GGT TTG CCA AAA 624
 Gln Val Ala Leu Ile Met Asn Ser Ser Gly Ser Thr Gly Leu Pro Lys
 195 200 205
 GGC GTA CAA CTT ACT CAC GAA AAT ACA GTC ACT AGA TTT TCT CAT GCT 672
 Gly Val Gln Leu Thr His Glu Asn Thr Val Thr Arg Phe Ser His Ala
 210 215 220
 AGA GAT CCG ATT TAT GGT AAC CAA GTT TCA CCA GGC ACC GCT GTT TTA 720
 Arg Asp Pro Ile Tyr Gly Asn Gln Val Ser Pro Gly Thr Ala Val Leu
 225 230 235 240
 ACT GTC GTT CCA TTC CAT CAT GGT TTT GGT ATG TTC ACT ACT CTA GGG 768
 Thr Val Val Pro Phe His His Gly Phe Gly Met Phe Thr Thr Leu Gly
 245 250 255
 TAT TTA ATT TGT GGT TTT CGT GTT GTA ATG TTA ACA AAA TTC GAT GAA 816
 Tyr Leu Ile Cys Gly Phe Arg Val Val Met Leu Thr Lys Phe Asp Glu
 260 265 270
 GAA ACA TTT TTA AAA ACT CTA CAA GAT TAT AAA TGT ACA AGT GTT ATT 864
 Glu Thr Phe Leu Lys Thr Leu Gln Asp Tyr Lys Cys Thr Ser Val Ile
 275 280 285
 CTT GTA CCG ACC TTG TTT GCA ATT CTC AAC AAA AGT GAA TTA CTC AAT 912
 Leu Val Pro Thr Leu Phe Ala Ile Leu Asn Lys Ser Glu Leu Leu Asn
 290 295 300
 AAA TAC GAT TTG TCA AAT TTA GTT GAG ATT GCA TCT GGC GGA GCA CCT 960
 Lys Tyr Asp Leu Ser Asn Leu Val Glu Ile Ala Ser Gly Gly Ala Pro
 305 310 315 320
 TTA TCA AAA GAA GTT GGT GAA GCT GTT GCT AGA CGC TTT AAT CTT CCC 1008
 Leu Ser Lys Glu Val Gly Glu Ala Val Ala Arg Arg Phe Asn Leu Pro
 325 330 335
 GGT GTT CGT CAA GGT TAT GGT TTA ACA GAA ACA ACA TCT GCC ATT ATT 1056
 Gly Val Arg Gln Gly Tyr Gly Leu Thr Glu Thr Thr Ser Ala Ile Ile
 340 345 350
 ATT ACA CCA GAA GGA GAC GAT AAA CCA GGA GCT TCT GGA AAA GTC GTG 1104
 Ile Thr Pro Glu Gly Asp Asp Lys Pro Gly Ala Ser Gly Lys Val Val
 355 360 365
 CCG TTG TTT AAA GCA AAA GTT ATT GAT CTT GAT ACC AAA AAA TCT TTA 1152
 Pro Leu Phe Lys Ala Lys Val Ile Asp Leu Asp Thr Lys Lys Ser Leu
 370 375 380
 GGT CCT AAC AGA CGT GGA GAA GTT TGT GTT AAA GGA CCT ATG CTT ATG 1200
 Gly Pro Asn Arg Arg Gly Glu Val Cys Val Lys Gly Pro Met Leu Met
 385 390 395 400
 AAA GGT TAT GTA AAT AAT CCA GAA GCA ACA AAA GAA CTT ATT GAC GAA 1248
 Lys Gly Tyr Val Asn Asn Pro Glu Ala Thr Lys Glu Leu Ile Asp Glu
 405 410 415
 GAA GGT TGG CTG CAC ACC GGA GAT ATT GGA TAT TAT GAT GAA GAA AAA 1296
 Glu Gly Trp Leu His Thr Gly Asp Ile Gly Tyr Tyr Asp Glu Glu Lys
 420 425 430
 CAT TTC TTT ATT GTC GAT CGT TTG AAG TCT TTA ATC AAA TAC AAA GGA 1344
 His Phe Phe Ile Val Asp Arg Leu Lys Ser Leu Ile Lys Tyr Lys Gly
 435 440 445
 TAC CAA GTA CCA CCT GCC GAA TTA GAA TCC GTT CTT TTG CAA CAT CCA 1392
 Tyr Gln Val Pro Pro Ala Glu Leu Glu Ser Val Leu Leu Gln His Pro
 450 455 460
 TCT ATC TTT GAT GCT GGT GTT GCC GGC GTT CCT GAT CCT GTA GCT GGC 1440
 Ser Ile Phe Asp Ala Gly Val Ala Gly Val Pro Asp Pro Val Ala Gly
 465 470 475 480
 GAG CTT CCA GGA GCC GTT GTT GTA CTG GAA AGC GGA AAA AAT ATG ACC 1488
 Glu Leu Pro Gly Ala Val Val Val Leu Glu Ser Gly Lys Asn Met Thr
 485 490 495
 GAA AAA GAA GTA ATG GAT TAT GTT GCA AGT CAA GTT TCA AAT GCA AAA 1536
 Glu Lys Glu Val Met Asp Tyr Val Ala Ser Gln Val Ser Asn Ala Lys
 500 505 510
 CGT TTA CGT GGT GGT GTT CGT TTT GTG GAT GAA GTA CCT AAA GGT CTT 1584
 Arg Leu Arg Gly Gly Val Arg Phe Val Asp Glu Val Pro Lys Gly Leu
 515 520 525
 ACT GGA AAA ATT GAC GGC AGA GCA ATT AGA GAA ATC CTT AAG AAA CCA 1632
 Thr Gly Lys Ile Asp Gly Arg Ala Ile Arg Glu Ile Leu Lys Lys Pro
 530 535 540
 GTT GCT AAG ATG 1644
 Val Ala Lys Met
 545
 (2) INFORMATION FOR SEQ ID NO: 14:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 548 amino acids
 (B) TYPE: amino acid
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 14
 Met Glu Asn Met Glu Asn Asp Glu Asn Ile Val Val Gly Pro Lys Pro
 1 5 10 15
 Phe Tyr Pro Ile Glu Glu Gly Ser Ala Gly Thr Gln Leu Arg Lys Tyr
 20 25 30
 Met Glu Arg Tyr Ala Lys Leu Gly Ala Ile Ala Phe Thr Asn Ala Val
 35 40 45
 Thr Gly Val Asp Tyr Ser Tyr Ala Glu Tyr Leu Glu Lys Ser Cys Cys
 50 55 60
 Leu Gly Lys Ala Leu Gln Asn Tyr Gly Leu Val Val Asp Gly Arg Ile
 65 70 75 80
 Ala Leu Cys Ser Glu Asn Cys Glu Glu Phe Phe Ile Pro Val Ile Ala
 85 90 95
 Gly Leu Phe Ile Gly Val Gly Val Ala Pro Thr Asn Glu Ile Tyr Thr
 100 105 110
 Leu Arg Glu Leu Val His Ser Leu Gly Ile Ser Lys Pro Thr Ile Val
 115 120 125
 Phe Ser Ser Lys Lys Gly Leu Asp Lys Val Ile Thr Val Gln Lys Thr
 130 135 140
 Val Thr Thr Ile Lys Thr Ile Val Ile Leu Asp Ser Lys Val Asp Tyr
 145 150 155 160
 Arg Gly Tyr Gln Cys Leu Asp Thr Phe Ile Lys Arg Asn Thr Pro Pro
 165 170 175
