MXPA00003774A - Human receptor proteins;related reagents and methods - Google Patents

Abstract

Nucleic acids encoding mammalian, e.g., human receptors, purified receptor proteins and fragments thereof. Antibodies, both polyclonal and monoclonal, are also provided. Methods of using the compositions for both diagnostic and therapeutic utilities are provided.

Description

HUMAN RECEPTOR PROTEINS: REAGENTS AND RELATED METHODS The present invention relates to compositions and methods for affecting the physiology of the mammal, including for example, the morphogenesis or function of the immune system. In particular, it provides nucleic acids, proteins and antibodies, for example, that regulate the development and / or the immune system together with the reagents and related methods. The diagnosis and therapeutic uses of these materials are also described.

BACKGROUND OF THE INVENTION Recombinant DNA technology generally refers to the comprehensive genetic information techniques of a donor source in vectors for subsequent processing, such as, for example, by introduction into a host, where the transferred genetic information is copied and / or expressed in the new environment. Commonly, genetic information exists in the form of a complementary DNA (cDNA) derived from the coding of messenger RNA (mRNA) for the product of the desired polypeptide. The vehicle is often a plasmid that has the ability to incorporate the _DNA for further replication and / or expression in a host and, in some cases, actually to control the expression of the cDNA and thus direct the synthesis of the product encoded in the host.

For some time, it was believed that the immunological response of the mammal is based on a series of complex cellular interactions, called the "immune network". Recent research has provided new knowledge in the compartment of this network. While it is still clear that most of the immune response does, in fact, revolve around the network-like interactions of lymphocytes, macrophages, granulocytes, and other cells, immunologists now generally take the view that soluble proteins known as lymphokines , cytokines or monocins, play a critical role in controlling these cellular interactions. Thus, there is considerable interest in the isolation, characterization and mechanisms of action of cellular modulatory factors, whose understanding leads to significant advances in the diagnosis and therapy of numerous abnormalities of medicine, for example, disorders of the immune system. Lymphokines apparently mediate cellular activities in a variety of ways. They have been shown to support the proliferation, growth and / or differentiation of pluripotent hematopoietic stem cells in a vast number of progenitors comprising the various cell lineages that make up a complex immune system. Adequate and balanced interactions between cellular components are necessary to obtain a healthy immune response. Different cell lineages often respond differently when lymphokines are administered together with other agents. Cell lineages especially important for the immune response include two classes of lymphocytes: B cells, which can produce and secrete immunoglobulins (proteins with the ability to recognition and binding to foreign matter to perform its removal), and T cells of several subsets that secrete lymphokines and induce or suppress B cells and several other cells (including other T cells) that make up the immune network. These lymphocytes interact with many other types of cells. Another important cell lineage is the barley cell (which has not been positively identified in all mammalian species), which is a connective tissue cell containing granules located near the capillaries throughout the body. These cells are found especially in high concentrations in the lungs, the skin and the gastrointestinal and genitourinary tracts. Mast cells play a central role in joy-related disorders, particularly in anaphylaxis as follows: when the selected antigens cross-link a class of immunoglobulins bound to the receptors on the surface of the barley cell, the barley cell is degranulated and releases mediators, for example, histamine, serotonin, heparin and prostaglandins, which cause allergic reactions, for example, anaphylaxis. Research to better understand and treat the various immune disorders has been impaired by the general inability to maintain the cells of the immune system in vitro. Immunologists have found that culturing many of these cells can be achieved through the use of the T cell and other cell supernatants, which contain several growth factors, including many of the lymphokines. The interleukin-1 family of proteins includes IL-1a, IL-1β, IL-1 RA, and recently IL-1? (Also designated as the Interferon-Gamma Inductor Factor, IGIF). This related family of genes has been implicated in a wide range of biological functions. See Dinarello (1994) FASEB J. 8.1314-1325; Dinarello (1991) Blood 77: 1627-1652; and Okamura et al., (1995) Nature 378: 88-91. From the above, it is evident that the discovery and development of the new soluble proteins and their receptors, which include those similar to lymphokines, should contribute with the new therapies. A number of degenerative or abnormal conditions directly or indirectly include the development, differentiation or function, for example, of the immune system and / or hematopoietic cells. In particular, the discovery and understanding of new receptors for lymphokine-like molecules that promote or enhance the beneficial activities of other lymphokines should be highly advantageous. The present invention provides new receptors for ligands that exhibit similarity to interleukin-1 type compositions and related compounds and methods for using them.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to new receptors related to IL-1 receptors and their biological activities. These receptors, for example, primate or rodent, are designated molecular structures of the IL-1 receptor type, IL-1 Receptor DNAX designation 8 (IL-1 RD8), IL-1 receptor DNAX designation 9 (IL-1 RD9) and IL-1 Receptor DNAX designation 10 (IL-1 RD10). The invention includes the nucleic acids encoding the same polypeptides and the methods for their production and use. The nucleic acids of the invention are characterized, in part, by their homology to the cloned complementary DNA sequences (cDNA) included herein. In certain embodiments, the invention provides a composition of matter selected from the group of: an isolated or recombinant IL-1 RD8 polypeptide comprising a segment of at least 12 contiguous amino acids of the Nr ID of Sec: 2 or 4, an IL- polypeptide 1 RD8 of natural sequence comprising the Nr ID of Sec: 2 or 4, a fusion protein comprising an IL-1 RD8 sequence; an isolated or recombinant IL-1 RD9 polypeptide comprising at least 12 contiguous amino acids of the Nr ID of Sec: 6, 8, 10, 12, 14, or 16; a natural sequence IL-1 RD9 comprising the Nr ID of Sec: 6, 8, 10, 12, 14, or 16; a fusion protein comprising the sequence IL-1 RD9; an isolated or recombinant IL-1 RD10 polypeptide comprising at least 12 contiguous amino acids of the Nr ID of Sec: 18 or 20; a natural sequence IL-1 RD10 comprising the Nr ID of Sec: 18 or 20: and a fusion protein comprising the sequence IL-1 RD10. In various embodiments, the recombinant or isolated polypeptide comprises a segment identical to the corresponding portion of an IL-1 RD8, as described, where: the amount of contiguous amino acid residues is: at least 17 amino acids; at least 21 amino acids; or at least 25 amino acids; or a corresponding portion of an IL-1 RD9, as described, where the amount of identical contiguous amino acid residues is: at least 17 amino acids; at least 21 amino acids; or at least 25 amino acids; or of an IL-1 RD10, as described above, where the amount of identical contiguous amino acid residues is: at least 17 amino acids; at least 21 amino acids; or at least 25 amino acids. In the embodiments of the polypeptide, the invention provides a composition of matter in which the IL-1 RD8 comprises a mature sequence illustrated in the Nr ID of Sec: 2 or 4; an IL-1 RD9 comprising a mature sequence illustrated in the Nr ID of Sec: 6, 8, 10, 12, 14, or 16; an IL-1 RD10 comprising a mature sequence illustrated in the Nr ID of Sec: 18 or 20; or the IL-1 RD8, IL-1 RD9 or IL-1 RD10 polypeptide: is from a warm-blooded animal, eg, a primate such as, for example, a human; comprising at least one segment of the polypeptide of the Nr ID of Sec: 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20; displays a number of portions that have segments identical to the specific sequence identifiers; is a natural allelic variant of a primate IL-1 RD8; an IL-1 RD9 of primate or rodent; or an IL-1 RD10 primate; it has a length of at least about 30 amino acids, exhibits at least two non-overlapping epitopes that are specific for: a primate IL-1 RD8, a primate or rodent IL-1 RD9, or primate IL-1 RD10; exhibits a sequence identity in a length of at least about 20 amino acids with respect to: a primate IL-1 RD8, a primate or rodent IL-1 RD9, or a primate IL-1 RD10; has a molecular weight of at least 100 kD with natural glycosylation; it is a synthetic polypeptide: it is bound to a solid substrate: it is combined with another chemical portion; it is a substitution of five times or less of a natural sequence; or it is a variant of elimination or insertion of a natural sequence. Certain preferred embodiments include compositions comprising: a polypeptide IL-1 RD8, 1L-1 RD9, or sterile IL-1 RD10; or the IL-1 RD8, IL-1 RD9, or IL-RD10 polypeptide and a vehicle, wherein the carrier is: an aqueous compound including water, saline and / or a pH regulator; and / or is formulated for oral, rectal, nasal, topical or parenteral administration; an IL-1 RD8, IL-1 RD9, or sterile IL-1 RD10 polypeptide: or the IL-1 RD8, IL-1 RD9, or IL-1 RD10 polypeptide, as described above, and a vehicle where the carrier is : an aqueous compound that includes water, saline and / or pH regulator; and / or formulated for oral, rectal, nasal, topical or parenteral administration. Certain fusion proteins are provided, for example, comprising: a mature polypeptide sequence illustrated in the Nr ID of Sec: 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20; a detection or purification marker, including a FLAG, His6, or Ig sequence; or a sequence of another receptor protein. Modes of the kit (kit) include a kit comprising this type of polypeptide, and: a compartment comprising the polypeptide; and / or the instructions for using or discarding the reagents in the kit. In embodiments of the binding compound, the invention provides a binding compound comprising an antigen binding site of an antibody, which specifically binds to a natural polypeptide: a polypeptide IL-1 RD8, IL-1 RD9, or IL -1 RD10 where: the polypeptide is a primate or rodent protein; the linking compound is an Fv, Fab or Fab2 fragment; the linking compound is combined with another chemical portion; or the antibody: it develops from a polypeptide sequence of a mature polypeptide comprising a sequence illustrated in the Nr ID of Sec: 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20; it develops from an IL-1 RD8 mature primate or rodent; it develops from a purified human IL-1 RD8; it develops from a purified mouse IL-1 RD9; he is immunoselected; it is a polyclonal antibody; binds to an IL-1 RD8, IL-1 RD9, or denatured IL-1 RD10, exhibits a Kd to the antigen of at least 30 μM; it is attached to a solid substrate, which includes a pearl or plastic membrane; it is in a sterile composition; or is detectably labeled, including a radioactive or fluorescent label; an IL-1 RD9 protein, where: the polypeptide is a primate or rodent protein; the linking compound is an Fv, Fab, or Fab2 fragment; the linking compound is combined with another chemical portion; or the antibody: it is developed against a polypeptide sequence of a mature polypeptide comprising a sequence sequence illustrated in the Nr ID of Sec: 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20; develops against a mature primate IL-1 RD9; develops to a purified human IL-RD9; he is immunoselected; it is a polyclonal antibody; binds to a denatured IL-1 RD9; exhibits a Kd with respect to the antigen of at least 30 μM; it is attached to a solid substrate, including a pearl or plastic membrane; is in a sterile composition, or is detectably labeled, including a radioactive or fluorescent label; the IL-1 RD10 protein, where: the polypeptide is a primate or rodent protein; the linking compound is an Fv, Fab, or Fab2 fragment; the linking compound is combined with another chemical portion; or the antibody: develops against a polypeptide sequence of a mature polypeptide comprising a sequence sequence illustrated in the Nr ID of Sec: 2, 4, 6, 8, 10, 12, 14, 16, 18 or 20; it develops against an IL-1 RD10 of mature primate; it is grown in a purified human IL-1 RD10; it is unselected; it is a polyclonal antibody; binds to a denatured IL-1 RD10; exhibits a Kd with respect to the antigen of at least 30 μM; it is attached to a solid substrate, including a pearl or plastic membrane; it is in a sterile composition; or is detectably labeled, including a radioactive or fluorescent label. Kits are provided, for example, those comprising the linking compound, and: a compartment comprising the linking compound; and / or the instructions for use or disposal of the reagents in the kit. Preferably, the kit is capable of performing a qualitative or quantitative analysis. Other embodiments include a composition comprising: a sterile binding compound, or the linking compound and a carrier, wherein the carrier is: an aqueous compound, including water, saline and / or a pH regulator; and / or is formulated for oral, rectal, nasal, topical or parenteral administration. Modalities of nucleic acid include an isolated or recombinant nucleic acid encoding a polypeptide or fusion protein, wherein: IL-1 RD8, IL-1 RD9, or IL-1 RD10 is from a mammal; said nucleic acid encodes an antigenic polypeptide sequence illustrated in the Nr ID Sec: 2, 4, 6, 8, 10, 12, 14, 16, 18 or 20; encodes a number of antigenic polypeptide sequences, sequence illustrated in the Nr ID of Sec: 2, 4, 6, 8, 10, 12, 14, 16, 18 or 20; exhibits at least about 30 nucleotides with respect to a natural cDNA encoding the segment; it is an expression vector; it also includes an origin of replication; belongs to a natural source; comprises a detectable label; comprises a synthetic nucleotide sequence; is less than 6 kb, preferably less than 3 kb, is from a mammal, including a primate; comprises a natural full-length coding sequence; is a hybridization probe for a gene encoding said IL-1 RD8, IL-1 RD9, or IL-1 RD10; it comprises a number of segments that do not overlap of at least 15, 18, 21 or 25 nucleotides illustrated in the Nr ID of Sec: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19; or is a PCR primer, PCR product, or mutagenesis primer. The invention further provides a cell comprising this recombinant nucleic acid; for example, where the cell is: a prokaryotic cell; a eukaryotic cell; a bacterial cell; a yeast cell; an insect cell; a mammalian cell; a mouse cell; a primate cell; or a human cell. Certain embodiments of the kit comprise the nucleic acid, and: a compartment comprising the nucleic acid; a compartment further comprising: an IL-1 RD8 of primate, an IL-1 RD9 of primate or rodent, or a primate IL-1 RD10 polypeptide; and / or the instructions for use or disposal of the reagents in the kit. Preferably, the kit is capable of performing a qualitative or quantitative analysis. In other embodiments of nucleic acid, the nucleic acid is one that: hybridizes under wash conditions of 40 ° C and less than 2M salt in the Nr ID of Sec: 1, 3, 5, 7, 9, 11, 13 , 15, 17, or 19; or exhibits identity of a stretch of at least about 30 nucleotides with respect to primate IL-1 RD8, an IL-1 RD9 of primate or rodent, or an IL-1 RD10 of primate. In several preferred embodiments: the washing conditions are: at 45 ° C and / or 500 mM salt; at 55 ° C and / or 150 mM salt; or the stretch is at least 55 nucleotides; or at least 75 nucleotides. Methods for modulating the physiology or development of a cell or cells for tissue culture are provided, for example, comprising contacting the cell with an agonist or antagonist of a primate IL-1 RD8, a primate IL-1 RD9 or rodent, or an IL-1 RD10 primate. Preferably, the cell is transformed with the nucleic acid encoding IL-1 RD8, IL-1 RD9, OR IL-1 RD10, and another IL-1R.

DETAILED DESCRIPTION OF THE INVENTION I. General The present invention provides the amino acid sequence and DNA sequence of a mammal, for example, primate or rodent IL-1 receptor-like molecules, this DNAX of IL-1 Receptor of molecules designation 8 (IL-1 RD8) , DNAX of the IL-1 Receptor designation 9 (IL-1 RD9) and DNAX of the IL-1 Receptor designation 10 (IL-1 RD10) having particularly defined properties, both structural and / or biological. These modalities increase the number of members of the IL-1 receptor family from 7 to at least 10. These receptors have been internally numbered with the designations DNAX D1, D2, D3, D4, D5, D6 and now D8, D9 and D10 , and are referred to as 1L-1 RD1 through D10. Several cDNAs encoding these molecules were obtained from the primate, for example, human or rodent, e.g., mouse cDNA sequence libraries. Another counterpart of the primate, rodent or other mammal would also be convenient. They describe or refer to some of the standard methods applicable for example, in Maniatis, et al. (1982) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor Press; Sambrook et al. (1989), Molecular Cloning: A Laboratory Manual, (2d ed.), Volumes 1-3, CSH Press, NY; Ausubel, et al. Biology, Greene Publishing Associates, Brooklyn, NY; o Ausubel, et al. (1987 and periodic supplements) Current Protocols in Molecular Bioloqv, Greene / Wiley, New York, each is incorporated herein for reference. A partial nucleotide and its corresponding amino acid sequence of the segment encoding human IL-1 RD8 is illustrated in the Nr Sec ID; 1 and 2, respectively. The IL-1 RD8 nucleotide of human supplementary and its corresponding sequence is provided in Sec. ID No. 3 and 4, respectively. Similarly, for primate IL-1 RD9, the partial nucleotides (Sec. No. ID: 5) and the corresponding amino acid sequences (Sec Sec. Nr: 6) of a segment encoding IL-1 RD9 are provided. of primate. The supplementary primate IL-1 RD9 is provided in the Nr ID of Sec: 7, 8, 9, and 10. The rodent modalities of IL-1 RD9 are provided in the Nr ID of Sec: 11, 12 with the rodent sequence IL-1 RD9 supplemental in the Nr ID of Sec: 13, 14, 15 and 16. For a human IL-1 RD10 modality, a partial nucleotide and its corresponding partial amino acid sequence is provided in the Nr ID of Sec: 17 and 18, respectively, with the additional human IL-1 RD10 nucleotide and its corresponding partial amino acid sequence provided in the Nr ID of Sec: 19 and 20, respectively. Some sequences provided lack some portions of these receptors, as suggested by the alignment of the sequences illustrated in tables 1-4). Note the alignment of IL-1 R10 with IL-1 RD8, and D3s, which are subunits of the alpha-type receptor. Table 4 shows the alignment of IL-1 RD9 of the primate and rodent. It is to be understood that this invention is not limited to the particular methods, compositions and receptors specifically included herein, as for example, the methods, compositions and receptors may, of course, vary. It should also be understood that the terminology used herein is for the purpose of describing only the particular embodiments, and is not intended to limit the scope of the present invention which is limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly used by those skilled in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety including figures, graphs and drawings.

TABLE 1 The alignment of the extracellular domains of several IL-1 Rs.hlL-1 RD10 is the Nr ID of Sec: 20; hlL-1 RD8 is the Nr ID of Sec: 3; mlL-1 RD3 is GenBank X85999; ML-1 RD6 is GenBank U49065; rlL-1 RD6 is GenBank U49066; mlL-1 RD4 is GenBank Y07519 and GenBank D13695; hlL-1 RD4 is GenBank D12763; ML-1 RD2 is GenBanK X59770; mlL-1 RD2 is GenBank X59769; ML-1 RD5 is GenBank U43672; mlL-1 RD5 is GenBank U43673; mlL-1 RD1 is GenBank M20658; M29752; ML-1 RD1 is GenBank X16896; clL-1 RD1 is GenBank 86325; and hFGR4 is GenBank P22455. Other counterparts of the species can be obtained from the public databases of sequences. mIL-lRD3 MGLL WYLMSLSFYG ILQSHASERC DDWLDTMR .. hIL-lRD6 M SLLLCGLSI ALPLSVTADG CKDIFMKN .. rI -lRD6 MGM PPLLFC VSF VLPLFVAAGN CTDVYMHH .. mI -lRD4 MI DRQRMG WA AILTLPMY T VTEGSKSS .. hIL-lRD4 MG FWILAILTIL MYSTAAKFSK QS hIL-l __- 2 MLRLYV LVMGVSAFTL QPAAHTGAAR SCRFRGRHYK mIL-lRD2 MFILLVLVTG VSAFTTPTW HTGKVSESPI TSEKPTVHGD NCQFRGREFK lL-lRDlO hIL-lRD5 MNCRE LPLTLWVLIS VSTAESCTSR PHITWE ... MII -lRD5 MHHEE LILTLCILIV KSASKSCIHR SQIHWE ... mLL-IRDI ME MK VLLGLICLMV PLLSLEIDVC TEYPNQIVLF hIL-IRDI MK VLLRLICFIA LLISSLEADK CKEREEKIIL cil-IRDI MHKMT STFLLIGHLI LIP FSAEE CVICNYFV V hIL-lRDß M KPPFLLALW CSWSTNLKM VSKR SVDGC IDWSVDLKTY hFGR4 ... MRLLLAL LGVLLSVPGP PVLSLEASEE VELEPCLAPS LEQQEQELTV mlL- 1RD3 QIQVFEDEPA RIKCPLFEHF LKYNYSTAHS SGLTLLWY T RQDRDLEEPI hlL- 1RD6 .EILSASQPF AFNCTFPPI TS GEVSVTWYKN ..SSKIPV rIL - 1RD6 .EMISEGQPF PFNCTYPPV TN GAVN TWHRT ..PSKSPI mlL- 1RD4 .. GLENEAL IVRCPQRG R STYPVE YYS ..DTNESI hlL- 1RD4 ..WGLENEAL IVRCPRQG K PSYTVDWYYS ..QTNKSI hlL- 1RD2 REFRLEGEPV ALRCPQVP YW LWA .... SVS PRINLTWHKN ..DSARTV mlL- 1RD2 SELRLEGEPV VLRCPLAPHS DIS SS SHSFLTWSKL ..DSSQLI hlL- 1RD10 hlL- 1RD5 -GEPFY LKHCSCSLAH The ETTTKSWYKS ... SGSQEHV mlL- TRD5 .GEPFY LKPCGISAPV HRN ETATMRWFKG ... SASHEYR mlL - 1RD1 LSV ..NEID IRKCPLTPN KM HGDTIIWYKN .... DSKTPI hIL-IRDI VSS..ANEID VRPCPLNPN E HKGTITWYKD .... DSKTPV cI -IRDI GEPT AISCPVITL PMLH SDYNLTWYRN .... GSNMPI hIL-lRD8 ..MALAGEPV RVKCALFYSY IRTNYSTAQS TG RLMWYKN ..KGDLEEPI hFGR4 .... ALGQPV RLCCGRAERG G HWYKE .... GSRLAP mIL-lRD3 NFRLP ENRI SKEKDVLWFR PTLLNDTGNY TCMLRNTTYC SKVAFPLEW hIL-lRD6 SKII. QSRI HQDETWILFL PMEWGDSGVY QCVIKGRDSC HRIHVNLTVF rIL-lRD6 SINR. HVRI HQDQSWILFL PLALEDSGIY QCVIKDAHSC YRIAINLTVF mIL-lRD4 PTQK. RNRI FVSRDRLKFL PARVEDSGIY ACVIRSPNLN KTGYLNVTIH hI -lRD4 PTQE. RNRV FASGQLLKFL PAEVADSGIY TCIVRSPTFN RTGYANVTIY hIL-lRD2 PGEE. ETRM WAQDGALWLL PALQEDSGTY VCTTRNASYC DKMSIELRVF mIL-lRD2 PRDEP ..RM WVKGNILWIL PAVQQDSGTY ICTFRNASHC EQMSVELKVF hI -IRDIO hIL-lRD5 ELNPRSSSRI ALHDCVLEFW PVELNDTGSY FFQMKN..YT QKWK NVIRR mIL-lRD5 ELNNRSSPRV TFHDHTLEFW PVEMEDEGTY ISQVGN..DR RNWTLNVTKR Rall-lRDl SADR..DSRI HQQNEHLWFV PAKVEDSGYY YCIVRNSTYC LKTKVTVTVL hI -IRDI STEQ..ASRI HQHKEKLWFV PA VEDSGHY YCWRNSSYC LRIKISAKFV cil-IRDI TTER..RARI HQRKGLLWFI PAALEDSGLY ECEVRSLNRS KQKIINLKVF hIL-lRD8 IFS ... EVRM SKEEDSIWFH SAEAQDSGFY TCVLRNSTYC MKVSMSLTVA hFGR4 AG RV RGWRGRLEIA SFLPEDAGRY LCLARGSMIV LQNLTLITGD mIL-lRD3 QK DSC FNSAMRFPVH KMYIEHGIHK hIL-IRD. EK HWCDTSIGG LP.NLSDEYK QILHLGKDDS rI -lRD6 RK HWCDSSNEE SSINSSDEYQ QWLPIGKSGS mIL-lRD KK PPSCN. IPDY.LMYS TVRGSDKNFK hIL-lRD4 KK QSDCN .VPDY.LMYS TVSGSEKNSK hIL-lRD2 IN TDA FLPFI .. SYP QILTLSTSGV mIL-lRD2 KN TEA SLPHV..SYL QISALSTTGL IL-IRDIO hIL-lRD5 NK HSC FTERQ ..VTS KIVEVKKFFQ mIL-lRD5 NK HSC FSDKL..VTS RDVEVNKSLH mlL-IRDI IN DPGIC .YSTQ.ATFP QRLHIAGDGS hIL-IRDI IN EPNLC .YNAQ.AIFK QKLPVAGDGG cI -IRDI KN DNGLC .FNGE.MKYD QIVKSANAGK hIL-lRD8 IN ESGLC. YNSR IRYL EKSEVTKRKE hFGR4 SLTSSNDDED PKSHRDPSNR HSYPQQAPYW THPQRMEKKL HAVPAGNTVK mIL-lRD3 ITCPNVDGYF. SSVKPSVT WYKGCTEIVD FHN ... VLPE GMNLSFFIPL hIL-lRD6 LTCHLHFPKS .. -CVLGPIK WYKDCNEIKG E RFT VLETRLLVSN rIL-lRD6 LTCHLYFPES ... CVLDSIK WYKGCEEIKV S KKFC PTGTKLLVNN mIL-lRD4 ITCPTIDLY. ... NWTAPVQ WFKNCKALQE P RFR AHRSYLFIDN hIL-lRD4 IYCPTIDLY. ... NWTAPLE WFKNCQALQG S RYR AHKSFLVIDN IL-lRD2 LVCPDLSEFT R.DKTDVKIQ WYKDSLLLDK DNEK..FLSV RGTTHLLVHD mIL-lRD2 LVCPDLKEFI S . SNADGKIQ WYKGAILLDK GNKE .. FLSA GDPTRLLISN hIL-IRDIO hIL-lRD5 ITCENSYYQ. ... TLVNSTS LYKNCKKLLL ENN ... -KNP TIKKNAEF .. mIL-lRD5 I CKNPNYE. ... ELIQDTW LYKNCKEISK TPRI ... LKD AEFGDAEF .. mlL-IRDI LVCPYVSYFK DENNELPEVQ WYKNCKPLLL DN .... VSFF GVKDKLLVRN hIL-IRDI LVCPYMEFFK NENNELPKLQ WYKDCKPLLL DN .... IHFS GVKDRLIVMN cIL-IRDI IICPDLENFK DEDNINPEIH WYKECKSGFL EDKR .. LVLA EGENAI IN hIL-lRD8 ISCPDMDDFK KSD.QEPDW WYKECKPKMW R SIII QKGNALLIQE hFGR4 FRCPAAG ... ... NPTPTIR WLKDGQAFHG ENRIGGIRLR HQHWSLVMES mIL-lRD3 VSNN .. GNYT CWTYPENGR LFHLTRTVTV KWGS. PKDA LPPQIYSPND hlL-lRD- VSAEDRGNYA CQAILTHSGK QYEVLNGITV SITERAGYGG SVP.KIIYPK rIL-lRD6 IDVEDSGSYA CSARLTHLGR IFTVRNYIAV NTKE. VGSGG RIP.NITYPK mIL-lRD4 VTHDDEGDYT CQFTHAENGT NYIVTATRSF TVE. EKGFS. MFPVITNPPY hIL-lRD4 VMTEDAGDYT CKFIHNENGA NYSVTATRSF TVKDEQGFS. LFPVIGAPAQ hIL-lRD2 VALEDAGYYR CVLTFAHEGQ QYNITRSIEL RIKKK. -KEE TIPVIISP .. mIL-lRD2 TSMDDAGYYR CVMTFTYNGQ EYNITRNIEL RVKGT .. TTE PIPVIISP .. hIL-IRDIO ... EFG..TS CE .. KYGGF V..VRRTTEL TVTAPLTDKP PKLLYPMESK hIL-lRD5 ... EDQGYYS CVHFLHHNGK LFNITKTFNI TIVED .. RSN IVPVLLGP. K mIL-lRD5 ... GDEGYYS CVFSVHHNGT RYNITKTVNI TVIEG .. RSK VTPAILGP. K mlL-IRDI VAEEHRGDYI CRMSYTFRGK QYPVIRVIQF ITIDE .. NKR DRPVILSP.R hIL-IRDI VAEKHRGNYT CHASYTYLGK QYPITRVIEF ITLEE .. KP TRPVIVSP.A cil-IRDI VTIQDKGNYT CRMVYTYMGK QYNVSRTMNL EVKES .. PLK MRPEFIYP.N hIL-lRD8 VQEEDGGNYT CEL .. YEGK L. VRRTTEL KVTALLTDKP PKPLFPMENQ hFGR4 WPSDRGTYT CLVENAVGSI RYNYLLDVLE RSPH..RPIL QAGLPANTT. mIL-lRD3 RWYEKEPGE ELVIPCKVYF SFIMD.SHNE VWWTIDGKKP .DDVTVDITI hIL-lRD6 NHSIEVQLGT TLIVDCNVTD TK..D.NTNL RCWRVNNTLV DDYYDESKRI rIL-lRD6 NNSIEVQLGS TLIVDCNITD TK..E.NTNL RCWRVNNTLV DDYYNDFKRI rail-lRD4 NHTMEVEIGK PASIACS CF GKGSH. FLAD VLWQINKTW GNFGEARIQE hIL-lRD4 NEIKEVEIGK NANLTCSACF GKGTQ. FLAA VLWQLNGTKI TDFGEPRIQQ hIL-lRD2 LKTISASLGS RLTIPCKVFL GTGTP. LTTM LWWTANDTHI. ESAYPGGRV mIL-lRD2 LETIPASLGS RLIVPCKVFL GTGTS. SNTI VWWLANSTFI. SAAYPRGRV hIL-IRDIO LTIQETQLGD SANLTCRAFF GYSGD.VSPL IYWMKGEKFI EDLDENRVWE hIL-lRD5 LNHVAVELGK NVRLNCSALL N EEDV IYWMFGEENG ... SDPNIHE mIL-lRD5 CEKVGVELGK DVELNCSASL N KDDL FYWSIRKEDS ... SDPNVQE tnlL-lRDl NETIEADPGS MIQLICNVTG Q FSDL VYWKWNGSEI. EWNDPFLAE hIL-IRDI NETMEVDLGS QIQ ICNVTG Q LSDI AYWKWNGSVI. DEDDPVLGE CIL-1RD1 NNTIEVELGS HWMECNVSS GV .... YGLL PYWQVNDEDV .DSFDSTYRE 1HL-1RD8 PSVIDVQLGK PLN1PCKAFF GFSGE.SGPM IYWMKGEKFI. EELAGHIRE hFGR4 AWGS DVELLCKVYS DA ... QPHIQ ..WLKHIVIN GSSFGA..DG mIL-lRD3 NESVSYSSTE D .. ETRTQIL SIKKVTPEDL RRNYVCHARN TKGEAEQAAK hIL-lRD6 R? GVETHVSF REHNLYTVNI TFLEVKMEDY GLPFMCHAG. .. -VSTAYII rIL-lRD6 QEGIETNLSL RNHILYTVNI TFLEVKMEDY GHPFTCHAA. ... VSAAYII mIL-lRD4 EEGRNESSSN D. MDCLTSVL RITGVTEKDL SLEYDCLALN LHGMIRHTIR hIL-lRD4 EEGQNQSFSN G.LACLDMVL RIADVKEEDL LLQYDCLALN LHGLRRHTVR hIL-lRD2 TEGPRQEYSE NN? NYIEVPL IFDPVTREDL HMDFKCWHN TLSFQTLRTT mIL-lRD2 TEGLHHQYSE NDENYVEVSL IFDPVTREDL HTDFKCVASN PRSSQSLHTT hIL -_. RD10 SDIRILKEHL G.EQEVSISL IVDSVEEGDL .GNYSCYVEN GNGRRHASVL IL-lRD5 EKEMRIMTPE G .KWHASKVL RIENIGESNL NVLYNCTVAS TGGTDTKSFI mIL-lRD5 DRKETTTWIS EGKLHASKIL RFQKITENYL NVLYNCTVAN EEAIDTKSFV mlL-IRDI DYQFVEHPST KRKYTLITTL NISEVKSQFY RYPFICWKN TNIFESAHVQ IL-IRDI DYYSVENPAN KRRSTLITVL NISEIESRFY KHPFTCFAKN THGIDAAYIQ CIL-1RD1 QFYEEGMPHG .. IAVSGTKF NISEVKLKDY AYKFFCHFIY DSQEFTSYIK hIL-lRD8 GEIRLLKEHL G. EKEVELAL IFDSWEADL AN. YTCHVEN RNGRKHASVL hFGR4 FPYVQVLKTA DINSSEVEVL YLRNVSAED. AGEYTCLAGN SIGLSYQSAW mIL-lRD3 VKQKV .... I PPRYTVELAC GFGATVFLW VLIWY hIL-lRD6 LQLP .. A PDFRAYLIGG LIALVAVAVS WYIYNIFKI DIVLWY rIL-lRD6 LKRP .. A PDFRAYLIGG LMAFLLLAVS ILYIYNTFKV DIVLWY mIL-lRD4 LRRK .. Q PSKECPSHIA IYYIVAGCSL LLMFINVLVI VL hIL-lRD4 LSRK .. N PSKEC hIL-lRD2 VKEASS. . .TFSWGIVLA PLSLAFLVLG GIWM mIL-lRD2 VKEVSS. . -TFSWSIALA P SLIILWG AIW. hIL-IRDIO LHKREL. . . MYTVELAGG LGAILLLLVC LVTIYKCY hIL-lRD5 LVRKADMADI P .. GHVFTRG MIIAVLILVA WCLVTVCVI and MIL-lRD5 LVRKEIPDIP ... GHVFTGG VTVLVLASVA AVCIVI CVI and MLL-IRDI LIYP V PDFKNYLIGG FIILTATIVC CVCIY hIL-IRDI LIYP V TNFQKHMIGI CVTLTVIIVC SVFIY FLC-lRDl LEHP V QNIRGYLIGG GISLIFLLFL ILIVY hIL-lRD8 LRKKD ..... IYKIELAGG LGAIFLLLVL LWIYKCY hFGR4 LTVL. E EDPTWTAAAP EARYTDIILY ASGSLALAVL LLLAGLY TABLE 2 Alignment of the intracellular domains of several IL-1 Rs. hlL-1 RD9 is the Nr ID of Sec: 8; mlL-1 RD9 is the NR ID of Sec: 14; hlL-1 RD1 is GenBank X16896; ML-1 RD6 is GenBank U49065; mlL-1 RD3 is GenBank X85999; hulL-1 RD8 is the Nr ID of Sec: 3; and mlL-1 RD4 is GenBank Y07519.