 Gly Phe Gln Ala Ser Ser Phe Lys Thr Val Glu Val Asp Arg Lys Glu
 180 185 190
 Gln Val Ala Leu Ile Met Asn Ser Ser Gly Ser Thr Gly Leu Pro Lys
 195 200 205
 Gly Val Gln Leu Thr His Glu Asn Thr Val Thr Arg Phe Ser His Ala
 210 215 220
 Arg Asp Pro Ile Tyr Gly Asn Gln Val Ser Pro Gly Thr Ala Val Leu
 225 230 235 240
 Thr Val Val Pro Phe His His Gly Phe Gly Met Phe Thr Thr Leu Gly
 245 250 255
 Tyr Leu Ile Cys Gly Phe Arg Val Val Met Leu Thr Lys Phe Asp Glu
 260 265 270
 Glu Thr Phe Leu Lys Thr Leu Gln Asp Tyr Lys Cys Thr Ser Val Ile
 275 280 285
 Leu Val Pro Thr Leu Phe Ala Ile Leu Asn Lys Ser Glu Leu Leu Asn
 290 295 300
 Lys Tyr Asp Leu Ser Asn Leu Val Glu Ile Ala Ser Gly Gly Ala Pro
 305 310 315 320
 Leu Ser Lys Glu Val Gly Glu Ala Val Ala Arg Arg Phe Asn Leu Pro
 325 330 335
 Gly Val Arg Gln Gly Tyr Gly Leu Thr Glu Thr Thr Ser Ala Ile Ile
 340 345 350
 Ile Thr Pro Glu Gly Asp Asp Lys Pro Gly Ala Ser Gly Lys Val Val
 355 360 365
 Pro Leu Phe Lys Ala Lys Val Ile Asp Leu Asp Thr Lys Lys Ser Leu
 370 375 380
 Gly Pro Asn Arg Arg Gly Glu Val Cys Val Lys Gly Pro Met Leu Met
 385 390 395 400
 Lys Gly Tyr Val Asn Asn Pro Glu Ala Thr Lys Glu Leu Ile Asp Glu
 405 410 415
 Glu Gly Trp Leu His Thr Gly Asp Ile Gly Tyr Tyr Asp Glu Glu Lys
 420 425 430
 His Phe Phe Ile Val Asp Arg Leu Lys Ser Leu Ile Lys Tyr Lys Gly
 435 440 445
 Tyr Gln Val Pro Pro Ala Glu Leu Glu Ser Val Leu Leu Gln His Pro
 450 455 460
 Ser Ile Phe Asp Ala Gly Val Ala Gly Val Pro Asp Pro Val Ala Gly
 465 470 475 480
 Glu Leu Pro Gly Ala Val Val Val Leu Glu Ser Gly Lys Asn Met Thr
 485 490 495
 Glu Lys Glu Val Met Asp Tyr Val Ala Ser Gln Val Ser Asn Ala Lys
 500 505 510
 Arg Leu Arg Gly Gly Val Arg Phe Val Asp Glu Val Pro Lys Gly Leu
 515 520 525
 Thr Gly Lys Ile Asp Gly Arg Ala Ile Arg Glu Ile Leu Lys Lys Pro
 530 535 540
 Val Ala Lys Met
 545
 (2) INFORMATION FOR SEQ ID NO: 15:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 1644 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: both
 (D) TOPOLOGY: both
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (ix) FEATURE:
 (A) NAME/KEY: CDS
 (B) LOCATION: 1..1644
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 15
 ATG GAA AAC ATG GAG AAC GAT GAA AAT ATT GTG TAT GGT CCT GAA CCA 48
 Met Glu Asn Met Glu Asn Asp Glu Asn Ile Val Tyr Gly Pro Glu Pro
 1 5 10 15
 TTT TAC CCT ATT GAA GAG GGA TCT GCT GGA GCA CAA TTG CGC AAG TAT 96
 Phe Tyr Pro Ile Glu Glu Gly Ser Ala Gly Ala Gln Leu Arg Lys Tyr
 20 25 30
 ATG GAT CGA TAT GCA AAA CTT GGA GCA ATT GCT TTT ACT AAC GCA CTT 144
 Met Asp Arg Tyr Ala Lys Leu Gly Ala Ile Ala Phe Thr Asn Ala Leu
 35 40 45
 ACC GGT GTC GAT TAT ACG TAC GCC GAA TAC TTA GAA AAA TCA TGC TGT 192
 Thr Gly Val Asp Tyr Thr Tyr Ala Glu Tyr Leu Glu Lys Ser Cys Cys
 50 55 60
 CTA GGA GAG GCT TTA AAG AAT TAT GGT TTG GTT GTT GAT GGA AGA ATT 240
 Leu Gly Glu Ala Leu Lys Asn Tyr Gly Leu Val Val Asp Gly Arg Ile
 65 70 75 80
 GCG TTA TGC AGT GAA AAC TGT GAA GAA TTC TTT ATT CCT GTA TTA GCC 288
 Ala Leu Cys Ser Glu Asn Cys Glu Glu Phe Phe Ile Pro Val Leu Ala
 85 90 95
 GGT TTA TTT ATA GGT GTC GGT GTG GCT CCA ACT AAT GAG ATT TAC ACT 336
 Gly Leu Phe Ile Gly Val Gly Val Ala Pro Thr Asn Glu Ile Tyr Thr
 100 105 110
 CTA CGT GAA TTG GTT CAC AGT TTA GGC ATC TCT AAG CCA ACA ATT GTA 384
 Leu Arg Glu Leu Val His Ser Leu Gly Ile Ser Lys Pro Thr Ile Val
 115 120 125
 TTT AGT TCT AAA AAA GGA TTA GAT AAA GTT ATA ACT GTA CAA AAA ACG 432
 Phe Ser Ser Lys Lys Gly Leu Asp Lys Val Ile Thr Val Gln Lys Thr
 130 135 140
 GTA ACT GCT ATT AAA ACC ATT GTT ATA TTG GAC AGC AAA GTG GAT TAT 480
 Val Thr Ala Ile Lys Thr Ile Val Ile Leu Asp Ser Lys Val Asp Tyr
 145 150 155 160
 AGA GGT TAT CAA TCC ATG GAC AAC TTT ATT AAA AAA AAC ACT CCA CAA 528
 Arg Gly Tyr Gln Ser Met Asp Asn Phe Ile Lys Lys Asn Thr Pro Gln
 165 170 175
 GGT TTC AAA GGA TCA AGT TTT AAA ACT GTA GAA GTT AAC CGC AAA GAA 576
 Gly Phe Lys Gly Ser Ser Phe Lys Thr Val Glu Val Asn Arg Lys Glu
 180 185 190
 CAA GTT GCT CTT ATA ATG AAC TCT TCG GGT TCA ACC GGT TTG CCA AAA 624
 Gln Val Ala Leu Ile Met Asn Ser Ser Gly Ser Thr Gly Leu Pro Lys
 195 200 205
 GGT GTG CAA CTT ACT CAT GAA AAT GCA GTC ACT AGA TTT TCT CAC GCT 672
 Gly Val Gln Leu Thr His Glu Asn Ala Val Thr Arg Phe Ser His Ala
 210 215 220
 AGA GAT CCA ATT TAT GGA AAC CAA GTT TCA CCA GGC ACG GCT ATT TTA 720
 Arg Asp Pro Ile Tyr Gly Asn Gln Val Ser Pro Gly Thr Ala Ile Leu
 225 230 235 240
 ACT GTA GTA CCA TTC CAT CAT GGT TTT GGT ATG TTT ACT ACT TTA GGC 768
 Thr Val Val Pro Phe His His Gly Phe Gly Met Phe Thr Thr Leu Gly
 245 250 255
 TAT CTA ACT TGT GGT TTT CGT ATT GTC ATG TTA ACG AAA TTT GAC GAA 816
 Tyr Leu Thr Cys Gly Phe Arg Ile Val Met Leu Thr Lys Phe Asp Glu
 260 265 270
 GAG ACT TTT TTA AAA ACA CTG CAA GAT TAC AAA TGT TCA AGC GTT ATT 864
 Glu Thr Phe Leu Lys Thr Leu Gln Asp Tyr Lys Cys Ser Ser Val Ile
 275 280 285
 CTT GTA CCG ACT TTG TTT GCA ATT CTT AAT AGA AGT GAA TTA CTC GAT 912
 Leu Val Pro Thr Leu Phe Ala Ile Leu Asn Arg Ser Glu Leu Leu Asp
 290 295 300
 AAA TAT GAT TTA TCA AAT TTA GTT GAA ATT GCA TCT GGC GGA GCA CCT 960
 Lys Tyr Asp Leu Ser Asn Leu Val Glu Ile Ala Ser Gly Gly Ala Pro
 305 310 315 320
 TTA TCT AAA GAA ATT GGT GAA GCT GTT GCT AGA CGT TTT AAT TTA CCG 1008
 Leu Ser Lys Glu Ile Gly Glu Ala Val Ala Arg Arg Phe Asn Leu Pro
 325 330 335
 GGT GTT CGT CAA GGC TAT GGT TTA ACA GAA ACA ACC TCT GCA ATT ATT 1056
 Gly Val Arg Gln Gly Tyr Gly Leu Thr Glu Thr Thr Ser Ala Ile Ile
 340 345 350
 ATC ACA CCG GAA GGC GAT GAT AAA CCA GGT GCT TCT GGC AAA GTT GTG 1104
 Ile Thr Pro Glu Gly Asp Asp Lys Pro Gly Ala Ser Gly Lys Val Val
 355 360 365
 CCA TTA TTT AAA GCA AAA GTT ATC GAT CTT GAT ACT AAA AAA ACT TTG 1152
 Pro Leu Phe Lys Ala Lys Val Ile Asp Leu Asp Thr Lys Lys Thr Leu
 370 375 380
 GGC CCG AAC AGA CGT GGA GAA GTT TGT GTA AAG GGT CCT ATG CTT ATG 1200
 Gly Pro Asn Arg Arg Gly Glu Val Cys Val Lys Gly Pro Met Leu Met
 385 390 395 400
 AAA GGT TAT GTA GAT AAT CCA GAA GCA ACA AGA GAA ATC ATA GAT GAA 1248
 Lys Gly Tyr Val Asp Asn Pro Glu Ala Thr Arg Glu Ile Ile Asp Glu
 405 410 415
 GAA GGT TGG TTG CAC ACA GGA GAT ATT GGG TAT TAC GAT GAA GAA AAA 1296
 Glu Gly Trp Leu His Thr Gly Asp Ile Gly Tyr Tyr Asp Glu Glu Lys
 420 425 430
 CAT TTC TTT ATC GTG GAT CGT TTG AAG TCT TTA ATC AAA TAC AAA GGA 1344
 His Phe Phe Ile Val Asp Arg Leu Lys Ser Leu Ile Lys Tyr Lys Gly
 435 440 445
 TAT CAA GTA CCA CCT GCT GAA TTA GAA TCT GTT CTT TTG CAA CAT CCA 1392
 Tyr Gln Val Pro Pro Ala Glu Leu Glu Ser Val Leu Leu Gln His Pro
 450 455 460
 AAT ATT TTT GAT GCC GGC GTT GCT GGC GTT CCA GAT CCT ATA GCT GGT 1440
 Asn Ile Phe Asp Ala Gly Val Ala Gly Val Pro Asp Pro Ile Ala Gly
 465 470 475 480
 GAG CTT CCG GGA GCT GTT GTT GTA CTT GAA AAA GGA AAA TCT ATG ACT 1488
 Glu Leu Pro Gly Ala Val Val Val Leu Glu Lys Gly Lys Ser Met Thr
 485 490 495
 GAA AAA GAA GTA ATG GAT TAC GTT GCT AGT CAA GTT TCA AAT GCA AAA 1536
 Glu Lys Glu Val Met Asp Tyr Val Ala Ser Gln Val Ser Asn Ala Lys
 500 505 510
 CGT TTG CGT GGT GGT GTC CGT TTT GTG GAC GAA GTA CCT AAA GGT CTC 1584
 Arg Leu Arg Gly Gly Val Arg Phe Val Asp Glu Val Pro Lys Gly Leu
 515 520 525
 ACT GGT AAA ATT GAC GGT AAA GCA ATT AGA GAA ATA CTG AAG AAA CCA 1632
 Thr Gly Lys Ile Asp Gly Lys Ala Ile Arg Glu Ile Leu Lys Lys Pro
 530 535 540
 GTT GCT AAG ATG 1644
 Val Ala Lys Met
 545
 (2) INFORMATION FOR SEQ ID NO: 16:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 548 amino acids
 (B) TYPE: amino acid
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 16
 Met Glu Asn Met Glu Asn Asp Glu Asn Ile Val Tyr Gly Pro Glu Pro
 1 5 10 15
 Phe Tyr Pro Ile Glu Glu Gly Ser Ala Gly Ala Gln Leu Arg Lys Tyr
 20 25 30
 Met Asp Arg Tyr Ala Lys Leu Gly Ala Ile Ala Phe Thr Asn Ala Leu
 35 40 45
 Thr Gly Val Asp Tyr Thr Tyr Ala Glu Tyr Leu Glu Lys Ser Cys Cys
 50 55 60
 Leu Gly Glu Ala Leu Lys Asn Tyr Gly Leu Val Val Asp Gly Arg Ile
 65 70 75 80
 Ala Leu Cys Ser Glu Asn Cys Glu Glu Phe Phe Ile Pro Val Leu Ala
 85 90 95
 Gly Leu Phe Ile Gly Val Gly Val Ala Pro Thr Asn Glu Ile Tyr Thr
 100 105 110
 Leu Arg Glu Leu Val His Ser Leu Gly Ile Ser Lys Pro Thr Ile Val
 115 120 125
 Phe Ser Ser Lys Lys Gly Leu Asp Lys Val Ile Thr Val Gln Lys Thr
 130 135 140
 Val Thr Ala Ile Lys Thr Ile Val Ile Leu Asp Ser Lys Val Asp Tyr
 145 150 155 160
 Arg Gly Tyr Gln Ser Met Asp Asn Phe Ile Lys Lys Asn Thr Pro Gln
 165 170 175
 Gly Phe Lys Gly Ser Ser Phe Lys Thr Val Glu Val Asn Arg Lys Glu
 180 185 190
 Gln Val Ala Leu Ile Met Asn Ser Ser Gly Ser Thr Gly Leu Pro Lys
 195 200 205
 Gly Val Gln Leu Thr His Glu Asn Ala Val Thr Arg Phe Ser His Ala
 210 215 220
 Arg Asp Pro Ile Tyr Gly Asn Gln Val Ser Pro Gly Thr Ala Ile Leu