HuIL-lRDl SDGKTYDAYI LYPKTVGEG. .. STSDCDIF VFKVLPEVLE KQCGYKLFIY HUIL-1RD6 VDGKLYDAYV LYPKPHKES. .. QRHAVDAL VLNILPEVLE RQCGYKLFIF MOIL-1RD3 LDGKEYDIYV SYAR NVEEEEF VLLTLRGVLE NEFGYKLCIF HUIL-1RD8 DDNKEYDAYL SYTKVDQDTL DCDNPEEEQF ALEVLPDVLE KHYGYKLFIP HU.IL-1RD5 TDGKTYDAFV SYLKECRP .. .. ENGEEHTF AVEILPRVLE KHFGYKLCIF MOIL-1RD9 HuIL-lRD9 KYGYSLCLL MOIL-1RD4 NDGKLYDAYI IYPRVFRGS. AAGTHSVEYF VHHTLPDVLE NKCGYKLCIY HuIL- 1RD1 GRDDYV. GED IVEVINENVK KSRRLIIILV RETSGFSWLG GSSEEQIAMY HuIL- 1RD6 GRDEFP. GQA VANVIDENVK LCRRLIVIW PESLGFGLLK NLSEEQIAVY MoIL- 1RD3 DRDSLPGGIV TDETLS. FIQ KSRRLLWLS PNYVLQG. TQ ALLELKAGLE HuIL-1RD8 ERDLIPSG.T YMEDLTRYVE QSRRLII LT PDYILRR.GW SIFELESRLH HuIL-1RD5 ERD PGGAV VDEIHS.LIE KSRRLIIVLS KSYMSN ... E VRYELESGLH MoIL-1RD9 DRDVTP. GGV YADDIVSIIK KSRRGIFILS PSYLNG ... P RVFELQAAVN HuIL- 1RD9 ERDVAP. GGV YAEDIVSIIK RSRRGIFILS PNYVNG ... SIFELQAAVN MoIL- 1RD4 GRDLLP. GQD AATWESSIQ NSRRQVFVLA PHMMHSK..E FAYEQEIALH HuIL-1RD1 NALVQDGIKV VLLELEKIQ DYEKM PESIKFIKQK HGAIRWSGDF HuIL-1RD6 SALIQDGMKV ILIELEKIE DYTVM PESIQYIKQK HGAIRWHGDF MoIL-1RD3 NMASRGNINV ILVQYKAVK. ... DMKVKEL KRAKTVLT .. ..VIKWKGEK HuIL- 1RD8 NMLVSGEIKV ILIECTELKG KVNCQEVESL KRSIKLLS .. ..LIKWKGSK HuIL- 1RD5 EALVERKIKI ILIEFTPVT DFTFL PQSLKLLKSH R .VLKWKADK MoIL- 1RD9 LALVDQTLKL ILIKFCSFQ EPESL PYLVKKALRV LPTVTWKGLK HuIL- 1RD9 LALDDQTLKL ILIKFCYFQ EPESL PHLVKKALRV LPTVTWRGLK MoIL- 1RD4 SALIQNNSKV ILIEMEPLG. EASRLQVGDL QDSLQHLVKI QGTIKWREDH HuIL-lRDl TQGPQSAKTR FWKNVRYHMP VQRRSPSSKH HUIL-1RD6 TEQSQCMKTK FWKTVRYHMP PRRCRPFLRS MOIL-1RD3 SKYPQ ... GR FWKQLQVAMP VKKSPRWSSN HUIL-1RD8 SSKLN ... SK FWKHLVYEMP IKKKEMLPRC HUIL-1RD5 SLSYN ... SR FWKNLLYLMP AKTVKPGRDE MOIL-1RD9 SVHAS ... SR FWTQIRYHMP VKNSNRFMFN TABLE 3 Alignment of primate IL-1RD8 and primate IL-1 RD10.RD8 MKPPFLLAI-V VCSWSTN K MVSKRNSVDG CIDWSVDUrT YM? LAGEPVR R1DO RD8 VKCALFYSYI RTNYSTAQST GLR1JÍ YKNK GDI-EEPIIFS EVRMSXEEDS RD10 RD8 I FHSAEAQD SGFYTCVLRN STYCMKVSMS LTVAKNESG CYNSRIRYLE RD10 RD8 KSEVTKRKEI SCPDMDDFKK SDO.EPDWWY KECKPKM RS IIIQKGNALL PD10 RD8 IQ? VQ? EDGG NYTCELKYEO KLVRRTTELK VTALLTDKPP XP FPMENQP RD10 EFG. .TSCELKYGG F RRTT? I_T VTAPLTDKPP K LYPMESKL RD8 SVIDVQLGKP LNIPCKAFFG FSGESGPMIY WMKGEKFIEE LAG.HIREGB RD10 TIQETQLGDS ANt, TCRAFFG YSGDVSPLXY WMKGEKPIED DENRVWESD 1-D8 IRLLKEHLGE KEVELALIFD SWEADLANY TCHVENR GR KHASVLLR K RDIO IRILKEKLCE QEVSISLrvD SVEEGDLGNY SCYVENGNGR RHASVLLHKR RD8 DLIYKIELAG- GLGAIFLL V LLWIYKCYN lELMLFYRQH PGADETNDDN RDIO ELWYTVELAG GLGAILLLLV CLVTIYKCYK IEIM FYRNH FGAEELDGDN RD8 KEYDAYLSYT KVDQDTLDCD NPEEEQFALE VLPDVIiEKHY GYKLFIPERD RD10 KDYDAYLSYT KVDPDQWNQE TGEEERFA AND ILPDM EKHY GYKLFIPDRD RD8 LIPSGTYMED LTRYVEQSRR LIlVXiTPDYI LRRGWSIFEL ESR HNHLVS RD10 IPTGTYIED VARCVDQSKR LIIWTPNYV VRRG SIFE ETRJ-RNM VT RD8 GEIKVILIEC TELKGKVNCQ EVES KRSIK LLSLIKWKGS KSSKLNSKTW RD10 GEIKVILIEC SELRGIMNYQ EVEALiKHTIK LLTVIX HGP KCNKLNSXF RD8 KHLVYEMPIK KKEMLPRCHV LDSAEQGLFG ELQPIPSIAM TS-TSATLVS RD10 K___QYEMPFK RIEPITHEQA LDVSEQGPFG ELQTVSAISM AAATS ALAT RD8 SQADLP.EFH PS..DSMQIR HCCRGYKHEI PAT.T PVI > S LGNHHTYCN1.

RD10 AHPDLRSTFH NTYHSQMRQK HYYRSYEYDV PPTGTLPLTS IGNQHTYCNI RD8 PLTLLNGQLP LNNTLKD..T QEFHRNSSLL PLSSKELSFT SDIW RD10 PKT INGQPvP QTKSSREQNP DEAH NSAIL PLLFRETSIS SVIW TABLE 4 Alignment and comparison of IL-1 RD9 of primate and rodent. hIL-lRD9 MLCLGWIFLWLVAGERIKGFNISGCSTKKLLWTYSTRSEEEFVLFCDLPE mIL-lRD9 MLCLGWVFLWFVAGEKTTGFNHSACATKKLLWTYSARGAENFVLFCDLQE ****** *** **** _ *** * * ********* * * ******* * hIL-lRD9 PQKSHFCHRNRLSPKQVPEHLPFMGSN-DLSDVQWYQQPSNGDPLEDIRK mIL-lRD9 LQEQKFSHASQLSPTQSPAHKPCSGSQKDLSDVQWYMQPRSGSPLEEISR *. *. *. *** * * * * **. ******** ** * * hIL-lRD9 SYPHIIQDKCTLHFLTPGVNNSGSYICRPKMIKSPYDVACCVKMILEVKP mIL-lRD9 NSPHMQSE-GMLHILAPQTNSIWSYICRPR-IRSPQDMACCIKTVLEVKP ** ** * * * ****** * ** * *** * ** *** hIL-lRD9 QTNASCEYSASHKQDLLLGSTGSISCPSLSCQSDAQSPAVTWYKNGKLLS mIL-lRD9 QRNVSCGNTAQDEQVLLLGSTGSIHCPSLSCQSDVQSPEMTWYKDGRLLP * * ** * ********* ********* ß * **** *** # *. ** 1HL-1RD9 VERSNRIWDEVYDYHQGTYVCDYTQSDTVSSWTVRAWQVRTIVGDTKL mIL-lRD9 EHKKNPIEMADIYVFNQGLWCDYTQSDOTSSWTVRAWKVRTIGKDINV * * * ** * ********* ********** **** hIL-lRD9 KPDILDPVEDTL? VELGKPLTISCKARFGFERVFNPVIKWYIKDSDLEWE mIL-lRD9 KPEILDPITDTLDVELGKPLTLPCRVQFGFQRLSKPVIKWYVKESTQEWE ** **** *** ******** * *** * ****** * * *** hIL -_. RD9 VS VPEAKS I KSTLKDEI IERNI ILEKVTQRDLRRKFVCFVQNS IGNTTQS mIL-lRD9 MSVFEEKRIQSTFKNEVIERTIFLREVTQRDLSRKFVCFAQNSIGNTTRT. ** * * * _ ** * * _ *** _ * * ****** ****** ******** _ UIL 1RD9 VQLKEKRGWLLYILLGTIGTLVAVLAASALLYRHWI? IVLLYRTYQSKD mIL-lRD9 IRLRKKEEWFVYILLGTALMLVGVLVAAAFLYWYWIEWLLCRTYKNKD ****** ** ** * * * * * * ** *** *** ** * ** hIL-lRD9 QTLGDKKDFDAFVSYAKWSSFPSEATSSLSEEHLALSLFPDVLENKYGYS MIL-1RD9 ETLGDKKEFDAFVSYSNWSSPETDAVGSLSEEHLALNLFPEVLEDTYGYR *** *** ******* *** * ********* *** *** *** hIL-lRD9 LCLLERDVAPGGVYAEDIVSIIKRSRRGIFILSPNYVNGPSIFELQAAVN mIL-lRD9 LCLLDRDVTPGGVYADDIVSIIKKSRRGIFILSPSYLNGPRVFELQAAVN **** _ *** _ * ***** # ******* < ********** * F *** # ******** hIL-lRD9 LALDDQTLKLILIKFCYFQEPESLPHLVKKALRVLPTVTWRGLKSVPPNS mIL-lRD9 LALVDQTLKLILIKFCSFQEPESLPYLVKKALRVLPTVTWKGLKSVHASS *** ************ *** ***** ************** ***** * 3HL-1RD9 RFWAKMRYHMPVKNSQGFTWNQLRITSRIFQ WKGLSRTETTGR mIL-lRD9 RFWTQIRYHMPVKNSNRFMFNGLRIFLKGFSPEKDLVTQKPLEGMPKSGN *** ********* * * *** * * * * ÜIL-1RD9 SSQPKEW mIL-lRD9 DHGAQNLLLYSDQKRC The structural analysis of the IL-1 RD10 sequence of the primate (Nr ID of Sec: 18 and 20), compared with other IL-1 Rs, demonstrates that there are specific characteristics, which are conserved with the IL-1 RD10 modality described here. For example, there are characteristic Ig domains, and subdomains. The corresponding regions of IL-1 RD10 (Nr ID of Sec: 18 and 20) are: F2 to gly7; g2 from vaH O to thr23; a3 from Ieu30 to met33; a3 'from thr38 to gln40; b3 from ala48 to ala54; c3 from pro64 to Iys70; c3 'between glu72 to phe74; d3 between val83 to Iys92; e3 between gln98 to valí 06; and f3 from tyr1 17 to trpl 26. The structural analysis of the rodent IL-1 RD9 sequence (Nr ID of Sec: 12, 14 and 16), compared to other IL-1 Rs, shows that there are specific characteristics (see paintings). For example, there are characteristic Ig domains and their subdomains. The corresponding regions of IL-1 RD9 (Nr Sec ID: 12, 14 and 16) are: Ig1 domain from gly18 to pro127, with cys 105 probably bound to cys52 (or possibly cys48); Ig2 domain from gly128 to pro229, with cys153 probably linked to cys199; and the Ig3 domain from glu230 to Iys333, with cys251 probably bound to cys315; the transmembrane segment from val336 to tyr360; the THD domain from gly381 to val539; the conserved trp residues probably correspond to residues 64, 169 and 267. The alignment of the IL-1 RD9 modalities are illustrated in Table 4. There are characteristic beta strand sections, and alpha helical structures, as described above for IL- 1 RD10. The corresponding segments of the human IL-1 RD9 sequence (Nr ID of Sec: 6, 8, and 10) are approximately: βB from gly3 to vall 3; 2 from pro15 to Iys28; ßc from ser30 to ser46; a3 from Ie47 to gln61; ßD from Iys64 to glu75; a4 from glu77 to Ieu87; ßE from val93 to Ieu98; and a5 from arg106 to vall 17. The corresponding segments of the mouse IL-1 RD9 sequence (Nr Sec ID: 12, 14 and 16) are approximately: a3 up to gln10; ßD from Iys13 to glu24; 4 from glu26 to leu36; ßE from va42 to Ieu47; and a5 from arg55 to val66. As used herein, the term: receptor D8 type IL-1 (IL-1 RD8), receptor D9 type IL-1 (IL-1 RD9), or receptor 10 type IL-1 (IL-1 RD10) will be used for describing a polypeptide comprising a segment having or sharing the amino acid sequence illustrated in the Nr ID of Sec: 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20, or a substantial fragment. The invention further includes a polypeptide variation of the respective IL-1 RD8, IL-1 RD9, IL-1 RD10 alleles whose sequences are provided, for example, a mutein or soluble extracellular or intracellular construction. Typically, these agonists or antagonists will exhibit less than about 10% sequence difference, and will thus often have between 1 and 11 substitutions, for example 2-, 3-, 5-, 7- fold, and others. . It also includes allelic variants and other variants, for example, natural polymorphic variants, of the described polypeptide. Typically, its corresponding biological ligand is linked, perhaps in a dimerized state with an alpha receptor subunit, with high affinity, for example, at least about 10 nM, usually better than about 30 nM, preferably better than about 10 nM. , and more preferably better than about 3 nM. The term will also be used here to refer to naturally occurring forms, eg, allele, polymorphic variants and metabolic variants of the mammalian protein. This invention also includes polypeptides having a substantial amino acid sequence identity with the amino acid sequences illustrated in the Nr ID of Sec: 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20, preferably with contiguous amino acid residue segments identical to the segments of the Sec ID Nr: 4, 10 or 20. It will include sequence variants with relatively few substitutions, for example, typically less than about 25, commonly less than about 15, preferably less than around 3-5. Other embodiments include forms associated with an alpha sub-unit, for example, IL-1 RD4, IL-1 RD5, or IL-1 RD6. A "fragment" or "segment" of substantial polypeptide, is a stretch of amino acid residues of at least about 8 contiguous amino acids, generally at least 10 contiguous amino acids, more generally at least 12 contiguous amino acids, often at least 14 contiguous amino acids, more often at least 16 contiguous amino acids, typically at least 18 contiguous amino acids, more typically at least 20 contiguous amino acids, usually at least 22 contiguous amino acids, more usually at least 24 contiguous amino acids, preferably at least 26 contiguous amino acids, more preferably at least 28 contiguous amino acids, and, in the particularly preferred embodiments, at least about 30 or more contiguous amino acids, usually 40, 50, 70, 90 1 10, etc. The sequences of the segments of different polypeptides can be compared with each other in stretches of suitable length. In many cases, the match will include a number of distinctive segments, for example, without overlapping the specified length. Typically, the amount will be at least two, more usually at least three, and preferably 5, 7 or even more. While the minimum length is provided, other longer lengths of various sizes may be suitable, for example, a length of 7, and two of 12. Similar characteristics are applied to the nucleic acid segments. The amino acid sequence homology, or sequence identity, is determined by optimizing the matches of the residue, if necessary, by entering intervals in the required manner. See, for example, Needleham, et al., (1970), J. Mol. Biol. 48: 443-453; Sankoff, et al., (1983) chapter one in Time Warps, String Edits, and Macromolecules: The Theorv and Practice of Seguence Comparison, Addison-Wesley, Reading, MA; and software packages from IntelliGenetics, Mountain View, CA; and the University of Wisconsin, Genetics Computer Group (GCG), Madison, Wl; each of them is incorporated here for reference. This changes when conservative substitutions are considered as coincidences. Conservative substitutions typically include substitutions within the following groups: glycine, alanine, valine, isoleucine, leucine, aspartic acid, glutamic acid, asparagine, glutamine, serine, threonine, lysine, arginine and phenylalanine, tyrosine. The homologous amino acid sequences are intended to include natural allelic and interspecies variations in the cytokine sequence. Typical homologous polypeptides will have a homology between 50-100% (if intervals can be introduced) and 60-100% (if conservative substitutions are included) with an amino acid sequence segment screened at the Sec ID Nr; 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20. The homology measurements will be at least about 70%, generally at least 76%, more generally at least 81%, often at least 85%, more commonly at least 88%, typically at least 90%, more typically at least 92%, usually at least 94%, more usually at least 95%, preferably at least 96%, and more preferably at least 97%, and in the particularly preferred embodiments, at least 98% or more. The degree of homology will vary with the length of the compared segments. Homologous polypeptides, such as, for example, allelic variants, will share most of the biological activities with the modalities described in the Sec ID Nr; 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20. As used herein, the term "biological activity" is used to describe, without limitation, effects on inflammatory responses, innate immunity and / or morphogenic development by means of the respective ligands. For example, these receptors must, like IL-1 receptors, mediate phosphatase or phosphorylase activities, whose activities are easily measured by standard procedures. See, for example, Hardie, et al., (Eds. 1995) The Protein Kinase Factbook. vols. I and II, Academic Press, San Diego, CA; Hanks et al., (1991), Meth. Enzvmol 200: 38-62; Hunter et al. (1992) Cell 70: 375-388; Lewin (1990) CeJ 61: 743-752; Pines et al., (1991) Cold Spring Harbor Svmp. Quant. Biol, 56: 449-463; and Parker et al. (1993) Nature, 363: 736-738. Other activities include antigenic or immunogenic functions. The receptors exhibit biological activities very similar to the adjustable enzymes, regulated by the ligand binding. However, the rotational amount of enzyme is closer to an enzyme than to a receptor complex. Moreover, the quantities of occupied receptors needed to induce this enzyme activity is lower than most receptor systems, and can be close to dozens per cell, in contrast to most receptors that will develop quantities in thousands per cell. The receptors, or their portions, can be useful as enzymes that label phosphate to label general or specific substrates. The terms ligand, agonist, antagonist and its analogue, for example, an IL-1 RD8, IL-1 RD9 or IL-1 RD10, include molecules that modulate characteristic cellular responses in IL-1 ligand proteins, as well as well as to molecules that possess more standard structural binding competence characteristics of ligand-receptor interactions, for example, when the receptor is a natural receptor or an antibody. Cellular responses are probably mediated by linking several IL-1 ligands to related cellular receptors but possibly different from type I or type II IL-1 receptors. See, for example, Belvin and Anderson (1996) Ann. Rev. Cell Dev.Biol. 12: 393-416; Morisato and Anderson (1995) Ann.Rev. Genetics 29: 371-3991 and Hultmark (1994) Nature 367: 1 16-1 17. Further, a ligand is a molecule that serves as a natural ligand to which said receptor or its analogue is linked, or a molecule that is a functional analogue of the natural ligand. The functional analog may be a ligand with structural modifications, or it may be an unrelated molecule having a molecular form that interacts with the appropriate ligand binding determinants. Ligands can serve as agonists or antagonists, see for example Goodman, et al (eds. 1990) Goodman and Gilman's: The Pharmacological Bases of Therapeutics Pergamon Press, New York. The rational design of the drug can also be based on structural studies of the molecular forms of a receptor or antibody and other filmmakers or ligands. The effectors may be other proteins that mediate other functions in the response to ligand binding, or other proteins that normally interact with the receptor. A means of determining which sites interact with other specific proteins is the determination of the physical structure, for example, X-ray crystallography or dimensional NMR techniques. This will provide guidance as to which amino acid residues form the molecular contact regions. For a detailed description of the structural determination of the protein, see for example, Blundell and Johnson (1976) Protein Crystallography, Academic Press, New York, which is incorporated herein by reference.