 225 230 235 240
 Thr Val Val Pro Phe His His Gly Phe Gly Met Phe Thr Thr Leu Gly
 245 250 255
 Tyr Leu Thr Cys Gly Phe Arg Ile Val Met Leu Thr Lys Phe Asp Glu
 260 265 270
 Glu Thr Phe Leu Lys Thr Leu Gln Asp Tyr Lys Cys Ser Ser Val Ile
 275 280 285
 Leu Val Pro Thr Leu Phe Ala Ile Leu Asn Arg Ser Glu Leu Leu Asp
 290 295 300
 Lys Tyr Asp Leu Ser Asn Leu Val Glu Ile Ala Ser Gly Gly Ala Pro
 305 310 315 320
 Leu Ser Lys Glu Ile Gly Glu Ala Val Ala Arg Arg Phe Asn Leu Pro
 325 330 335
 Gly Val Arg Gln Gly Tyr Gly Leu Thr Glu Thr Thr Ser Ala Ile Ile
 340 345 350
 Ile Thr Pro Glu Gly Asp Asp Lys Pro Gly Ala Ser Gly Lys Val Val
 355 360 365
 Pro Leu Phe Lys Ala Lys Val Ile Asp Leu Asp Thr Lys Lys Thr Leu
 370 375 380
 Gly Pro Asn Arg Arg Gly Glu Val Cys Val Lys Gly Pro Met Leu Met
 385 390 395 400
 Lys Gly Tyr Val Asp Asn Pro Glu Ala Thr Arg Glu Ile Ile Asp Glu
 405 410 415
 Glu Gly Trp Leu His Thr Gly Asp Ile Gly Tyr Tyr Asp Glu Glu Lys
 420 425 430
 His Phe Phe Ile Val Asp Arg Leu Lys Ser Leu Ile Lys Tyr Lys Gly
 435 440 445
 Tyr Gln Val Pro Pro Ala Glu Leu Glu Ser Val Leu Leu Gln His Pro
 450 455 460
 Asn Ile Phe Asp Ala Gly Val Ala Gly Val Pro Asp Pro Ile Ala Gly
 465 470 475 480
 Glu Leu Pro Gly Ala Val Val Val Leu Glu Lys Gly Lys Ser Met Thr
 485 490 495
 Glu Lys Glu Val Met Asp Tyr Val Ala Ser Gln Val Ser Asn Ala Lys
 500 505 510
 Arg Leu Arg Gly Gly Val Arg Phe Val Asp Glu Val Pro Lys Gly Leu
 515 520 525
 Thr Gly Lys Ile Asp Gly Lys Ala Ile Arg Glu Ile Leu Lys Lys Pro
 530 535 540
 Val Ala Lys Met
 545
 (2) INFORMATION FOR SEQ ID NO: 17:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 2009 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: both
 (D) TOPOLOGY: both
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (ix) FEATURE:
 (A) NAME/KEY: CDS
 (B) LOCATION: 69..1715
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 17
 GGAATTCGGC ACGAGGTTAC AATTACAACT TCGAAGTCCC TAAACGGTAG AGGAAAAGTT 60
 TTTGAAAA ATG GAA ATG GAA AAG GAG GAG AAT GTT GTA TAT GGC CCT CTG 110
 Met Glu Met Glu Lys Glu Glu Asn Val Val Tyr Gly Pro Leu
 1 5 10
 CCA TTC TAC CCC ATT GAA GAA GGA TCA GCT GGA ATT CAG TTG CAT AAG 158
 Pro Phe Tyr Pro Ile Glu Glu Gly Ser Ala Gly Ile Gln Leu His Lys
 15 20 25 30
 TAC ATG CAT CAA TAT GCC AAA CTT GGA GCA ATT GCT TTT AGT AAC GCC 206
 Tyr Met His Gln Tyr Ala Lys Leu Gly Ala Ile Ala Phe Ser Asn Ala
 35 40 45
 CTT ACT GGA GTT GAC ATT TCT TAC CAA GAA TAC TTT GAT ATT ACA TGT 254
 Leu Thr Gly Val Asp Ile Ser Tyr Gln Glu Tyr Phe Asp Ile Thr Cys
 50 55 60
 CGT TTA GCT GAG GCC ATG AAA AAC TTT GGT ATG AAA CCG GAA GAA CAT 302
 Arg Leu Ala Glu Ala Met Lys Asn Phe Gly Met Lys Pro Glu Glu His
 65 70 75
 ATT GCT TTG TGC AGT GAA AAT TGT GAA GAA TTT TTC ATC CCT GTA CTT 350
 Ile Ala Leu Cys Ser Glu Asn Cys Glu Glu Phe Phe Ile Pro Val Leu
 80 85 90
 GCT GGT CTT TAC ATT GGG GTA GCT GTT GCA CCT ACT AAT GAA ATT TAC 398
 Ala Gly Leu Tyr Ile Gly Val Ala Val Ala Pro Thr Asn Glu Ile Tyr
 95 100 105 110
 ACA TTG CGT GAA CTT AAT CAT AGT TTG GGC ATC GCA CAA CCA ACT ATT 446
 Thr Leu Arg Glu Leu Asn His Ser Leu Gly Ile Ala Gln Pro Thr Ile
 115 120 125
 GTA TTC AGC TCC AGA AAA GGC TTA CCT AAA GTT TTA GAA GTG CAA AAA 494
 Val Phe Ser Ser Arg Lys Gly Leu Pro Lys Val Leu Glu Val Gln Lys
 130 135 140
 ACA GTT ACA TGC ATC AAA AAA ATT GTT ATT TTA GAT AGT AAA GTA AAC 542
 Thr Val Thr Cys Ile Lys Lys Ile Val Ile Leu Asp Ser Lys Val Asn
 145 150 155
 TTT GGG GGC CAC GAT TGT ATG GAA ACT TTT ATT AAG AAA CAT GTA GAA 590
 Phe Gly Gly His Asp Cys Met Glu Thr Phe Ile Lys Lys His Val Glu
 160 165 170
 TTA GGT TTT CAA CCA AGT AGC TTT GTA CCC ATT GAT GTA AAG AAC CGT 638
 Leu Gly Phe Gln Pro Ser Ser Phe Val Pro Ile Asp Val Lys Asn Arg
 175 180 185 190
 AAA CAA CAC GTT GCT TTG CTT ATG AAT TCT TCT GGC TCT ACT GGT TTA 686
 Lys Gln His Val Ala Leu Leu Met Asn Ser Ser Gly Ser Thr Gly Leu
 195 200 205
 CCT AAA GGT GTA CGA ATT ACC CAC GAA GGT GCA GTT ACA AGA TTC TCA 734
 Pro Lys Gly Val Arg Ile Thr His Glu Gly Ala Val Thr Arg Phe Ser
 210 215 220
 CAC GCT AAG GAT CCA ATT TAC GGA AAC CAA GTT TCA CCT GGT ACT GCT 782
 His Ala Lys Asp Pro Ile Tyr Gly Asn Gln Val Ser Pro Gly Thr Ala
 225 230 235
 ATT TTA ACT GTC GTT CCG TTC CAT CAT GGA TTT GGA ATG TTT ACC ACT 830
 Ile Leu Thr Val Val Pro Phe His His Gly Phe Gly Met Phe Thr Thr
 240 245 250
 TTA GGA TAC TTT GCT TGT GGA TAC CGT GTT GTA ATG TTA ACA AAA TTT 878
 Leu Gly Tyr Phe Ala Cys Gly Tyr Arg Val Val Met Leu Thr Lys Phe
 255 260 265 270
 GAT GAA GAA CTA TTT TTG AGA ACT TTG CAA GAT TAT AAG TGT ACC AGT 926
 Asp Glu Glu Leu Phe Leu Arg Thr Leu Gln Asp Tyr Lys Cys Thr Ser
 275 280 285
 GTT ATT CTG GTA CCA ACG TTA TTT GCT ATT CTC AAC AAG AGT GAA TTG 974
 Val Ile Leu Val Pro Thr Leu Phe Ala Ile Leu Asn Lys Ser Glu Leu
 290 295 300
 ATC GAT AAG TTC GAT TTA TCT AAT CTA ACT GAA ATT GCT TCT GGT GGA 1022
 Ile Asp Lys Phe Asp Leu Ser Asn Leu Thr Glu Ile Ala Ser Gly Gly
 305 310 315
 GCT CCT TTG GCA AAA GAA GTT GGC GAA GCA GTC GCT AGA AGA TTT AAT 1070
 Ala Pro Leu Ala Lys Glu Val Gly Glu Ala Val Ala Arg Arg Phe Asn
 320 325 330
 CTA CCC GGT GTC CGT CAG GGT TAC GGA TTA ACA GAA ACG ACA TCT GCA 1118
 Leu Pro Gly Val Arg Gln Gly Tyr Gly Leu Thr Glu Thr Thr Ser Ala
 335 340 345 350
 TTT ATT ATT ACC CCA GAA GGT GAT GAT AAA CCT GGA GCA TCT GGA AAA 1166
 Phe Ile Ile Thr Pro Glu Gly Asp Asp Lys Pro Gly Ala Ser Gly Lys
 355 360 365
 GTA GTA CCC TTA TTC AAA GTA AAA GTT ATT GAT CTT GAC ACT AAA AAA 1214
 Val Val Pro Leu Phe Lys Val Lys Val Ile Asp Leu Asp Thr Lys Lys
 370 375 380
 ACT TTG GGT GTC AAC CGA CGA GGA GAG ATC TGT GTA AAA GGA CCC AGT 1262
 Thr Leu Gly Val Asn Arg Arg Gly Glu Ile Cys Val Lys Gly Pro Ser
 385 390 395
 CTT ATG TTA GGC TAC TCG AAC AAT CCG GAA GCA ACA AGA GAA ACT ATT 1310
 Leu Met Leu Gly Tyr Ser Asn Asn Pro Glu Ala Thr Arg Glu Thr Ile
 400 405 410
 GAT GAA GAG GGT TGG TTG CAC ACA GGA GAT ATT GGA TAT TAC GAC GAA 1358
 Asp Glu Glu Gly Trp Leu His Thr Gly Asp Ile Gly Tyr Tyr Asp Glu
 415 420 425 430
 GAC GAA CAT TTC TTC ATT GTC GAT CGT TTG AAA TCA TTA ATC AAA TAC 1406
 Asp Glu His Phe Phe Ile Val Asp Arg Leu Lys Ser Leu Ile Lys Tyr
 435 440 445
 AAG GGG TAC CAG GTA CCA CCT GCT GAA TTG GAA TCC GTT CTT TTG CAA 1454
 Lys Gly Tyr Gln Val Pro Pro Ala Glu Leu Glu Ser Val Leu Leu Gln
 450 455 460
 CAT CCA AAT ATA TTT GAT GCT GGT GTG GCT GGT GTC CCC GAT CCC GAT 1502
 His Pro Asn Ile Phe Asp Ala Gly Val Ala Gly Val Pro Asp Pro Asp
 465 470 475
 GCT GGC GAA CTT CCA GGG GCT GTA GTT GTA ATG GAA AAA GGA AAA ACT 1550
 Ala Gly Glu Leu Pro Gly Ala Val Val Val Met Glu Lys Gly Lys Thr
 480 485 490
 ATG ACT GAA AAG GAA ATT GTG GAT TAT GTT AAT AGT CAA GTA GTG AAC 1598
 Met Thr Glu Lys Glu Ile Val Asp Tyr Val Asn Ser Gln Val Val Asn
 495 500 505 510
 CAC AAA CGT CTG CGT GGT GGC GTT CGT TTT GTG GAT GAA GTA CCT AAA 1646
 His Lys Arg Leu Arg Gly Gly Val Arg Phe Val Asp Glu Val Pro Lys
 515 520 525
 GGT CTA ACT GGT AAA ATT GAT GCT AAA GTA ATT AGA GAA ATT CTT AAG 1694
 Gly Leu Thr Gly Lys Ile Asp Ala Lys Val Ile Arg Glu Ile Leu Lys
 530 535 540
 AAA CCA CAA GCC AAG ATG TAAATCAGTC AAAATGCTAT TCATGTAACT 1742
 Lys Pro Gln Ala Lys Met
 545
 AAACTACTCA TAAGAAGACA ATTTAAAATT AAGTCATTAC ACACTTAGTG TTATATCTCA 1802
 AAAGTAGTGG GAGTTTGACA TTTATCTCAA TAATTTATCG AATGGATGCT TGTATTAGTT 1862
 TCTTATTGTT AATTATAGCT TTAAAGAACG ACTCCTTTAA TATATATTTA CTTGCATTCC 1922
 AATGGTTATA TTGTAACGGG CACGTTTCCC TGATATGTGT GAAATATACG TCAATTGCAT 1982
 TATTAAAAAA AAAAAAAAAA AAAAAAA 2009
 (2) INFORMATION FOR SEQ ID NO: 18:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 548 amino acids
 (B) TYPE: amino acid
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 18
 Met Glu Met Glu Lys Glu Glu Asn Val Val Tyr Gly Pro Leu Pro Phe
 1 5 10 15
 Tyr Pro Ile Glu Glu Gly Ser Ala Gly Ile Gln Leu His Lys Tyr Met
 20 25 30
 His Gln Tyr Ala Lys Leu Gly Ala Ile Ala Phe Ser Asn Ala Leu Thr
 35 40 45
 Gly Val Asp Ile Ser Tyr Gln Glu Tyr Phe Asp Ile Thr Cys Arg Leu
 50 55 60
 Ala Glu Ala Met Lys Asn Phe Gly Met Lys Pro Glu Glu His Ile Ala
 65 70 75 80
 Leu Cys Ser Glu Asn Cys Glu Glu Phe Phe Ile Pro Val Leu Ala Gly
 85 90 95
 Leu Tyr Ile Gly Val Ala Val Ala Pro Thr Asn Glu Ile Tyr Thr Leu
 100 105 110
 Arg Glu Leu Asn His Ser Leu Gly Ile Ala Gln Pro Thr Ile Val Phe
 115 120 125
 Ser Ser Arg Lys Gly Leu Pro Lys Val Leu Glu Val Gln Lys Thr Val
 130 135 140
 Thr Cys Ile Lys Lys Ile Val Ile Leu Asp Ser Lys Val Asn Phe Gly
 145 150 155 160
 Gly His Asp Cys Met Glu Thr Phe Ile Lys Lys His Val Glu Leu Gly
 165 170 175
 Phe Gln Pro Ser Ser Phe Val Pro Ile Asp Val Lys Asn Arg Lys Gln
 180 185 190
 His Val Ala Leu Leu Met Asn Ser Ser Gly Ser Thr Gly Leu Pro Lys
 195 200 205