II. Activities IL-1 receptor-like polypeptides will have a number of different biological activities, for example, in phosphate metabolism, they are added or removed from specific substrates, typically proteins. This will generally cause the modulation of an inflammatory function, different from the innate immune response or a morphological effect. For example, a coding sequence of the human IL-1 RD9 gene probably has 60-80% identity with the sequence encoding the nucleotide of mouse IL-1 RD9. At the amino acid level, a reasonable identity is also likely to exist. The receptors will also exhibit immunogenic activity, for example, by being able to produce a selective immune response.

The resulting antiserum or antibodies will exhibit both selectivity and binding affinity. The polypeptides will also be antigenic, by binding the antibodies developed there, in the natural or denatured state. The biological activities of the IL-1 RDs will generally be related to the addition or removal of the phosphate moieties with respect to the substrates, typically specifically, but occasionally non-specifically. Substrates can be identified, or conditions for enzymatic activity can be tested by standard methods, for example, as described in Hardie, et al., (Eds.1995) The Protein Kinase FactBook vols I and II, Academic Press, San Diego, CA; Hanks et al., (1991) Meth. Enzymol. 200: 38-62; Hunter et al., (1992) Cell 70: 375-388; Lewin (1990) CeN 61: 743-752; Pines et al., (1991) Cold Spring Harbor Svmp. Quant. Biol 56: 449-463; and Parker et al., (1993) Nature 363: 736-738.

III. Nucleic Acids This invention relates to the use of an isolated nucleic acid or fragments, for example, which encode these or the related proteins or their fragments, for example, encoding the corresponding polypeptide, preferably one that is biologically active. In addition, this invention includes isolated or recombinant DNA such as, for example, polypeptides or polypeptides having characteristic sequences of the respective IL-1 RDs, individually or as a group. Typically, the nucleic acid is capable of hybridizing, under suitable conditions, with a segment of nucleic acid coding sequence illustrated in the Nr ID of Sec: 1, 3, 5, 7, 9, 11, 13, 15, 17, or 19 but preferably not with a corresponding segment of other receptors. Said biologically active polypeptide may be a full-length polypeptide, or fragment and will typically have an amino acid sequence segment highly homologous to that illustrated in the Sec ID Nr: 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20. Furthermore, this invention includes the use of the isolated or recombinant nucleic acid or its fragments, which encode polypeptides having fragments that are equivalent to the IL-1 RD9 proteins. The isolated nucleic acids may have respective regulatory sequences at sites 5 and 3 ', for example, promoters, promoters, poly-A aggregate signals, and others of the wild-type gene. An "isolated" nucleic acid is a nucleic acid, e.g., an RNA, DNA, or a mixed polymer, which is substantially pure, e.g., separated from other components that naturally accompany the natural sequence, e.g., ribosomes, polymerases. , and lateral genomic sequences of the originating species. The term includes a nucleic acid sequence that has been removed from its natural environment, and includes recombinant or cloned DNA isolates, which are thus distinguished from natural compositions, and chemically synthesized analogs or biologically synthesized analogs by means of the heterologous systems. A substantially pure molecule includes the isolated forms of the molecule, complete or substantially pure. An isolated nucleic acid will generally be a homogeneous composition of molecules, but will have in some embodiments, some heterogeneity, preferably less. This heterogeneity is typically found at non-critical polymer ends or portions with respect to a desired biological function or activity.

A "recombinant" nucleic acid is typically defined by its production method or by its structure. With respect to this production method, for example, a product prepared by means of a process, the process is the use of recombinant nucleic acid techniques, for example, those which include the human invention in the nucleotide sequence. Typically this intervention includes in vitro manipulation, although under circumstances it may include more classical animal development techniques. Alternatively, it may be a nucleic acid prepared to generate a sequence comprising the fusion of two fragments that are not naturally contiguous with each other, but is intended to exclude products of nature, for example, natural mutants such as those found in their natural state. . Thus, for example, products prepared by transforming cells with an unnatural vector, such as nucleic acids comprising a derived sequence using any synthetic oligonucleotide process, are included. This process is often performed to replace a codon with a redundant codon encoding the same amino acid or a conservative amino acid, while typically being introduced or removed to a restriction enzymatic recognition site. Alternatively, the process is performed to join the nucleic acid segments of the desired functions to generate a single genetic entity comprising a desired combination of functions not found in the commonly available natural forms, for example, encoding a fusion protein . Restriction enzyme recognition sites are often the target of these artificial manipulations, but other site-specific targets, eg, promoters, DNA replication sites, regulatory sequences, control sequences or other useful features may be incorporated by means of design. A similar concept is intended for a recombinant polypeptide, e.g., fusion. This will include a dimeric repeater. Specifically included are synthetic nucleic acids which, by redundancy of genetic code, encode the equivalent polypeptides in fragments of IL-1 RD9 and fusions of sequences from several different related molecules, for example, other members of the IL-1 receptor family. . A "fragment" in the context of the nucleic acid is a contiguous segment of at least about 17 contiguous nucleotides, generally at least 21 contiguous nucleotides, more generally 25 contiguous nucleotides, typically about 30 contiguous nucleotides, more commonly about 35 contiguous nucleotides , often at least 39 contiguous nucleotides, more often at least 45 contiguous nucleotides, typically at least 50 contiguous nucleotides, more typically at least 55 contiguous nucleotides, usually at least 60 contiguous nucleotides, more usually at least 66 contiguous nucleotides, preferably at minus 72 contiguous nucleotides, more preferably at least 79 contiguous nucleotides, and in particularly preferred embodiments will be at least 85 or more contiguous nucleotides, e.g., 100, 120, 140, etc. Typically, the fragments of the different genetic sequences can be compared to each other in stretches of suitable length, particularly, defined segments such as, for example, the domains described below. A nucleic acid encoding an IL-1 RD8, IL-1 RD9 or IL-1 RD10 will be particularly useful for identifying genes, mRNA, and CADN species that encode themselves or intimately related proteins, as well as to DNAs encoding polymorphic, allelic or other genetic variants, for example, from different individuals or related species. The preferred probes for these classifications are those regions of interleukin that are conserved between different polymorphic variants or that contain nucleotides that lack specificity, and preferably they will have a full or almost length. In other situations, the specific sequences of the polymorphic variant will be more useful. This invention further includes recombinant nucleic acid molecules and fragments having a nucleic acid sequence identical to or highly homologous to the given isolated DNA. In particular, the sequences will often be operably linked to the DNA segments that control the transcription, translation, and replication of DNA. These additional segments will typically aid in the expression of the desired nucleic acid segment. The homologous or highly identical nucleic acid sequences, when compared to each other, e.g., the IL-1 RD9 sequences, exhibit significant similarity. Standards for homology in nucleic acids are measurements for homology generally used in the art by means of sequence comparison or are based on hybridization conditions. The comparative hybridization conditions are described in more detail below. Substantial identity in the context of nucleic acid sequence comparison means that the segments, or their complementary filaments, when compared are identical when they are optimally aligned, with the appropriate insertions or nucleotide deletions, by at least about 60% of the nucleotides, generally at least 66%, ordinarily at least 71%, often at least 76%, more often at least 80%, usually at least 84% more usually at less 88%, typically at least 91%, more typically at least about 93%, preferably at least about 95%, more preferably at least about 96 and 98% or more, and at particular embodiments, of about 99% or more of the nucleotides, including, for example, the segments encoding the structural domains such as, for example, the segments described below. Alternatively, substantial identity will exist when the segments are hybridized under conditions of selective hybridization, in a filament or its complement, generally using a sequence derived from the Nr ID of SEQ. 1, 3, 5, 7, 9, 11, 13, 15, 17, or 19. Typically, selective hybridization will occur when there is at least 55% homology over a stretch of at least about 14 nucleotides, more typically from at least about 65%, preferably at least 75%, and more preferably at least about 90%. See Kanehisa (1984) Nuc. Acids Res 12: 203-213, which is incorporated herein for reference. The length of the comparison by homology, as we describe, can be on longer stretches, and in certain embodiments will be on a stretch of at least 17 nucleotides, generally at least 20 nucleotides, ordinarily at least about 24 nucleotides, usually at least about 28 nucleotides, typically at least about 32 nucleotides, more typically at least about 40 nucleotides, preferably at least about 50 nucleotides, and more preferably at least about 75 and 100 or more nucleotides. The astringent conditions, with respect to homology in the hybridization context, will be the combined astringent conditions of the salt, temperature, organic solvents and other parameters typically controlled in the hybridization reactions. Stringent temperature conditions will usually include temperatures greater than around 30 ° C, more usually higher than around 37 ° C, typically higher than around 45 ° C, more typically higher around 55 ° C, preferably greater than about 65 ° C, and more preferably higher around 70 ° C. The astringent conditions of the salt will normally be less than about 500 mM, usually less than about 400 mM, more usually less than about 300 mM.; typically less than about 200 mM, preferably less than about 100 mM, and more preferably less than about 80 mM, even down to less than about 20 mM. However, the combination of parameters is much more important than the measurement of any single parameter. See, for example, Wetmur and Davidson (1968) J. Mol. Biol. 31: 349-370, which is incorporated herein by reference. The signal must be at least 2X on the background, generally at least 5-10X on the background, and even more. For sequence comparison, typically one sequence acts as a reference sequence, with which the test sequences are compared. When a sequence comparison algorithm is used, the test and reference sequences are reported to a computer, the subsequent coordinates are designed, if necessary, and the parameters of the sequence algorithm program are designated. The sequence comparison algorithm then calculates the percent identity of the sequence for the test sequence (s) with respect to the reference sequence, based on the parameters designated in the program. The optical alignment of the sequences for comparison can be carried out, for example, by means of the local homology algorithm of Smith and Waterman (1981) Adv. Appl. Math. 2: 482, by means of the homology alignment algorithm of Needleman and Wunsch (1970), J. Mol. Biol. 48: 443. by means of the similarity search method of Pearson and Lipman (1988) Proc. Nat'l Acad Sci. USA 85: 2444, through computerized implementations of these algorithms (GAP, BESTFIT, FASTA and TFASTA in the Wisconsin Genetics software package, Genetics Computer Group, 575 Science Dr., Madison, Wl) , or by means of visual inspection (see Ausubel et al., supra). An example of a useful algorithm is PILEUP.PILEUP creates a multiple sequence alignment of a group of related sequences using the progressive alignments, in pairs to demonstrate a relationship and percent sequence identity. It also diagrams a tree or dendrogram that shows the agglomeration relationships used to create an alignment. PILEUP uses a simplification of the progressive alignment method of Feng and Doolittle (1987) J. Mol. Evol. 35: 351-360. The method used is similar to the method described by Higgins and Sharp (1989) CABIOS 5: 151-153. The program can align up to 300 sequences, each with a maximum length of 5,000 nucleotides or amino acids. The multiple alignment procedure begins with the pairwise alignment of the two most similar sequences, producing a group of two aligned sequences. This group is then aligned with the next most related sequence or group of aligned sequences. Two groups of sequences are aligned by means of a simple extension of the alignment in pairs of two individual sequences. The final alignment is achieved through a series of progressive alignments, in pairs. The program is run by designing specific sequences and their amino acid and nucleotide coordinates for the regions of the sequence comparison and designing the parameters of the program. For example, a reference sequence can be compared to other test sequences and determine the percentage sequence identity relation using the following parameters: default interval weight (3.00), weight of the default interval length (0.10), and heavy final intervals. Another example of an algorithm that is suitable for determining percent sequence identity and sequence similarity is the BLAST algorithm, which is described in Altschul, et al., (1990) J. Mol. Biol. 215: 403-410. The software to perform BLAST analysis is available from the National Center for Biotechnology Information (http: www.ncbi.nlm.nih.gov/): This algorithm includes first identifying high performance sequence pairs (HSPs) by identifying short words from the length W in the row sequence, which do not match or satisfy some thresholds T positively valued when they are aligned with a word of the same length in a sequence of the database. T is referred to as the neighbor word yield threshold (Altschul, et al., Supra). This initial word acts as a starting point to start searches for longer HSPs that contain them. The word Hits then extends in both directions along each sequence as long as the performance of the cumulative alignment can be increased. The extension of the word hit in each direction stops when: the cumulative alignment score fails for the amount X of its maximum value achieved; the cumulative score returns to zero or less, due to the accumulation of one or more negative residue alignments; or the end of any sequence was reached. The parameters W; T and X of the BLAST algorithm determine the sensitivity and speed of alignment. The BLAST program uses the default determinations a word length (W) of 1 1, the alignments (B) of the BLOSUM62 score matrix (See Henikoff and Henikoff (1989) Proc. Nat'l Acad.Sci. USA 89: 10915) of 50, the expectation (E) of 10, M = 5, N = 4, and a comparison of both filaments. In addition to calculating percent sequence identity, the BLAST algorithm performs a statistical analysis of the similarity between the two sequences (see, for example, Karlin and Altschul (1993) Proc Nat'l Acad. Sci. USA 90: 5873-5787) . A measure of similarity provided by the BLAST algorithm is the smallest sum probability (P (N)), which provides an indication of the probability by which a match occurs between two nucleotide or amino acid sequences. For example, a nucleic acid is considered to be similar to the reference sequence if the smallest sum probability in a comparison between the test nucleic acid and the reference nucleic acid is less than about 0.1, more preferably less than about 0.01, and more preferably less than about 0.001. Another indication that two polypeptide nucleic acid sequences are substantially identical is that the polypeptide encoded by the first nucleic acid is immunologically cross reactive with the polypeptide encoded by the second nucleic acid, as described above. In this manner, a polypeptide is typically substantially identical to a second polypeptide, for example, when the two peptides differ only in their conservative substitutions. Another indication that two nucleic acid sequences are substantially identical is that the two molecules hybridize to each other under stringent conditions, as described above. The isolated DNA can be rapidly modified by means of nucleotide substitutions, nucleotide deletions, nucleotide insertions and nucleotide inversions. These modifications cause new DNA sequences encoding this polypeptide or its derivatives. These modified sequences can be used to produce mutant proteins (muteins) or to promote the expression of variant species. Increased expression may include gene amplification, increased transcription, increased translation and other mechanisms. These mutant IL-1 type derivatives RD9 include predetermined or site-specific mutations of the polypeptide or its fragments, including inactive mutations using the degeneracy of the "Mutant LI-1 RD9" genetic code as used herein encompasses a polypeptide which is within the definition of homology of IL-1 R9 as determined above, but which has an amino acid sequence that differs from the other IL-1 RD type polypeptides as found naturally, either by deletion, substitution or insertion. In particular "site-specific mutant IL-1 RD9" includes a polypeptide having substantial homology to the Nr ID polypeptide of Sec: 6, 8, 10, 12, 14, or 14, and typically shares the majority of the biological activities or effects of the forms described here.