 Gly Val Arg Ile Thr His Glu Gly Ala Val Thr Arg Phe Ser His Ala
 210 215 220
 Lys Asp Pro Ile Tyr Gly Asn Gln Val Ser Pro Gly Thr Ala Ile Leu
 225 230 235 240
 Thr Val Val Pro Phe His His Gly Phe Gly Met Phe Thr Thr Leu Gly
 245 250 255
 Tyr Phe Ala Cys Gly Tyr Arg Val Val Met Leu Thr Lys Phe Asp Glu
 260 265 270
 Glu Leu Phe Leu Arg Thr Leu Gln Asp Tyr Lys Cys Thr Ser Val Ile
 275 280 285
 Leu Val Pro Thr Leu Phe Ala Ile Leu Asn Lys Ser Glu Leu Ile Asp
 290 295 300
 Lys Phe Asp Leu Ser Asn Leu Thr Glu Ile Ala Ser Gly Gly Ala Pro
 305 310 315 320
 Leu Ala Lys Glu Val Gly Glu Ala Val Ala Arg Arg Phe Asn Leu Pro
 325 330 335
 Gly Val Arg Gln Gly Tyr Gly Leu Thr Glu Thr Thr Ser Ala Phe Ile
 340 345 350
 Ile Thr Pro Glu Gly Asp Asp Lys Pro Gly Ala Ser Gly Lys Val Val
 355 360 365
 Pro Leu Phe Lys Val Lys Val Ile Asp Leu Asp Thr Lys Lys Thr Leu
 370 375 380
 Gly Val Asn Arg Arg Gly Glu Ile Cys Val Lys Gly Pro Ser Leu Met
 385 390 395 400
 Leu Gly Tyr Ser Asn Asn Pro Glu Ala Thr Arg Glu Thr Ile Asp Glu
 405 410 415
 Glu Gly Trp Leu His Thr Gly Asp Ile Gly Tyr Tyr Asp Glu Asp Glu
 420 425 430
 His Phe Phe Ile Val Asp Arg Leu Lys Ser Leu Ile Lys Tyr Lys Gly
 435 440 445
 Tyr Gln Val Pro Pro Ala Glu Leu Glu Ser Val Leu Leu Gln His Pro
 450 455 460
 Asn Ile Phe Asp Ala Gly Val Ala Gly Val Pro Asp Pro Asp Ala Gly
 465 470 475 480
 Glu Leu Pro Gly Ala Val Val Val Met Glu Lys Gly Lys Thr Met Thr
 485 490 495
 Glu Lys Glu Ile Val Asp Tyr Val Asn Ser Gln Val Val Asn His Lys
 500 505 510
 Arg Leu Arg Gly Gly Val Arg Phe Val Asp Glu Val Pro Lys Gly Leu
 515 520 525
 Thr Gly Lys Ile Asp Ala Lys Val Ile Arg Glu Ile Leu Lys Lys Pro
 530 535 540
 Gln Ala Lys Met
 545
 (2) INFORMATION FOR SEQ ID NO: 19:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 1725 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: both
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (ix) FEATURE:
 (A) NAME/KEY: CDS
 (B) LOCATION: 32..1675
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 19
 GAGACACTAA CGCGCTAATA TCATTGCAAG A ATG GAA GAT GCA AAA AAT ATT 52
 Met Glu Asp Ala Lys Asn Ile
 1 5
 ATG CAC GGT CCA GCG CCA TTC TAT CCT TTG GAG GAT GGA ACT GCT GGA 100
 Met His Gly Pro Ala Pro Phe Tyr Pro Leu Glu Asp Gly Thr Ala Gly
 10 15 20
 GAA CAA TTG CAC AAA GCA ATG AAG AGG TAT GCA CAG GTT CCA GGG ACA 148
 Glu Gln Leu His Lys Ala Met Lys Arg Tyr Ala Gln Val Pro Gly Thr
 25 30 35
 ATT GCT TTT ACT GAT GCG CAT GCA GAG GTA AAT ATT ACA TAT TCC GAA 196
 Ile Ala Phe Thr Asp Ala His Ala Glu Val Asn Ile Thr Tyr Ser Glu
 40 45 50 55
 TAT TTT GAA ATG GCT TGC CGG TTA GCC GAA ACT ATG AAG AGG TAC GGA 244
 Tyr Phe Glu Met Ala Cys Arg Leu Ala Glu Thr Met Lys Arg Tyr Gly
 60 65 70
 CTT GGT TTA CAA CAC CAC ATT GCT GTT TGT AGC GAA AAT TCT CTT CAG 292
 Leu Gly Leu Gln His His Ile Ala Val Cys Ser Glu Asn Ser Leu Gln
 75 80 85
 TTT TTT ATG CCT GTA TGC GGG GCT CTA TTT ATT GGA GTT GGA GTT GCA 340
 Phe Phe Met Pro Val Cys Gly Ala Leu Phe Ile Gly Val Gly Val Ala
 90 95 100
 TCA ACA AAT GAT ATT TAC AAT GAA CGT GAA TTA TAC AAC AGT TTG TCC 388
 Ser Thr Asn Asp Ile Tyr Asn Glu Arg Glu Leu Tyr Asn Ser Leu Ser
 105 110 115
 ATA TCA CAA CCT ACA ATA GTA TCC TGT TCC AAA AGA GCG CTG CAA AAA 436
 Ile Ser Gln Pro Thr Ile Val Ser Cys Ser Lys Arg Ala Leu Gln Lys
 120 125 130 135
 ATC CTA GGG GTA CAA AAG AAA TTA CCT ATA ATT CAG AAA ATT GTT ATT 484
 Ile Leu Gly Val Gln Lys Lys Leu Pro Ile Ile Gln Lys Ile Val Ile
 140 145 150
 CTG GAT TCT CGA GAG GAT TAT ATG GGG AAA CAA TCT ATG TAC TCG TTC 532
 Leu Asp Ser Arg Glu Asp Tyr Met Gly Lys Gln Ser Met Tyr Ser Phe
 155 160 165
 ATT GAA TCT CAT TTA CCT GCA GGT TTT AAT GAA TAT GAT TAC ATA CCG 580
 Ile Glu Ser His Leu Pro Ala Gly Phe Asn Glu Tyr Asp Tyr Ile Pro
 170 175 180
 GAT TCA TTT GAC CGC GAA ACA GCA ACA GCA CTT ATA ATG AAT TCA TCG 628
 Asp Ser Phe Asp Arg Glu Thr Ala Thr Ala Leu Ile Met Asn Ser Ser
 185 190 195
 GGA TCT ACT GGA TTG CCC AAG GGA GTT GAG CTT ACT CAC CAA AAT GTG 676
 Gly Ser Thr Gly Leu Pro Lys Gly Val Glu Leu Thr His Gln Asn Val
 200 205 210 215
 TGT GTT AGA TTT TCT CAC TGC AGA GAT CCT GTG TTT GGT AAT CAA ATT 724
 Cys Val Arg Phe Ser His Cys Arg Asp Pro Val Phe Gly Asn Gln Ile
 220 225 230
 ATT CCC GAT ACT GCG ATT TTA ACA GTT ATA CCA TTT CAT CAT GGT TTT 772
 Ile Pro Asp Thr Ala Ile Leu Thr Val Ile Pro Phe His His Gly Phe
 235 240 245
 GGA ATG TTT ACA ACA CTA GGA TAT TTA ACG TGT GGA TTT CGT ATT GTG 820
 Gly Met Phe Thr Thr Leu Gly Tyr Leu Thr Cys Gly Phe Arg Ile Val
 250 255 260
 CTT ATG TAT AGA TTT GAA GAG GAA TTA TTT TTA CGA TCA CTT CAA GAT 868
 Leu Met Tyr Arg Phe Glu Glu Glu Leu Phe Leu Arg Ser Leu Gln Asp
 265 270 275
 TAT AAA ATT CAA AGT GCG TTG CTG GTA CCT ACT CTA TTT TCA TTC TTT 916
 Tyr Lys Ile Gln Ser Ala Leu Leu Val Pro Thr Leu Phe Ser Phe Phe
 280 285 290 295
 GCC AAA AGC ACC TTA GTC GAT AAA TAC GAT TTA TCC AAC TTA CAT GAA 964
 Ala Lys Ser Thr Leu Val Asp Lys Tyr Asp Leu Ser Asn Leu His Glu
 300 305 310
 ATT GCG TCT GGT GGA GCT CCC CTC GCG AAA GAA GTT GGA GAA GCT GTA 1012
 Ile Ala Ser Gly Gly Ala Pro Leu Ala Lys Glu Val Gly Glu Ala Val
 315 320 325
 GCA AAA CGT TTT AAG CTG CCG GGA ATA CGA CAA GGG TAT GGA CTT ACT 1060
 Ala Lys Arg Phe Lys Leu Pro Gly Ile Arg Gln Gly Tyr Gly Leu Thr
 330 335 340
 GAA ACT ACC TCA GCT ATT ATA ATT ACA CCA GAA GGG GAT GAT AAA CCA 1108
 Glu Thr Thr Ser Ala Ile Ile Ile Thr Pro Glu Gly Asp Asp Lys Pro
 345 350 355
 GGA GCA TGT GGT AAA GTT GTT CCA TTC TTT TCT GCC AAA ATT GTT GAT 1156
 Gly Ala Cys Gly Lys Val Val Pro Phe Phe Ser Ala Lys Ile Val Asp
 360 365 370 375
 CTG GAT ACG GGT AAA ACT TTG GGT GTT AAT CAG AGG GGG GAA TTA TGT 1204
 Leu Asp Thr Gly Lys Thr Leu Gly Val Asn Gln Arg Gly Glu Leu Cys
 380 385 390
 GTG AAA GGC CCA ATG ATA ATG AAG GGT TAC GTA AAC AAC CCA GAA GCA 1252
 Val Lys Gly Pro Met Ile Met Lys Gly Tyr Val Asn Asn Pro Glu Ala
 395 400 405
 ACA AGT GCA TTG ATA GAC AAA GAT GGT TGG TTA CAC TCT GGT GAC ATA 1300
 Thr Ser Ala Leu Ile Asp Lys Asp Gly Trp Leu His Ser Gly Asp Ile
 410 415 420
 GCT TAC TAC GAC AAA GAT GGT CAC TTC TTC ATA GTA GAT CGT TTG AAA 1348
 Ala Tyr Tyr Asp Lys Asp Gly His Phe Phe Ile Val Asp Arg Leu Lys
 425 430 435
 TCG TTA ATT AAA TAC AAA GGT TAT CAG GTA CCG CCT GCC GAA TTA GAA 1396
 Ser Leu Ile Lys Tyr Lys Gly Tyr Gln Val Pro Pro Ala Glu Leu Glu
 440 445 450 455
 TCG ATA TTG CTG CAA CAT CCC TTC ATA TTT GAT GCA GGT GTT GCA GGA 1444
 Ser Ile Leu Leu Gln His Pro Phe Ile Phe Asp Ala Gly Val Ala Gly
 460 465 470
 ATT CCC GAC CCA GAT GCC GGT GAA CTT CCT GCA GCC GTT GTT GTC TTA 1492
 Ile Pro Asp Pro Asp Ala Gly Glu Leu Pro Ala Ala Val Val Val Leu
 475 480 485
 GAG GAA GGC AAA ACG ATG ACT GAA CAA GAA GTG ATG GAT TAT GTT GCG 1540
 Glu Glu Gly Lys Thr Met Thr Glu Gln Glu Val Met Asp Tyr Val Ala
 490 495 500
 GGA CAA GTA ACT GCT TCT AAG CGT TTA CGT GGA GGA GTT AAG TTT GTG 1588
 Gly Gln Val Thr Ala Ser Lys Arg Leu Arg Gly Gly Val Lys Phe Val
 505 510 515
 GAC GAA GTA CCT AAA GGT CTA ACT GGA AAG ATT GAT GGA AGA AAA ATC 1636
 Asp Glu Val Pro Lys Gly Leu Thr Gly Lys Ile Asp Gly Arg Lys Ile
 520 525 530 535
 AGG GAG ATC CTT ATG ATG GGA AAA AAA TCC AAA TTG TAATTCCTTC 1682
 Arg Glu Ile Leu Met Met Gly Lys Lys Ser Lys Leu
 540 545
 GGTTTACTAT ATTCTAACGA AATTTCTACT ACCATAAACA ATC 1725
 (2) INFORMATION FOR SEQ ID NO: 20:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 547 amino acids
 (B) TYPE: amino acid
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 20
 Met Glu Asp Ala Lys Asn Ile Met His Gly Pro Ala Pro Phe Tyr Pro
 1 5 10 15
 Leu Glu Asp Gly Thr Ala Gly Glu Gln Leu His Lys Ala Met Lys Arg
 20 25 30
 Tyr Ala Gln Val Pro Gly Thr Ile Ala Phe Thr Asp Ala His Ala Glu
 35 40 45
 Val Asn Ile Thr Tyr Ser Glu Tyr Phe Glu Met Ala Cys Arg Leu Ala
 50 55 60
 Glu Thr Met Lys Arg Tyr Gly Leu Gly Leu Gln His His Ile Ala Val
 65 70 75 80
 Cys Ser Glu Asn Ser Leu Gln Phe Phe Met Pro Val Cys Gly Ala Leu
 85 90 95
 Phe Ile Gly Val Gly Val Ala Ser Thr Asn Asp Ile Tyr Asn Glu Arg
 100 105 110
 Glu Leu Tyr Asn Ser Leu Ser Ile Ser Gln Pro Thr Ile Val Ser Cys
 115 120 125
 Ser Lys Arg Ala Leu Gln Lys Ile Leu Gly Val Gln Lys Lys Leu Pro
 130 135 140
 Ile Ile Gln Lys Ile Val Ile Leu Asp Ser Arg Glu Asp Tyr Met Gly
 145 150 155 160
 Lys Gln Ser Met Tyr Ser Phe Ile Glu Ser His Leu Pro Ala Gly Phe
 165 170 175
 Asn Glu Tyr Asp Tyr Ile Pro Asp Ser Phe Asp Arg Glu Thr Ala Thr
 180 185 190
 Ala Leu Ile Met Asn Ser Ser Gly Ser Thr Gly Leu Pro Lys Gly Val
 195 200 205
 Glu Leu Thr His Gln Asn Val Cys Val Arg Phe Ser His Cys Arg Asp
 210 215 220
 Pro Val Phe Gly Asn Gln Ile Ile Pro Asp Thr Ala Ile Leu Thr Val
 225 230 235 240
 Ile Pro Phe His His Gly Phe Gly Met Phe Thr Thr Leu Gly Tyr Leu
 245 250 255