Although site-specific mutation sites are predetermined, mutants do not need to be site-specific. Mutagenesis of mammalian IL-1 RD9 can be achieved by preparing insertions or deletions of amino acid in the gene, connected with the expression. The substitutions, eliminations, insertions or many combinations can be generated to arrive at a final construction. Inserts include amino- or carboxy-terminal fusions. The random mutagenesis can be carried out in the target codon. The expressed mammalian IL-1 RD9 mutants can be classified in their desired activity, providing some aspect of the structure-activity relationship. The methods for preparing substitution mutations at the predetermined sites in DNA having a known sequence are known in the art, for example, by means of mutagenesis of the M13 primer. See also Sambrook, et al., (1989) and Ausubel, et al., (1987 and Periodic Supplements). Mutations in DNA should not normally place the coding sequences outside of the reading frames and preferably will not create complementary regions that could hybridize to produce a secondary mRNA structure such as loops or hooks. The phosphoramidite method described by Beaucage and Carruthers (1981) Tetra. Letts. 22; 1859-1862, will produce suitable synthetic DNA fragments. A fragment of two filaments will often be obtained by synthesis of the complementary filament or by twisting to the filament under suitable conditions or by adding the complementary filament using the DNA polymerase with a suitable primer sequence. Polymerase chain reaction (PCR) techniques can often be applied in mutagenesis. Alternatively, mutagenesis primers are methods commonly used to generate the defined mutations at the predetermined sites. See, for example, Innis, et al., (Eds. 1990) PCR Protocols: A Guide to Methods and Applications. Academic Press; San Diego, CA; and Dieffenbach and Dveksler (1995, eds) PCR Primer: A Laboratory Manual. Cold Spring Harbor Press, CSH, NY. Suitable primers of length for example, 15, 20, 25 or longer can be prepared using the sequence provided.

IV. Proteins, peptides As described above, the present invention includes primate IL-1 RD8, primate IL-1 RD9 or rodent, and primate IL-1 RD10, for example, whose sequences are described, for example, in tables 1 -3, and are described here. The descriptions of the characteristics of IL-1 RD9 are applicable in most cases, with appropriate modifications, also to IL-1 RD8 and / or IL-1 RD10. Allelic variants and other variants are also contemplated, including, for example, to fusion proteins that combine portions of these sequences with others, including epitope markers and functional domains. Particularly interesting constructions will be intact intracellular or extra domains. The present invention also provides recombinant polypeptides, for example, heterologous fusion proteins that use segments of these rodent proteins. A heterologous fusion protein is a fusion of proteins or segments that are natural but not normally fused in the same way. In this manner, the fusion product of, for example, an IL-1 RD9 with another IL-1 receptor is a continuous protein molecule having sequences fused to a typical polypeptide linkage, typically prepared as a product of translation and exhibiting properties, for example, sequence or antigenicity, derived from each original peptide. A similar concept applies to heterologous nucleic acid sequences. In addition, new constructs can be prepared by combining similar functional or structural domains of other related proteins, for example, IL-1 receptors or Toll-like receptors, including species variants. For example, ligand-link segments or other segments can be "ingested" between different polypeptides or new fusion fragments. See, for example, Cunningham, et al., (1989) Science 243: 1330-1336; and O'Dowd, et al., (1988) J. Biol. Chem. 263: 15985-15992, each incorporated herein by reference. In this way, novel chimeric polypeptides that exhibit new combinations of specificities will result from the functional binding of the receptor-binding specificities. For example, the ligand binding domains of other receptor molecules can be added or substituted for other domains different from it or related proteins. The resulting protein will often have the function and properties of the hybrid. For example, a fusion protein can include a target domain that can serve to provide sequestration of the fusion protein in a particular subcellular organelle. The candidate fusion partners and sequences can be selected from several sequence databases, for example, GenBank, c / o NCBI, and BCG, University of Wisconsin Biotechnology Computing Group, Madison, Wl, which are incorporated herein by reference. The present invention particularly provides muteins that bind to ligands of the IL-1 type, and / or that are affected in signal transduction. The structural alignment of human IL-1 RD9 with other members of the IL-RL family shows conserved characteristics / residues. See pictures 1-4. The alignment of the human IL-1 RD9 sequence with other members of the IL-1 R family indicates several structurally and functionally shared characteristics. See also, Bazan et al., (1996) Nature 379: 591; Lodi et al., (1994) Science 263: 1762-1766; Sayle and Milner-White (1995) TIBS 20: 374-376 and Gronenberg, et al., (1991) Protein Engineering 4: 263-269. The ligands IL-1a and IL-1β bind an IL-1 receptor type I (IL-1 RD1) as the primary receptor and this complex then forms a high affinity receptor complex with the IL-1 receptor of the lll type (IL -1 RD3). These receptor subunits probably share with the receptors the new members of the IL-1 ligand family. See, for example, USSN 60 / 044,165 and USSN 60 / 055.1 1 1. It is likely that the ligand IL-1? of signals through a receptor comprising the association of IL-1 RD9 (alpha component) with IL-1 RD5 (beta component). Ligands IL-15 and IL-1e, each probably signaling through a receptor comprising the association of one of IL-1 RD4, IL-1 RD6, or IL-1 RD9 (alpha components) with one of IL -1 RD3, IL-1 RD5, IL-1 RD7, IL-1 RD8, or IL-1 RD10 (beta components). Similar variations in other counterparts of IL-1 R sequence species, eg, D1-D6, D8, D9 or D10 receptors, in the corresponding regions, should provide similar interactions with the ligand or substrate. Substitutions with rodent or primate, for example, mouse sequences or human sequences, are particularly preferred. Conversely, conservative substitutions outside the ligand binding interaction regions probably retain most of the signaling activities; and conservative substitutions outside the intracellular domains probably retain most of the ligand binding properties. The "derivatives" of primate or mouse IL-1 RD9 include mutants of the amino acid sequence, deglucosylation variants, metabolic derivatives and covalent conjugates or aggregation with other chemical moieties. The covalent derivatives can be prepared by linking the functionalities with the groups found in the amino acid side chains IL-1 RD9 or in the N- or C- terms, for example, by means known in the art. . These derivatives may include, without limitation, aliphatic esters or amides of the carboxyl terminus, or carboxyl side chains containing residues, O-acyl derivatives of the hydroxyl group-containing residues, and N-acyl derivatives of the group amino terminal amino acid or residues that contain the amino group, for example, lysine or arginine. The acyl groups are selected from the group of alkyl portions including the normal alkyl of C3 to C18, thus forming the alkanoyl aroyl species. In particular, glycosylation alterations are included, for example, prepared by modifying the glycosylation designs of a polypeptide during its synthesis and processing, or in other processing steps. Particularly preferred means for achieving this are exposure of the polypeptide to glycosylating enzymes derived from cells that normally provide this processing, for example, mammalian glycosylation enzymes. Deglycosylation enzymes are also contemplated. In addition, versions of the same primary amino acid sequence that have other minor modifications are included, including phosphorylated amino acid residues, for example, phosphotyrosine, phosphoserine or phosphothreonine. A major group of derivatives are the covalent conjugates of the receptors or their fragments with other polypeptides. These derivatives can be synthesized in a recombinant culture such as, for example, N-terminal or C-terminal fusions or through the use of agents known in the art for their utility in crosslinking proteins by means of the reactive side groups. Preferred derivation sites with the crosslinking agents are in free amino groups, carbohydrate moieties, and cysteine residues. Fusion polypeptides are also provided between the receptors and other homologous or heterologous proteins. The homologous polypeptides may be fusions between different receptors, for example, causing a hybrid protein that exhibits a binding specificity for multiple and different IL-1 ligands, or a receptor that may have amplified or weakened the specificity of the substrate effect. Similarly, heterologous fusions can be constructed that could exhibit a combination of properties or activities of the derived proteins. Typical examples are fusions of a reporter polypeptide, for example, luciferase with a segment or domain of a receptor, eg, a ligand binding segment, such that the presence or location of a desired ligand can be readily determined. See, for example, Dull, et al., U.S. Patent. No. 4,859,609, which is incorporated herein by reference. Other gene fusion partners include glutathione-S-transferase (GST), β. bacterial galactosidase, trpE, Protein A, β-lactamase, alpha amylase, alcohol hydrogenase and alpha match factor of yeast. See, for example, Godowski, et al., (1988) Science 241: 812-816. The phosphoramidite method described by Beaucage and Carruthers (1981) Tetra. Letts. 22: 1859-1862, will produce suitable synthetic DNA fragments. A double filament fragment will often be obtained by synthesizing the complementary filament or twisting the filament under suitable conditions or by adding the complementary filament using the DNA polymerase with a suitable primer sequence. These polypeptides may also have amino acid residues that have been chemically modified by means of phosphorylation, sulfonation, biotinylation, or the addition or removal of other portions, particularly those having molecular forms similar to the phosphate groups. In some embodiments, the modifications will be useful marker reagents, or serve as purification targets, e.g., affinity ligand. The fusion proteins were typically prepared by means of recombinant nucleic acid methods or by means of synthetic polypeptide methods. Techniques for the manipulation and expression of nucleic acid are described generally in, for example, Sambrook et al. , (1989) Molecular Cloning: A Laboratorv Manual (2nd ed.) Vol. 1-3, Cold Spring Harbor Laboratory and Ausbel et al., (Eds. 1987 and periodic supplements) Current Protocols in Molecular Biology, Greene / Wiley, New York, which are incorporated here for reference. Techniques for the synthesis of polypeptides are described for example, in Merrifield (1963) J. Amer. Chem. Soa 85: 2149-2156; Merrifield (1986) Science 232: 341-347; and Atherton et al., (1989) Solid Phase Peptide Synthesis: A Practical Approach, IRL Press, Oxford, each of which is incorporated for reference. See also Dawson et al., (1994) Science 266: 776-779 for methods for preparing larger polypeptides. This invention also contemplates the use of the derivatives of an IL-1 RD8, IL-1 RD9, or IL-1 RD10 different from variations in the amino acid sequence or glycosylation. These derivatives may include the covalent or aggregation association with the chemical portions. These derivatives are generally included in three classes: (1) salts, (2) covalent modifications of side chain residue and terminal residue, and (3) adsorption complexes, for example, with cell membranes. These covalent or aggregation derivatives are useful as immunogens, as reagents in immunoassays or in purification methods such as, for example, affinity purification of a receptor or other binding molecule, for example, an antibody. For example, an IL-1 ligand can be immobilized by means of covalent binding to a solid support such as, for example, bromo-activated cyanogen Sepharose, by means of methods known in the art, or it can be adsorbed on polyolefin surfaces. , with or without the crosslinking of glutaraldehyde, for use in the assay or purification of an IL-1 receptor, antibodies or other similar molecules. The ligand may also be labeled with a detectable group, for example, with radioactive iodine by means of the chloramine T method, covalently linked to rare earth chelates, or conjugated to another fluorescent portion for use in diagnostic assays. An IL-1 RD8, IL-1 RD9, or IL-1 RD10 of this invention can be used as an immunogen for the production of antiserum or specific antibodies, for example, capable of distinguishing between other members of the IL-1 receptor family, for IL-1 RD8, IL-1 RD9 or IL-1 RD10 or several of its fragments. IL-1 RD8, IL-1 RD9 or IL-1 RD10 can be used to classify monoclonal antibodies or antigen binding fragments prepared for immunization with various forms of impure preparations containing the protein. In particular, the term "antibodies" also encompasses the antigen binding fragments of natural antibodies, eg, Fab, Fab2, Fv, etc. Purified IL-1 RD9 can also be used as a reagent to detect antibodies generated in response to the presence of high levels of expression, or immunological disorders that lead to the production of the antibody to the endogenous receptor. Additionally, the IL-1 RD8, IL-1 RD9, or IL-1 RD10 fragments can also serve as immunogens to produce the antibodies of the present invention, as we will describe later. For example, this invention contemplates antibodies that have binding affinity with or were developed against the amino acid sequences illustrated, for example, in the Nr ID of Sec: 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20, its fragments, or several homologous peptides. In particular, this invention contemplates antibodies that have binding affinity to, or have been developed against, specific fragments that are presumed or are actually exposed to the outer surface of the IL-1 RD8 IL-1 RD9 polypeptide, or IL-1 RD10 natural. Various preparations of the desired selectivity in the link can be prepared by means of suitable cross-absorptions, etc.

Blocking the physiological response to receptor ligands may result from inhibition of ligand binding to the receptor, probably through competitive inhibition. Thus, in the in vitro assays of the present invention, antibodies or antigen binding segments of these antibodies are often used, or fragments attached to the solid phase substrates. These assays will also allow the determination for diagnosis of the effects of mutations and modifications of the ligand binding region, or other mutations and modifications, for example, that affect the signaling or enzymatic function. This invention also contemplates the use of competent drug classification assays, for example, where the neutralization of antibodies in the receptor or fragments compete with a test compound to bind to a ligand or other antibody. In this manner, antibodies or neutralizing fragments can be used to detect the presence of a polypeptide that shares one or more of the binding sites to the receptor and can also be used to occupy binding sites on a receptor that could bind to a ligand.

V. Preparation of nucleic acids and protein. The DNA encoding the polypeptides or their fragments can be obtained by means of chemical synthesis, classification into cDNA libraries, or classification of genomic libraries prepared from a wide variety of cell lines or tissue samples. The natural sequences can be isolated using the standard methods and sequences provided herein, for example, in Tables 1-3. Other counterparts of the species can be identified by means of hybridization techniques, or by means of several PCR techniques, combined with or searching the sequence databases, for example, GenBank. This DNA can be expressed in a wide variety of host cells for the synthesis of a full-length receptor or its fragments which can in turn, for example, be used to generate polyclonal or monoclonal antibodies; for link studies; for the construction and expression of the modified ligand binding or kinase / phosphatase domains; and for structure / function studies. The variants or fragments can be expressed in host cells that are transformed or transfected with the appropriate expression vectors. These molecules may be substantially free of protein or cellular contaminants, different from those derived from the recombinant host and are therefore particularly useful in pharmaceutical compositions when combined with a pharmaceutically acceptable carrier and / or diluent. The protein or its portions can be expressed as fusions with other proteins. Expression vectors are typically self-replicating DNA or RNA constructs containing the desired receptor gene or its fragments, usually operably linked to the appropriate genetic control elements that are recognized in a suitable host cell. These control elements are capable of performing expression within a suitable host. The specific type of control elements necessary to effect the expression will depend on the eventual host cell used. Generally, the elements of genetic control may include a prokaryotic promoter system or a control system for expression of the eukaryotic promoter, and typically include a transcriptional promoter, an optional operator to control the initiation of transcription, transcription enhancers to elevate the level of mRNA expression, a sequence encoding an appropriate ribosome binding site, and sequences that complete transcription and translation. Expression vectors also usually contain an origin of replication that allows the vector to replicate independently of the host cell. The vectors of this invention include those that contain DNA that encodes a protein, as we describe or its fragment encoding a biologically active equivalent polypeptide. The DNA can be under the control of a viral promoter and can encode a selection marker. This invention further contemplates the use of these expression vectors which are capable of expressing eukaryotic cDNA coding for this polypeptide in a prokaryotic or eukaryotic host, where the vector is compatible with the host and where the eukaryotic cDNA encoding the receptor is inserted. in the vector such that the growth of the host containing the vector expresses the cDNA in question. Usually, expression vectors are designed for stable replication in host cells or for amplification to greatly increase the total copy amount of the desired gene per cell. It is not always necessary to require that an expression vector replicate in a host cell, for example, it is possible to perform transient expression of the polypeptide or its fragments in several hosts using vectors that do not contain an origin of replication that is recognized by the host cell . It is also possible to use vectors that cause the integration of the portion encoding the polypeptide or its fragments into a host DNA by means of recombination. Vectors, as used herein, include plasmids, viruses, bacteriophage, integrable DNA fragments, and other vehicles that allow the integration of DNA fragments into the host genome. Expression vectors are specialized vectors that contain genetic control elements that perform the expression of operably linked genes. Plasmids are the most commonly used form of the vector but other forms of vectors having an equivalent function that are known in the art are also suitable for use herein. See, for example, Pouweis, et al., (1985 and Supplements) Cloning Vectors: A Laboratorv Manual. Elsevier, N.Y., and Rodriquez, et al., (Eds.) Vectors: A Survev of Molecular Cloning Vectors and Their Uses, Buttersworth, Boston, 1988, which are incorporated herein for reference. Transformed cells are preferably mammalian cells, which have been transformed or transfected with receptor vectors constructed using recombinant DNA techniques. The transformed host cells usually express the desired polypeptide or its fragments, but for the purpose of cloning, amplifying and manipulating their DNA, they do not need to express the target protein. This invention also contemplates transformed cells by culture in a nutrient medium, thus allowing the receptor to accumulate in the cell membrane. The polypeptide can be recovered, from the culture or in certain cases, from the culture medium. For the purpose of this invention, the nucleic sequences are operably linked when functionally related to each other. For example, DNA for a pre-sequence or secretory leader is operably linked to a polypeptide if it is expressed as a preprotein or participates in the direction of the polypeptide to the cell membrane or in the secretion of the polypeptide. A promoter is operably linked to a coding sequence if it controls transcription of the polypeptide; A ribosome binding site is operably linked to a coding sequence if it is located to allow translation. Usually, operatively linked means contiguous and within the reading frame, however, certain genetic elements such as, for example, the repressor genes are not linked contiguously but are still linked to the sequences of the operator which in turn control the expression. Suitable host cells include prokaryotes, lower eukaryotes, and major eukaryotes. Prokaryotes include both gram negative and gram positive organisms, for example, E. coli and B. subtilis. Lower eukaryotes include yeasts, for example S. cerevisiae and Pichia. and to the species of the genus Dictvostelium. Larger eukaryotes include cell lines from the tissue culture of animal cells, of non-mammalian origin, e.g., insect cells, and birds, and of mammalian origin, e.g., humans, primates, and rodents. The prokaryotic host-vector systems include a wide variety of vectors for many different species. As used herein, E, coli and its vectors will be used generically to include the equivalent vectors used in other prokaryotes. A representative vector for amplifying DNA is pBR322 or many of its derivatives. Vectors that can be used to express the receptor and its fragments include, but are not limited to, vectors such as those containing the lac promoter (pUC-series); trp promoter (pBR322-trp); Ipp promoter (the pIN series), lambda-pP or pR promoters (pOTS), or hybrid promoters such as ptac (pDR540). See Brosius, et al., (1988) "Expression Vectors Employing Lambda-, trp-, lac-, and Ipp-derived Promoters", in Vectors: A Survev of Molecular Cloning Vectors and Their Uses, (eds. Rodríguez and Denhardt) , Buttersworth, Boston, chapter 10, pages 205-236, which is incorporated herein by reference. Lower eukaryotes, for example, yeasts and Dictyostelium can be transformed with vectors containing the sequence IL-1 RD9. For the purpose of this invention, the most common lower eukaryotic host is baker's yeast, Saccharomyces cerevisiae. It will be used to generically represent lower eukaryotes even though a number of other strains and species are also available. Yeast vectors are typically formed by an origin of replication (less of the integrating type), a selection gene, a promoter, DNA encoding the receptor or its fragments, and sequences for the termination of translation, polyadenylation and termination of transcription. Suitable expression vectors for yeast include these constitutive promoters such as the 3-phosphoglycerate kinase and various other promoters of the glycolytic enzyme gene or these inducible promoters such as the alcohol dehydrogenase 2 promoter or the metallothionine promoter. Suitable vectors include derivatives of the following types: low number of self-replicating copies (such as the Yrp series), high number of self-replicating copies (such as the Yep series); integrating types (such as the Yip series), or mini-chromosomes (such as the Ycp series). Higher eukaryotic tissue culture cells are usually the preferred host cells for the expression of the functionally active interleukin protein. In principle, many larger eukaryotic tissue culture cell lines can be worked, for example, the baculovirus expression systems of insects, from a source of invertebrates or vertebrates. However, mammalian cells are preferred. Transformation or transfection and propagation of these cells have become routine procedures. Examples of useful cell lines include HeLa cells, Chinese hamster ovary (CHO) cell lines, baby rat kidney cell lines (BRK), insect cell lines., bird cell lines, and monkey cell lines (COS). Expression vectors for these cell lines usually include an origin of replication, a promoter, a translation initiation site, RNA binding sites (if genomic DNA is used), a polyadenylation site, and a transcription termination site . These vectors also usually contain a selection gene or an amplification gene. Suitable expression vectors can be plasmids, viruses or retroviruses carrying promoters derived, for example, from sources such as adenovirus, SV40, parvovirus, vaccinia virus or cytomegalovirus. Representative examples of suitable expression vectors include pCADNI; pCD, see Okayama, et al., (1985) Mol. Cell. Biol. 5: 1 136-1 142: pMCI neo PoliA; see Thomas, et al., (1987) Cell 51: 503-512; and a baculovirus vector such as, for example, pAC 373 or pAC 610. For secreted proteins, an open reading frame usually encodes a polypeptide formed by a mature or covalently bound product at its N terminus to a signal peptide. The signal peptide is inserted before the secretion of the mature or active polypeptide. The insertion site can be predicted with a high degree of accuracy of the empirical rules, for example, von-Heijne (1986) Nucleic Acids Research 14: 4683-4690 and Nielsen, et al., (1997) Protein Eng. 10: 1 -12, and the precise amino acid composition of the signal peptide often does not appear to be critical to its function, for example, Randall et al., (1989) Science 243: 1 156-1 159; Kaiser et al., (1987) Science 235: 312-317. It will often be convenient to express these polypeptides in a system that provides a specific or defined glycosylation design. In this case, the usual design will be provided naturally by the expression system. However, the design will be modifiable by exposing the polypeptide, eg, a non-glycosylated form, to the appropriate glycosylating proteins introduced into the heterologous expression system. For example, the receptor gene can be co-transformed with one or more genes encoding mammalian enzymes or other glycosylating enzymes. Using this method, certain mammalian glycosylation designs will be achieved in prokaryote or other cells. The source of IL-1 RD8, IL-1 RD9 or IL-1 RD10 can be a eukaryotic or prokaryotic host expressing IL-1 RD8, IL-1 RD9, or IL-1 RD10 as described above. The source can also be a cell line such as, for example, Swiss 3T3 mouse fibroblasts, but other mammalian cell lines are also contemplated in this invention, the cell line being that of the human species. Now that the sequences are known, primate IL-1 Rs, fragments and their derivatives can be prepared by conventional processes to synthesize peptides. These include processes such as those described in Stewart and Young (1984) Solid Phase Peptide Svnthesis, Pierce Chemical Co., Rockford, IL; Bodanszky and Bodansky (1984) The Principies of Peptide Svnthesis, Springer-Verlag, New York, all are incorporated here for reference. For example, an azide process, a process with acid chloride, a process with acid anhydride, a process with mixed anhydride and a process with active ester (for example, p-nitrophenyl ester, N-hydroxysuccinimide ester, or cyanomethyl) can be used. ester), a carbodiimidazole process, an oxidant-reducing process, or a dicyclohexylcarbodiimide (DCCD) / additive process. The solid phase or solution phase syntheses are applicable to the above processes. Similar techniques can be used with the partial IL-1 RD9 sequences. The proteins, polypeptides, fragments or derivatives of IL-1 RD8, IL-1 RD9 or IL-1 RD10 are suitably prepared according to the above processes in the manner typically used in the synthesis of the peptide, generally by means of a process called in steps which comprises condensing an amino acid at the terminal amino acid, one by one in sequence or by means of connecting fragments of the peptide at the terminal amino acid. Amino groups that are not used in the binding reaction typically must be protected to prevent binding at the wrong location. If the solid phase synthesis is adopted, the C-terminal amino acid is attached to an insoluble or support vehicle through its carboxyl group. The insoluble carrier is not particularly limited as long as it has a binding capacity to the reactive carboxyl group. Examples of these insoluble carriers include halomethyl resins, such as, for example, chloromethyl resin or bromomethyl resin, hydroxymethyl resins, phenol resins, tert-alkyloxycarbonylhydrazide resins, and the like. A protected group amino acid is linked in sequence by means of the condensation of its activated carboxyl group and the reactive amino group of the previously formed peptide or chain, to synthesize the peptide step by step. After synthesizing the entire sequence, the peptide is separated from the insoluble carrier to produce the peptide. This solid phase method was described by Merrifield, et al.; (1963) in J. Am. Chem. Soc. 85: 2149-2156, which is incorporated herein by reference. The protein and its separated fragments can be isolated and purified from the reaction mixture by means of a peptide separation, for example, by extraction, precipitation, electrophoresis, various forms of chromatography and the like. The receptors of this invention can be obtained in varying degrees of purity depending on the intended uses. Purification can be achieved through the use of the protein purification techniques described herein, see below, or through the use of the antibodies described in immunosorbent affinity chromatography methods. This immunoabsorbent affinity chromatography is carried out by first binding the antibodies to a solid support and then contacting the bound antibodies with the solubilized lysates of the appropriate cells, lysates of other cells expressing the receptor, or lysates or supernatants of cells that produce to the polypeptide as a result of DNA techniques, see below.

Generally, the purified protein will have at least about 40% purity, ordinarily at least about 50% purity, usually at least about 60% purity, typically at least about 70% purity, more typically at least about 80%, preferably at least about 90% pure and more preferably at least about 95% pure, and in particular embodiments, 97-99% or more. The purity usually has a basis in weight but it can also have a molar base. It will be appropriate to apply different tests. Similar concepts apply to polynucleotides and antibodies.

VI Antibodies Antibodies can be developed from various IL-1 RD8, IL-1 RD9, or mammalian IL-1 RD10 described herein, for example, primate IL-1 RD9 polypeptides and their fragments, both in natural and in its recombinant forms, the difference is that the antibodies to the active receptor will more likely recognize the epitopes that are only present in the natural conformations. Detection of the denatured antigen can also be useful in eg Western analysis. Anti-idiotypic antibodies, which would be useful as agonists or antagonists of the natural receptor or of an antibody, are also contemplated. Antibodies, including binding fragments and single chain versions, against predetermined fragments of the polypeptide can be developed by immunizing animals with the conjugates of the fragments with immunogenic proteins. The monoclonal antibodies were prepared from cells that secrete the desired antibody. These antibodies can be selected for binding to the normal or defective protein, or they can be classified for agonistic or antagonistic activity. These monoclonal antibodies usually bind at least one KD of about 1 mM, more usually at least about 300 μM, typically at least about 100 μM, more typically at least about 30 μM, preferably at least about 10 μM. μM, and more preferably at least about 3 μM or more. The antibodies, including the antigen binding fragments of this invention may have a significant diagnostic or therapeutic value. They can be potent antagonists that bind to the receptor and inhibit binding to the ligand or inhibit the ability of the receptor to produce the biological response, for example, acting on its substrate. They may also be useful as non-neutralizing antibodies and may bind to toxins or radionuclides to bind to producer cells or cells located at the source of interleukin. Moreover, these antibodies can be combined with drugs or other therapeutic agents, directly or indirectly by means of a linker. The antibodies of this invention may also be useful in diagnostic applications. As capture or non-neutralizing antibodies, they can bind to the receptor without inhibiting the ligand or substrate. As neutralizing antibodies, they can be useful for competent binding assays. They can also be useful for detecting or quantifying the ligand. They can be used as reagents for the Western blot analysis, or for the immunoprecipitation or immunopurification of the respective protein. Protein fragments can be attached to other materials, particularly polypeptides, such as polypeptides fused or covalently linked to be used as immunogens. The mammalian IL-1 Rs and their fragments can be fused or covalently linked to a variety of immunogens, such as, for example, a limpet hemocyanin, bovine serum albumin, tetanus toxoid, etc. See Microbiology, Hoeber Medical Division, Harper and Row 1969; Landsteiner (1962) Specificity of Serological Reactions, Dover Publications, New York; and Williams, et al., (1967) Methods in Immunoloqy and Immunochemistry, Vol 1 Academic Press, New York; each of them is incorporated here for reference, for descriptions of the methods for preparing the polyclonal antiserum. A typical method includes the hyperimmunization of an animal with an antigen. The blood of the animal is then collected after repeated immunizations and the gamma globulin is isolated. In some cases, it is convenient to prepare monoclonal antibodies from several mammalian hosts, such as mice, rodents, primates, humans, etc. The description of the techniques for preparing these monoclonal antibodies can be found in, for example, Stites et al., (Eds.) Basic and Clinical Immunology (fourth ed.), Lange Medical Publications, Los Altos, CA, and references quoted here.; Harlow and Lane (1988) Antibodies: A Laboratorv Manual, CSH Press; Goding (1986) Monoclonal Antibodies: Principies and Practice (2nd ed.) Academic Press, New York; and particularly in Kohier and Milstein (1975) in Nature 256; 495-497, which describes a method for generating monoclonal antibodies. Each of these references is incorporated herein for reference. Briefly, this method includes injecting an animal with an immunogen. The animal is then sacrificed and the cells are taken from its spleen, which then fuses with the myeloma cells. The result is a hybrid cell or "hydridome" that is capable of reproducing in vitro. The population of hydridomes is then classified to isolate the individual clones, each secreting a single species of antibody for the immunogen. In this way, the individual antibody species obtained are the products of the immortalized and cloned single B cells of the immunized animal generated in response to a specific site recognized in the immunogenic substance. Other suitable techniques include in vitro exposure of the lymphocytes to the antigenic polypeptides or alternatively to the selection of antibody libraries in the phage or similar vectors. See, Huse et al., (1989) "Generation of a Large Combinatorial Library of the Immunoglobulin Repertoire in Phage Lambda", Science 246: 1275-1281; and Ward, et al., (1989) Nature 341: 544-546, each of which is incorporated herein by reference. The polypeptides and antibodies of the present invention can be used with or without modification, including chimeric or humanized antibodies. Frequently, polypeptides and antibodies will be labeled by covalently or non-covalently linking a substance that provides the detectable signal. A wide variety of labels and combination techniques are known and extensively reported in the scientific and patent literature. Suitable labels include radionuclides, enzymes, substrates, co-factors, inhibitors, fluorescent moieties, chemiluminescent portions, magnetic particles and the like. The patents that explain the use of these labels include the patents of E.U.A. Nr 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437; 4,275,149; and 4,366,241. In addition, recombinant or chimeric immunoglobulins can be produced, see Cabilly patent of E.U.A. No. 4,816,567, or can be prepared in transgenic mice, see Méndez et al., (1997) Nature Genetics 15: 146,156. These references are incorporated herein for reference. The antibodies of this invention can also be used by affinity chromatography in isolating IL-1 Rs. The columns can be prepared where the antibodies are bound to a solid support, for example, particles, such as, for example, agarose, Sephadex or the like, where a cell lysate can be passed through the column, the column is washed followed by concentrations of a soft denaturing, thus releasing the purified protein. The protein can be used to purify the antibody. The antibodies can also be used to classify the expression libraries for the particular expression products. Usually the antibodies used in this procedure will be labeled with a portion that allows easy detection of the presence of an antigen by means of antibody binding. Antibodies developed against an IL-1 R will also be used to develop anti-idiotypic antibodies. These will be useful for detecting or diagnosing various immunological conditions related to the expression of the protein or cells expressing the protein. They will also be useful as ligand agonists or antagonists, which may be competitive inhibitors or substitutes for natural ligands. An IL-1 R polypeptide that specifically binds to or is specifically immunoreactive with an antibody generated against a defined immunogen, such as, for example, an immunogen formed by the amino acid sequence of, for example, Sec. Nr ID: 4, 10, or 20, is typically determined in an immunoassay. The immunoassay typically uses a polyclonal antiserum that was developed for example, from a Sec. Nr ID polypeptide: 4, 10 or 20. This antiserum is selected to have low cross-reactivity against other members of the IL-1R family, for example, IL-1 Rs D1 to D8, preferably of the same species, and this cross-reactivity is removed by means of immunosorption before use in the immunoassay. To produce the antiserum for use in an immunoassay, the polypeptide of eg, the Nr ID of Sec: 4, 10 or 20 is isolated in the manner described herein. For example, the recombinant polypeptide can be produced in a mammalian cell line. A suitable host, eg, a mouse strain such as, for example, Balb / c, is immunized with the selected protein, typically using a standard adjuvant, such as, for example, the Freund adjuvant and a standard mouse immunization protocol (see Harlow and Lane, supra). Alternatively, a synthetic peptide derived from the sequences described herein and combined with a carrier polypeptide can be used as an immunogen. The polyclonal sera were collected and titrated against the immunogen peptide in an immunoassay, for example, a solid phase immunoassay with the immunogen immobilized on a solid support. The polyclonal antiserum with a titrant of 104 or more is selected and tested in its cross-reactivity against other members of the IL-1 R family, for example, IL-1 RD1 to IL-1 RD6, using a competitive binding immunoassay as per example, the one described in Harlow and Lane, supra, on pages 570-573. Preferably, at least two members of the IL-1 R family are used in this determination. These members of the IL-1 R family can be produced as recombinant and isolated polypeptides using standard molecular biology and protein chemistry techniques as described herein. Immunoassays in the competitive binding format can be used for cross-reactivity determinations. For example, the Nr ID of Sec: 4, 10 or 20 polypeptide can be immobilized on a solid support. The polypeptides added to the assay compete with the binding of the antiserum with the immobilized antigen. The ability of the above polypeptides competes with the binding of the antiserum to the immobilized polypeptide compared to the polypeptides of IL-1 RD1 to IL-1 RD6. The percentage cross-reactivity for the above polypeptides is calculated using standard calculations. Antisera are selected and pooled with less than 10% cross-reactivity with each of the listed polypeptides. The cross-reactive antibodies are then removed from the pooled antiserum by means of immunoabsorption with the proteins listed above. The immunoabsorbed and pooled antiserum is then used in a competitive binding immunoassay as described above to compare a second polypeptide with the immunogen polypeptide (e.g., the IL-1 RD8, IL-1 RD9, or IL-1 RD10 polypeptide). Nr Sec ID: 4,10 or 20). To prepare this comparison, two polypeptides are tested over a wide concentration range and the amount of each polypeptide required to inhibit 50% binding of the antiserum to the immobilized polypeptide is determined. If the amount of the second polypeptide required is less than two times the amount of polypeptide of the selected polypeptide or polypeptides that is required, then the second polypeptide is said to be specifically linked to an antibody generated for the immunogen. It should be understood that these IL-1 R polypeptides are members of a family of homologous polypeptides comprising at least 7 previously identified genes. For the particular gene product, such as, for example, IL-1 RD9, the term refers not only to the amino acid sequences described herein but also to other polypeptides that are allelic, non-allelic variants or species variants. It should also be understood that the terms include unnatural mutations introduced by means of deliberate mutation using conventional recombinant technology such as, for example, mutation of a single site, or by cutting short sections of DNA encoding proteins. respective or by means of the replacement of new amino acids or aggregate of new amino acids. These minor alterations will typically substantially maintain the immunoidentity of the original molecule and / or its biological activity. In this way, these alterations include polypeptides that are specifically immunoreactive with an IL-1 protein RD8, IL-1 RD9 or natural IL-1 RD10. The biological properties of the altered polypeptides can be determined by expressing the polypeptide in a suitable cell line and measuring the appropriate effect, for example, in the transfected lymphocytes. Particular modifications of the polypeptide considered minor would include the conservative substitution of amino acids with similar chemical properties, as described above for the IL-1 R family as a whole. Aligning a polypeptide optimally with the IL-1 Rs polypeptide and using the conventional immunoassays described herein to determine immunoidentity, the compositions of the polypeptide of the invention can be determined.