 Thr Cys Gly Phe Arg Ile Val Leu Met Tyr Arg Phe Glu Glu Glu Leu
 260 265 270
 Phe Leu Arg Ser Leu Gln Asp Tyr Lys Ile Gln Ser Ala Leu Leu Val
 275 280 285
 Pro Thr Leu Phe Ser Phe Phe Ala Lys Ser Thr Leu Val Asp Lys Tyr
 290 295 300
 Asp Leu Ser Asn Leu His Glu Ile Ala Ser Gly Gly Ala Pro Leu Ala
 305 310 315 320
 Lys Glu Val Gly Glu Ala Val Ala Lys Arg Phe Lys Leu Pro Gly Ile
 325 330 335
 Arg Gln Gly Tyr Gly Leu Thr Glu Thr Thr Ser Ala Ile Ile Ile Thr
 340 345 350
 Pro Glu Gly Asp Asp Lys Pro Gly Ala Cys Gly Lys Val Val Pro Phe
 355 360 365
 Phe Ser Ala Lys Ile Val Asp Leu Asp Thr Gly Lys Thr Leu Gly Val
 370 375 380
 Asn Gln Arg Gly Glu Leu Cys Val Lys Gly Pro Met Ile Met Lys Gly
 385 390 395 400
 Tyr Val Asn Asn Pro Glu Ala Thr Ser Ala Leu Ile Asp Lys Asp Gly
 405 410 415
 Trp Leu His Ser Gly Asp Ile Ala Tyr Tyr Asp Lys Asp Gly His Phe
 420 425 430
 Phe Ile Val Asp Arg Leu Lys Ser Leu Ile Lys Tyr Lys Gly Tyr Gln
 435 440 445
 Val Pro Pro Ala Glu Leu Glu Ser Ile Leu Leu Gln His Pro Phe Ile
 450 455 460
 Phe Asp Ala Gly Val Ala Gly Ile Pro Asp Pro Asp Ala Gly Glu Leu
 465 470 475 480
 Pro Ala Ala Val Val Val Leu Glu Glu Gly Lys Thr Met Thr Glu Gln
 485 490 495
 Glu Val Met Asp Tyr Val Ala Gly Gln Val Thr Ala Ser Lys Arg Leu
 500 505 510
 Arg Gly Gly Val Lys Phe Val Asp Glu Val Pro Lys Gly Leu Thr Gly
 515 520 525
 Lys Ile Asp Gly Arg Lys Ile Arg Glu Ile Leu Met Met Gly Lys Lys
 530 535 540
 Ser Lys Leu
 545
 (2) INFORMATION FOR SEQ ID NO: 21:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 550 amino acids
 (B) TYPE: amino acid
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 21
 Met Glu Asp Ala Lys Asn Ile Lys Lys Gly Pro Ala Pro Phe Tyr Pro
 1 5 10 15
 Leu Glu Asp Gly Thr Ala Gly Glu Gln Leu His Lys Ala Met Lys Arg
 20 25 30
 Tyr Ala Leu Val Pro Gly Thr Ile Ala Phe Thr Asp Ala His Ile Glu
 35 40 45
 Val Asn Ile Thr Tyr Ala Glu Tyr Phe Glu Met Ser Val Arg Leu Ala
 50 55 60
 Glu Ala Met Lys Arg Tyr Gly Leu Asn Thr Asn His Arg Ile Val Val
 65 70 75 80
 Cys Ser Glu Asn Ser Leu Gln Phe Phe Met Pro Val Leu Gly Ala Leu
 85 90 95
 Phe Ile Gly Val Ala Val Ala Pro Ala Asn Asp Ile Tyr Asn Glu Arg
 100 105 110
 Glu Leu Leu Asn Ser Met Asn Ile Ser Gln Pro Thr Val Val Phe Val
 115 120 125
 Ser Lys Lys Gly Leu Gln Lys Ile Leu Asn Val Gln Lys Lys Leu Pro
 130 135 140
 Ile Ile Gln Lys Ile Ile Ile Met Asp Ser Lys Thr Asp Tyr Gln Gly
 145 150 155 160
 Phe Gln Ser Met Tyr Thr Phe Val Thr Ser His Leu Pro Pro Gly Phe
 165 170 175
 Asn Glu Tyr Asp Phe Val Pro Glu Ser Phe Asp Arg Asp Lys Thr Ile
 180 185 190
 Ala Leu Ile Met Asn Ser Ser Gly Ser Thr Gly Leu Pro Lys Gly Val
 195 200 205
 Ala Leu Pro His Arg Thr Ala Cys Val Arg Phe Ser His Ala Arg Asp
 210 215 220
 Pro Ile Phe Gly Asn Gln Ile Ile Pro Asp Thr Ala Ile Leu Ser Val
 225 230 235 240
 Val Pro Phe His His Gly Phe Gly Met Phe Thr Thr Leu Gly Tyr Leu
 245 250 255
 Ile Cys Gly Phe Arg Val Val Leu Met Tyr Arg Phe Glu Glu Glu Leu
 260 265 270
 Phe Leu Arg Ser Leu Gln Asp Tyr Lys Ile Gln Ser Ala Leu Leu Val
 275 280 285
 Pro Thr Leu Phe Ser Phe Phe Ala Lys Ser Thr Leu Ile Asp Lys Tyr
 290 295 300
 Asp Leu Ser Asn Leu His Glu Ile Ala Ser Gly Gly Ala Pro Leu Ser
 305 310 315 320
 Lys Glu Val Gly Glu Ala Val Ala Lys Arg Phe His Leu Pro Gly Ile
 325 330 335
 Arg Gln Gly Tyr Gly Leu Thr Glu Thr Thr Ser Ala Ile Leu Ile Thr
 340 345 350
 Pro Glu Gly Asp Asp Lys Pro Gly Ala Val Gly Lys Val Val Pro Phe
 355 360 365
 Phe Glu Ala Lys Val Val Asp Leu Asp Thr Gly Lys Thr Leu Gly Val
 370 375 380
 Asn Gln Arg Gly Glu Leu Cys Val Arg Gly Pro Met Ile Met Ser Gly
 385 390 395 400
 Tyr Val Asn Asn Pro Glu Ala Thr Asn Ala Leu Ile Asp Lys Asp Gly
 405 410 415
 Trp Leu His Ser Gly Asp Ile Ala Tyr Trp Asp Glu Asp Glu His Phe
 420 425 430
 Phe Ile Val Asp Arg Leu Lys Ser Leu Ile Lys Tyr Lys Gly Tyr Gln
 435 440 445
 Val Ala Pro Ala Glu Leu Glu Ser Ile Leu Leu Gln His Pro Asn Ile
 450 455 460
 Phe Asp Ala Gly Val Ala Gly Leu Pro Asp Asp Asp Ala Gly Glu Leu
 465 470 475 480
 Pro Ala Ala Val Val Val Leu Glu His Gly Lys Thr Met Thr Glu Lys
 485 490 495
 Glu Ile Val Asp Tyr Val Ala Ser Gln Val Thr Thr Ala Lys Lys Leu
 500 505 510
 Arg Gly Gly Val Val Phe Val Asp Glu Val Pro Lys Gly Leu Thr Gly
 515 520 525
 Lys Leu Asp Ala Arg Lys Ile Arg Glu Ile Leu Ile Lys Ala Lys Lys
 530 535 540
 Gly Gly Lys Ser Lys Leu
 545 550