Vile. Types and Quantification Both the natural and recombinant forms of the IL-1 R type molecules of this invention are particularly useful in kits (kits) and test methods. For example, these methods would also be applied to the selection of binding activity, for example, ligands for these proteins. Several methods have been developed for automatic testing in recent years, so as to allow the selection of tens of thousands of compounds per year. See, for example, the automated BIOMEK workstation, Beckman Instruments, Palo Alto, California, and Fodor et al., (1991) Science 251: 767-773, which is incorporated herein by reference. The latter describes a means for testing the bond by means of a number of defined polymers synthesized on a solid substrate. The development of assays suitable for classifying an agonist / antagonist homologous ligand or polypeptides can be greatly facilitated by the provision of large quantities of purified IL-1 Rs, soluble in an active state as, for example, provided in this invention. The purified IL-1 RD8, IL-1 RD9, or IL-1 RD10 can be coated directly on plates for use in the aforementioned ligand classification techniques. However, non-neutralizing antibodies to these polypeptides can be used as capture antibodies to immobilize the receptor on the solid phase, useful for example for use in diagnosis. This invention also contemplates the use of the fragments of IL-1 RD8, IL-1 RD9, or IL-1 RD10, peptide and its fusion products in a variety of kits for diagnosis and methods to detect the presence of the protein to its ligand. Alternatively, or additionally, antibodies against the molecules can be incorporated into the kits and methods. Typically, the kit will have a compartment that contains, for example, both the IL-1 RD9 peptide or the gene segment or a reagent that recognizes one or the other. Typically, recognition reagents, in the case of the peptide, will be a ligand or antibody, or in the case of a segment of the gene, will generally be a hybridization probe. A preferred kit for determining the concentration of IL-1 RD8, IL-1 RD9, or IL-1 RD10 in a sample will typically comprise a labeled compound, e.g., ligand or antibody, which has a known binding affinity for IL- 1 RD9, a source of IL-1 RD9 (natural or recombinant) as a positive control, and a means to separate the binding of the free labeled compound, eg, a solid phase to immobilize IL-1 RD9 in the test sample. Typically, compartments containing reagents, and instructions will be provided. Antibodies, including antigen binding fragments, mammalian-specific IL-1 RD8, or fragment of a peptide, or fragments of the receptor are useful for diagnostic applications to detect the presence of elevated levels of the ligand and / or its fragments Diagnostic assays can be homogeneous (without a separation step between the free reagent and the antibody-antigen complex) or heterogeneous (with a separation step). Several commercial assays exist, such as, for example, the radioimmunoassay (RIA) enzyme-linked immunosorbent assay (ELISA), enzyme immunoassay (EIA), enzyme-linked immunoassay (EMIT), substrate-labeled fluorescent immunoassay (SLFIA), and Similar. For example, unlabeled antibodies can be used, using a second antibody that is labeled and that recognizes the antibody for an IL-1 R or for its particular fragment. These trials have also been extensively described in the literature. See, for example, Harlow and Lane (1998) Antibodies: A Laboratory Manual, CSH, and Coligan (ed.1991) and periodic supplements, Current Protocols in Immunology Greene / Wiley, New York. Anti-idiotypic antibodies may have a similar use to serve as agonists or antagonists of IL-1 Rs. These should be useful as therapeutic reagents under the right circumstances. Frequently, the reagents for the tests for the diagnosis are provided in the kits, in such a way that the sensitivity of the assay is optimized. For the invention, depending on the nature of the assay, the protocol and the label, both the labeled or unlabeled antibody, or the labeled ligand, are provided. It is usually provided together with other additives, such as, for example, pH regulators, stabilizers, materials necessary for the production of signal as substrates for enzymes and the like. Preferably, the kit will also contain instructions for proper use and disposal of the contents after use. Typically, the kit has compartments for each useful reagent, and will contain instructions for the proper use and disposal of reagents. Conveniently, the reagents are provided as a dry lyophilized powder, where the reagents can be reconstituted in an aqueous medium having the appropriate concentrations to perform the assay. The aforementioned constituents of the diagnostic tests can be used without modification or can be modified in a variety of ways. For example, labeling can be achieved by covalent or non-covalent bonding of a portion that directly or indirectly provides a detectable signal. In many of these assays, a test compound, IL-1 R, or antibodies can be labeled directly or indirectly. The possibilities for directing labeling include groups of labels: radiolabels such as 25l, enzymes (US patent No. 3,645,090) such as, for example, peroxidase and alkaline phosphatase and fluorescent labels (US Patent No. 3,940,475) to monitor the change in fluorescent intensity, change in wavelength, or fluorescence polarization. Both patents are incorporated herein for reference. The possibilities for indirect labeling include the biotinylation of a constituent followed by the binding with avidin bound to one of the above groups of labels. There are also numerous methods for separating the binding of the free ligand, or alternatively the binding of the free test compound. IL-1 R can be immobilized in several matrices followed by washing. Suitable matrices include plastic such as an ELISA plate, filters and beads. Methods for immobilizing the receptor in a matrix include, but are not limited to, direct adhesion to the plastic, the use of a capture antibody, the chemical connection, and biotin-avidin. The last step in this method includes the precipitation of the antibody / antigen complex by means of several methods including those using, for example, an organic solvent such as, for example, polyethylene glycol or a salt such as, for example, ammonium sulfate. Other suitable separation techniques include, without limitation, the magnetizable particle method of the fluorescein antibody described in Rattle, et al., (1984) Clin. Chem. 30 (9): 1457-1461, and the magnetic particle separation of the double antibody as described in the US patent. No. 4,659,678, each incorporated herein by reference. Methods for linking the protein or fragments to various labels have been reported extensively in the literature and do not require a detailed description here. Many of the techniques include the use of carboxyl groups activated both by the use of carbodiimide or active esters to form peptide bonds, the formation of thioethers by means of the reaction of a mercapto group with an activated halogen such as, for example, chloroacetyl , or an activated olefin such as, for example, maleimide, to bind, or the like. The fusion of the polypeptides will also find use in these applications. Another aspect of the diagnosis of this invention includes the use of oligonucleotide or polynucleotide sequences taken from the sequence of an IL-1 R: These sequences can be used as probes to detect IL-1 levels. 1 R in patients suspected of having an immune disorder. The preparation of both RNA and DNA nucleotide sequences, the labeling of the sequences, and the preferred size of the sequences have had a wide description and discussion in the literature. Normally, an oligonucleotide probe must be at least about 14 nucleotides, usually at least 18 nucleotides, and the polynucleotide probes can be formed by several kilobases. Various labels, more commonly radionuclides, particularly 32P, can be used. However, other techniques can also be used, such as, for example, biotin-modified nucleotides for introduction into the polynucleotide. Biotin serves as the site to bind avidin or antibodies, which can be labeled with a wide variety of labels, such as, for example, radionuclides, fluorescers, enzymes or the like. Alternatively, antibodies that can recognize specific duplexes, including DNA duplexes, RNA duplexes, hybrid DNA-RNA duplexes, or DNA-protein duplexes, can be used. The antibodies in turn can be labeled and carry out the assay in the place where the duplex is bound to a surface, such that after the formation of the duplex on the surface, the presence of the antibody bound to the duplex can be detected. The use of the probes in the novel anti-sense RNA can be carried out with conventional techniques such as, for example, nucleic acid hybridization, selection, recombinant probe, translation of the released hybrid (HRT), and translation of the arrested hybrid ( HART). It also includes amplification techniques such as the polymerase chain reaction (PCR).

Diagnostic kits that also test the qualitative or quantitative presence of other markers are also contemplated. The diagnosis or prognosis may depend on the combination of multiple indications used as markers. In this way, kits can test combinations of markers. See for example, Viallet et al., (1989) Progress in Growth Factor Res. 1: 89-97.

VIII. Therapeutic utility This invention provides reagents with a significant therapeutic value. IL-1 Rs (natural or recombinant), their fragments, mutein receptors, and antibodies, together with the compounds identified as possessing binding affinity to receptors or antibodies, should be useful for the treatment of conons exhibiting a Abnormal expression of the receptors of their ligands. This abnormality will typically manifest itself through immunological disorders. Adonally, this invention should provide a therapeutic value in various diseases or disorders associated with abnormal expression or abnormal firing of the ligand response. It has been suggested that IL-1 ligands are involved in morphological development, for example, the determination of dorso-ventral polarity, and immunological responses, particularly primitive innate responses. See, for example, Sun, et al., (1991) Eur. J. Biochem. 196: 247-254; Hultmark (1994) Nature 367: 1 16-1 17. Recombinant IL-1 Rs, muteins, their agonist or antagonist antibodies, or antibodies can be purified and then administered to the patient. These reagents can be recombined for therapeutic use with adonal active ingredients, for example, in pharmaceutically acceptable carriers or diluents, together with physiologically harmless stabilizers and excipients. These combinations can be sterile, for example, filtered and placed in dosage form as by lyophilization for doses or stored in stabilized aqueous preparations. This invention also contemplates the use of antibodies or binding fragments that do not have complementary linkage. Ligand classification using IL-1 R or its fragments can be performed to identify molecules that have binding affinity to the receptors. Subsequent biological assays can then be used to determine whether a putative ligand can provide a competent link, which can block the intrinsic stimulating activity. Fragments of the receptor can be used as a blocker or antagonist since it blocks the activity of the ligand. Similarly, a compound having an intrinsic stimulating activity can activate the receptor and is therefore an agonist since it stimulates the activity of the ligand, for example, by inducing signaling. This invention also contemplates the therapeutic use of antibodies to IL-1 Rs as antagonists. The amounts of reagents necessary for effective therapy will depend on many factors, including the means of administration, target site, physiological life of the reagent, pharmacological life, physiological state of the patient and other medications administered. In this way, the treatment dose should be titrated to optimize safety and efficacy. Typically, doses used in vitro can provide useful guidance in amounts useful for in situ administration of these reagents. The test in animals of the effective doses for the treatment of particular disorders will provide another predicative indication of the human dose. Various considerations are described, for example, in Gilman et al., (Eds. 1990) Goodman and Gilman's: The Pharmacological Bases of Therapeutics, 8th ed. Pergamon Press; and Remington's Pharmaceutical Sciences, 17th ed., (1990) Mack Publishing Co., Easton, Penn; each of them is incorporated here for reference. Methods for administration are described here and below, for example, for oral, intravenous administration, intraperitoneal, or intramuscular, transdermal diffusion, and others. Pharmaceutically acceptable carriers will include water, saline, pH regulators and other compounds described, for example, in the Merck Index, Merck and Co., Rahway, New Jersey. Because high-affinity binding, or turnover numbers, between the putative ligand and its receptors, low doses of these reagents would be expected to be effective. And the signaling pathway suggests that extremely low amounts of the ligand can be effective. Thus, dose ranges would ordinarily be expected in smaller amounts at concentrations of 1 mM, typically less than around concentrations of 10 μM, usually less than 100 nM, preferably less than about 10 pM (picomolar), and more preferably less than around 1fM (femtomolar) with a suitable vehicle. Slow release formulations, or the slow release device will often be used for continuous administration. The IL-1 Rs, their fragments, and antibodies or their fragments, antagonists and agonists can be administered directly to the host to be treated, depending on the size of the compounds, it may be convenient to combine them with carrier proteins such as ovalbumins or serum albumin before its administration. Therapeutic formulations can be administered in many conventional dose formulations. While it is possible to administer only the active ingredient, it is preferable to present it as a pharmaceutical formulation. The formulations comprise at least one active ingredient, as defined above, with one or more acceptable carriers. Each vehicle must be both pharmaceutically and physiologically acceptable in the sense that it is compatible with other ingredients and is not harmful to the patient. The formulations include those suitable for oral, rectal, nasal or parenteral administration, (including subcutaneous, intramuscular, intravenous or intradermal). The formulations may conveniently be presented in unit dosage forms and may be prepared by methods known in the pharmacy art. See, for example, Gilman et al., (Eds. 1990) Goodman and Gilman's: The Pharmacological Bases of Therapeutics, 8th Ed. Pergamon Press; and Remington's Pharmaceutical Sciences, 17 Ed., (1990) Mack Publishing Co., Easton, Penn; Avis et al., (Eds. 1993) Pharmaceutical Dosage Forms: Parenteral Medications Dekker, NY; Lieberman et al., (Eds 1990) Pharmaceutical Dosage Forms: Tablets, Dekker, NY; and Lieberman, et al., (eds 1990) Pharmaceutical Dosage Forms: Disperse Systems Dekker, NY. The therapy of this invention can be combined with or used in conjunction with other therapeutic agents, particularly agonists or antagonists or other members of the IL-1 family.

IX Ligands The description of the IL-1 receptors used herein provides a means to identify ligands, as described above. This ligand must bind specifically to the respective receptor with a reasonably high affinity. The binding constants of the typical ligand receptor will be at least about 30 mM, for example, generally at least about 3 mM; more generally at least about 300 μM, typically at least 30 μM, 3 μM, 300 nM, 30 nM, etc. Several constructions are available that allow labeling of the receptor to detect its ligand. For example, direct labeling of IL-1 R, fusing in it markers for secondary labeling, eg, FLAG or other epitope markers, etc., will allow detection of the receptor. This may be a histological method, such as an affinity method for biochemical purification, or labeling or selection in an attempt to clone the expression. A two-hybrid selection system can also be applied by preparing the appropriate constructs with the available IL-1 R sequences. See, for example, Fields and Song (1989) Nature 340: 245-246. Generally, the descriptions of the IL-1Rs will be applied analogously to the individual specific modalities directed to the reagents and compositions of IL-1 RD8, IL-1 RD9, or IL-1 RD10. The broad scope of this invention is best understood by reference to the following examples, which are not intended to limit the inventions to the specific embodiments.

EXAMPLES 1. - General methods Some of the standard methods are described or are mentioned in for example, Maniatis et al., (1982) Molecular Cloninq, A Laboratorv Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor Press; Sambrook et al., (1989) Molecular Cloning: A Laboratorv Manual (2nd Ed), volumes 1-3, CSH Press, NY; Ausubel et al., Biologv, Greene Publishing Associates, Brooklyn, NY; or Ausubel et al., (1987 and supplements) Current Protocols in Molecular Biology, Greene Wiley, New York. Methods for the purification of the protein include methods such as ammonium sulfate precipitation, column chromatography, electrophoresis, centrifugation, crystallization and others. See, for example, Ausubel et al., (1987 and periodic supplements); Coligan et al., (Ed. 1996 and periodic supplements), Current Protocols In Protein Science, Greene / Wiley, New York; Deutscher (1990) "Guide to Protein Purification" in Methods in Enzvmology, vol 182, and other volumes in these series; the manufacturer's literature about the use of protein purification products, for example, Pharmacia, Piscataway, N.J., or Bio-Rad, Richmond, CA. The combination with recombinant techniques allows fusion with suitable segments, for example, with a FLAG sequence or an equivalent that can be fused by means of a removable protease sequence. See, for example, Hochuli (1989) Chemische Industrie 12: 69-70; Hochuli (1990) "Purification of Recombinant Proteins with Metal Chelate Absorbent" in Setlow (ed.) Genetic Engineering, Principle and Methods 12: 87-98, Plenum Press, NY: and Crowe et al., (1992) OlExexpress: The Hiqh Level Expression and Protein Purification System QUIAGEN, Inc., Chatsworth, CA. Sequence analysis was performed by computer, for example, using the available software programs, including those from the GCG (U. Wisconsin) and GenBank sources. Public sequence databases were also used, for example, from GenBank, NCBI, SWISSPROT, and others. Many techniques applicable to IL-10 receptors can be applied to IL-1 Rs, as described in, for example, USSN 08 / 110,683 (IL-10 receptor) which is incorporated herein by reference. In addition, while many of the techniques described are directed to the IL-1 RD9 reagents, corresponding methods will typically be applicable to the reagents IL-1 RD8, and IL-1 RD10. See also, USSN 60 / 065,776, filed November 17, 1997, and USSN 60 / 078,008, filed March 12, 1998, both incorporated herein by reference.

II. Computer analysis Human sequences related to IL-1 Rs were identified in several EST databases using for example the BLAST server (Altschul, et al (1994) Nature Genet 6: 1 19-129). The methods based on the design and the sensitive profile (Bork and Gibson (1996) Meth. Enzvmol 266: 162-184) were used to identify a fragment of a gene that exhibited some homology with the IL-1 Rs. lll. Cloning of full-length human IL-1 R cDNAs PCR primers derived from the sequences IL-1 RD8, IL-1 RD9, or IL-1 RD10 (Nomura et al. (1994) DNA Res. 1: 27- were used. 35) to probe a suitable human cDNA library to give a full-length sequence of IL-1 RD9 or IL-1 RD10 cDNA or to probe a cDNA library derived from the human erythroleukemic TF-1 cell line (Kitamura et al. (1989) Blood 73: 375-380) to give the sequence of cDNA IL-1 R8. The full-length cDNAs for human IL-1 R9 were cloned, for example, by selection by DNA hybridization of phage? Gt10. PCR reactions were carried out using a T. aquaticus Taqplus DNA polymerase (Stratagene) under the appropriate conditions.

IV. Localization of mRNA IL-1 RD8, IL-1 RD9 and IL-1 RD10 Multiple human tissue (Cat # 1, 2) and spots of cancer cell lines (Cat # 7757-1), containing approximately 2 μg of poly (A) + RNA per lane, were compared to Clontech (Palo Alto, CA). The probes were redi-labeled with [a-32p] dATP, for example, using the random primer labeling kit Amersham Rediprime (RPN1633). The prehybridization and hybridizations were carried out at 65 ° C in 0.5 M Na2HPO4, 7% SDS, 0.5 M EDTA (pH 8.0). Washes with high astrigence were carried out, for example, at 65 ° C with two initial washes in 2 x SSC, 0.1% SDS for 40 minutes followed by a subsequent washing in 0.1 x SSC, 0. 1% SDS for 20 min. Then the membranes were exposed to -70 ° C to an X-ray film (Kodak) in the presence of intensifying screens. More detailed studies using Southerns from the cDNA library were performed with the human IL-1 RD9 clones to examine their expression in hemopoietic subsets or other cellular subsets. Two prediction algorithms were used that take advantage of the conservation and variation designs in the multiple aligned sequences, PHD (Rost and Sander (1994) Proteins 19: 55-72) and DSC (King and Sternberg (1996) Protein Sci. 5 : 2298-2310). Alternatively, two appropriate primers from tables 1, 2 or 3 were selected. RT-PCR was used on a sample of mRNA suitable for the presence of the message to produce a cDNA; for example, a sample that expresses the gene. The full-length clones can be isolated by means of hybridization of the cDNA libraries of the appropriate pre-selected tissues by PCR signal. The Northern Blots can be made. The message for the coding of the genes, for example, IL-1 RD9 will be tested by means of the appropriate technology, for example, PCR; immunoassay, hybridization or others. Organ and organ cDNA preparations are available, for example, from Clontech, Mountain View, CA. The identification of the sources of natural expression are useful, as already explained. And the identification of functional receptor subunit pairs will allow the prediction of what cells express, the combination of receptor subunits that will result in physiological responses for each of the IL-1 ligands. The message for IL-1 RD9 is quite rare, since it is not frequently found in sequence databases. This suggests, for example, a very rare message, or a highly restricted distribution. IL-1 R9 is predominantly expressed on T cells; NK cells, monocytes and dendritic cells. Southern analysis can be performed on the cDNA libraries: DNA (5 μg) of a primary amplified cDNA library is digested with the appropriate restriction enzymes to release the inserts, run on a 1% agarose gel, and transfers to a nylon membrane (Schleicher and Schuell, Keene, NH).

Samples for the isolation of human mRNA may include, for example, peripheral blood mononuclear cells (monocytes, T cells, NK cells, granulocytes, B cells), at rest (T100); peripheral blood mononuclear cells, activated with anti-CD3 for 2, 6, 12 h grouped (T101); T cell, Mot 72 THO clone, activated with anti-CD28 and anti-CD3 for 3, 6, 12 h grouped (T103); T cell, Mot 72 THO clone, anergic treated with a specific peptide for 2, 7, 12 h grouped (T104), T cell, TH1 grouped with (T107); T cell, TH1 clone HY06, activated with anti-CD28 and anti-CD3 for 3, 6, 12 h grouped (T108); T cell, TH1 clone HY06, anergic treated with a specific peptide for 2, 6, 12 h grouped (T109); T cell, TH2 clone HY935, latent (T110); T cell; TH2 clone HY935, activated with anti-CD28 and anti-CD3 for 2, 7, 12 h grouped (T11 1); T cells CD4 + CD45RO-T cells polarized 27 days in anti-CD28, IL-4, and polarized anti-IFN- ?, TH2, activated with anti-CD3 and anti-CD28 4 h (T1 16); tumor lines of Jurkat and Hut78 T cells, latent (T1 17); T cell clones, grouped, AD130.2, Tc783.12, Tc783.13, Tc783.58, Tc782.69, latent (T118); T cell clones randomized, T cell, latent (T119); splenocytes, latent (B100); splenocytes, activated with anti-CD40 and IL-4 (B101); B-cell EBV lines grouped WT49, RSB, JY, CVIR, 721,221, RM3, HSY, latent (B102); JY cell line B, activated with PMA and ionomycin for 1, 6 h grouped (B103); Clones NK 20 grouped, latent (K100); cloned NK 20 clones, activated with PMA and ionomycin for 6 h (K101); NKL clone, derived from peripheral blood of a patient with LGL leukemia, treated IL-2 (K106); cytotoxic clone NK 640-A30-1, latent (K107); Hemotopoietic precursor line TF1, activated with PMA and ionomycin for 1, 6 h grouped (C100); premonocytic line U937, latent (M100); U937 premonocytic line, activated with PMA and ionomycin for 1, 6 h grouped (M101); monocytes elutriated; activated with LPS, IFN ?, anti-IL-10 during 1, 2, 6, 12, 24 h grouped (M102), elutriated monocytes, activated with LPS; IFN ?, IL-10 for 1, 2, 6, 12, 24 h grouped (M103), elutriated monocytes, activated with LPS, IFN ?, anti-IL-10 for 4, 16 h grouped (M106); elutriated monocytes, activated with LPS, IFN ?, IL-10 for 4, 16 h grouped (M107); elutriated monocytes, activated with LPS for 1 h (M108); elutriated monocytes, activated with LPS for 6 h (M109); DC 70% CD1 a + of CD34 + GM-CSF, TNFa 12 days, latent (D101); DC 70% CD1 a +, CD34 + GM-CSF, TNFa 12 days, activated with PMA and ionomycin for 1 hr (D102); DC 70% CD1a +, CD34 + GM-CSF, TNFa 12 days, activated with PMA and ionomycin for 6 hr (D103); DC 95% CD1a +, CD34 + GM-CSF, TNFa 12 days FACS sorted, activated with PMA and ionomycin for 1, 6 h grouped (D104); DC 95% CD14 +, ex CD34 + GM-CSF, TNFa 12 days FACS ordered, activated with PMA and ionomycin 1, 6 hr grouped (D105); DC CD1a + CD86 +, CD34 + GM-CSF, TNFa 12 days FACS sorted, activated with PMA and ionomycin for 1, 6 h grouped (D106); DC monocytes GM-CSF, IL-4 5 days, latent (D107); DC monocytes GM-CSF, IL-4 5 days, latent (D108); DC of monocytes GM-CSF, IL-4 5 days, activated LPS 4, 16 h pooled (D109); DC monocytes GM-CSF, IL-4 5 days, activated TNFa, monocyte supe for 4, 16 h pooled (D1 10); benign tumor of leiomyoma L11 (X101); normal myometrium M5 (01 15); malignant leiomyosarcoma GS1 (X103); lung fibroblast sarcoma line MRC5, activated with PMA and ionomycin for 1, 6 h grouped (C101); cell line of renal epithelial carcinoma CHA, activated with PMA and ionomycin for 1, 6 h grouped (C102); fetal kidney 28 wk male (0100); fetal lung 28 wk male (0101); fetal liver 28 wk male (0102); fetal heart 28 wk male (0103), fetal brain 28 wk male (0104); fetal gallbladder 28 wk male (0106); fetal small intestine 28 wk male (0107); fetal adipose tissue 28 wk male (0108); fetal ovarian 25 wk female (0109); fetal uterus 25 wk female (0110); fetal testis 28 wk male (0111); fetal spleen 28 wk male (01 12); adult placenta 28 wk (01 13); and inflamed amygdala, 12 years old (X100), human skin sample with psoriasis; normal human skin sample; human group with rheumatoid arthritis; thyroid with Hashimoto's thyroiditis; normal human thyroid; human colon with ulcerative colitis; normal human colon, normal weight monkey colon; lung with pneumonia carnii pheumocística; allergic lung; group of three human smoker's lungs; group of two normal lungs; monkey lung with Ascaris; 24 hr; Monkey lung with Ascaris, 4 hr, normal weight monkey lung. The IL-1 RD8 message is described later in Table 5. There seems to be a correlation between the stage of tissue development and message levels: fetal and transformed tissues express high levels while normal adult tissues express low levels ( with the exception of the skeletal muscle). Other investigations of this phenomenon will need further experimentation. The message for the genes encoding IL-1 RD8 will be tested with the appropriate technology, for example, PCR, immunoassay, hybridization or others. Tissue and organ cDNA preparations are available for example, by Clontech, Mountain View, CA. As described, the identification of the sources of natural expression are useful. And the identification of functional receptor subunit pairs will allow the prediction of which cells express the combination of receptor subunits that will elicit the physiological response for each of the IL-1 ligands.

TABLE 5 Multiple tissue Northern Blots were performed with a radioguided probe, including the cytoplasmic region of the Interleukin-1 R8 receptor (IL-1 RD8). The results are summarized below. In all the listed cases there is a smaller band in 3.4 kb and in a few cases also a longer band in 4.0 kb.

V. Cloning of the counterparts of species of IL-1 RDs Several strategies were used to obtain counterparts of species of IL-1 RD8, IL-1 RD9, and IL-1 RD10 preferably from other primates. One of the methods is cross-hybridization using probes from DNA of closely related species. It may be useful to use evolutionary similar species as intermediate steps. Another method is to use specific PCR primers based on the identification of blocks of similarity or deferences between genes, eg, areas of polypeptides or nucleotide sequence highly conserved or non-conserved. In addition, the gene sequence databases can be classified for the related sequences of other species.

SAW. Production of the protein IL-1 RD8, IL-1 RD9 and mammalian IL-1 RD10 A suitable construction was prepared, for example, GST, fusion construct for example, in E. coli. For example, a mouse plasmid IGIF pGex was constructed and transformed into E. coli. Freshly transformed cells were grown, for example, in an LB medium containing 50 μg / ml ampicillin and induced with IPTG (Sigma, St. Louis, MO). After induction overnight, the bacteria were harvested and pellets containing, for example, the IL-1 R8 polypeptide were isolated. The pellets were homogenized, for example, in a TE buffer (50 mM Tris-base pH 8.0, 10 mM EDTA and 2 mM pephabloc) in 2 liters. This material was passed through a microfluidizer (Microfluidics, Newton, MA) three times. The fluidized supernatant was centrifuged in a Sorvall GS-3 rotor for 1 hour at 13,000 rmp. The resulting supernatant containing the IL-1 R polypeptide was filtered and passed over a glutathione-SEPHAROSE column equilibrated in 50 mM Tris-Base pH 8.0. Fractions containing the IL-1 RD9-GST fusion protein were pooled and inserted and inserted, for example, with thrombin (Enzyme Research Laboratories, Inc., South Bend, IN). The inserted group was then passed over a Q-SEPHAROSE column equilibrated in 50 mM Tris-Base. Fractions containing IL-1 RD9 were pooled and diluted in cold distilled H2O, to lower the conductivity, and passed over a new Q-SEPHAROSE column, alone or in succession with an immunoaffinity antibody column. The fractions containing the IL-1 RD9 polypeptide were grouped in aliquots and stored in a freezer at -70 ° C. Comparison of the CD spectrum with IL-1 R polypeptide may suggest that the protein is correctly folded. See Hazuda, et al., (1969) J. Bio Chem. 264: 1689-1693.

Vile. Determination of physiological forms of receptors Ligands IL-1a and IL-1β bind an IL-1 RD1 as the primary receptor and this complex then forms a high affinity receptor complex with IL-1 RD3. These receptor subunits are probably shared with the receptors for new members of the IL-1 ligand family. See for example, USSN 60 / 044,165 and USSN 60 / 055.1 1 1. The combination of IL-1 RD9 (type of subunit a, based on sequence analysis) will be combined with IL-1 RD5 (type of β subunit, based on sequence analysis) to form a heterodimeric receptor. Ligands IL-1d and IL-1 are probably signaling through a receptor comprising the association of IL-1 RD4, IL-1 RD6, or IL-1 RD9 (alpha components) with IL-1 RD3, IL- 1 RD8 or IL-1 RD10 (beta components). These defined subunit combinations can now be tested with the reagents provided. In particular, suitable constructs can be prepared for transformation or transfection of subunits into cells. Constructions for alpha chains can be prepared, for example, the forms IL-1 RD1, IL-1 RD4, IL-1 RD6 and IL-1 RD9. In a similar manner, the beta subunits IL-1 RD3, IL-1 RD5, IL-1 RD7, and IL-1 RD8 can be prepared. Structurally, IL-1 RD10 is the most similar to IL-1 RD8, suggesting that it may also be a subunit of the beta receptor. Combinatorial transfections of transformations can prepare cells that express defined subunits, which can be tested in their response to ligands IL-1. Suitable cell types can be used, for example, 293 T cells, Jurkat cells, with for example, a luciferase reporter construct controlled with nuclear Kappa B (NFkb) as described in for example, Otieno et al., (1997), Am. J Phvsiol 273-xxx. These combinations of various IL-1 ligands and receptors were tested to determine whether a functional signaling complex was formed using the constructed NFkb luciferase reporter controlled to indicate the formation of a functional (+) signaling complex or the non-formation of a functional signaling complex (-). The results are presented below, IL-1a + IL-1β + IL-1 RD1 + 11-1 RD3 = +; IL-1a + IL-1β + IL-1 RD1 + IL-1 RD5 = +; IL-1a + IL-1β + IL-1 RD1 + IL-1 RD8 = +; IL-1a + IL-1β + IL-1RD1 + IL-1RD10 can = + / ?; suggests that IL-1RD3, IL-1RD5, IL-1RD8 and IL-1RD10 can be functionally substituted with each other when in combination with IL-1a + IL-1β + IL-1RD1. Other combinations (below) show a failure in functional substitution; suggesting the importance of contextual dependence in substitution; for example, IL-1RD3, and IL-1RD8 can not functionally replace IL-1RD5 in the following combination: IL-1? + IL-1RD9 + IL-1RD5. IL + 1? + IL-1RD9 + IL-1RD5 = +; IL + 1? + IL-1 RD9 + IL-1 RD3 = -; IL + 1? + IL-1RD9 + IL-1RD8 = +; Another series of experiments tested the ability of the mouse (m) and human (h) homologs to functionally replace each other. The results are illustrated below, mlL-1? + MlL-1RD5 + mlL-1RD9 = +; m! L-1? + mlL-1 RD5 + WL-1 RD9 = -; mlL-1? + hiL-1 RD5 + ML-1 RD9 = -; mlL-1? + hlL-1 RD5 + mlL-1 RD9 = -; hIL-1? + mlL-1 RD5 + mlL-1 RD9 = -; hIL-1? + mlL-1RD5 + hIL-1RD9 = -; hIL-1? + hIL-1 RD5 + mIL-1 RD9 = -; hIL-1? + hIL-1 RD5 + hIL-1 RD9 = +; suggests that species homogeneity is necessary to form a functional complex in this particular constellation of ligand and receptor units. Biological assays will generally be directed to the ligand binding characteristic of the protein or to the receptor kinase / protease activity. The activity will typically be reversible, as are many other phosphatase or phosphorylase activities mediated by enzymatic actions, whose activities are easily measured by standard procedures. See, for example, Hardie, et al. (eds. 1995) The Protein Kinase FactBook, Volumes I and II, Academic Press, San Diego, CA; Hanks et al. (1991) Meth. Enzvmol 200: 38-62; Hunter et al. (1992) Cell 70: 375-388; Lewin (1990) Ce \\ 61: 743-752; Pines et al. (1991) Cold Spring Harbor Svmp. Quant. Biol. 56: 449-463; and Parker et al. (1993) Nature 363: 736-738. The family of interleukins 1 contains molecules, each of which is an important mediator of inflammatory disease. For a comprehensive review, see Dinarello (1996) "Biologic Basis for interleukin-1 in disease" Blood 87: 2095-2147. There are suggestions that several IL-1 ligands may play important roles in the initiation of the disease, particularly inflammatory responses. The discovery of new polypeptides related to the IL-1 family increases the identification of molecules that provide the molecular basis for the initiation of the disease and allow the development of therapeutic strategies of increased range and efficacy.

HIV: Preparation of antibodies specific for IL-1 Rs Inborn Balb / c mice were immunized intraperitoneally with recombinant forms of the polypeptide, for example, IL-1 RD8, IL-1 RD9, and purified IL-1 RD10, or NIH- cells 3T3 transfected stable. Animals were injected at appropriate times with protein, with or without an additional adjuvant, to further stimulate antibody production. Serum or hybridomas produced with the harvested spleens were collected. Alternatively, Balb / c mice were immunized with cells transformed with the gene or its fragments, endogenous or exogenous cells, or with isolated membranes enriched for the expression of the antigen. The serum was collected at the right time, typically after numerous administrations. Various techniques for gene therapy may be useful, for example, to produce proteins in situ, to generate an immune response. Monoclonal antibodies can be prepared. For example, the splenocytes were fused with a suitable fusion partner and the hybridomas were selected in the growth medium by means of standard methods. The supernatants of the hybridoma were classified in the presence of antibodies that bind to the desired IL-1 R, for example, by means of ELISA and another method. Antibodies that selectively recognize specific IL-1 R embodiments can also be selected or prepared. In another method, the synthetic peptides or purified protein are presented to an immune system to generate monoclonal or polyclonal antibodies. See, for example, Coligan (1991) Current Protocols in Immunology Wiley / Greene; and Harlow and Lane (1989) Antibodies: A Laboratorv Manual, Cold Spring Harbor Press. In suitable situations, the binding reagent is labeled in the manner described above, for example, fluorescence or other methods, or immobilized on a substrate for the panning methods. Nucleic acids can also be introduced into cells in an animal to produce the antigen, which serves to produce a immunological response. See, for example, Wang, et al. (1993) Proc. Nat'l Acad. Sci. 90: 4156-4160; Barry et al. (1994) BioTechnigues 16: 616-619; and Xiang, et al. (1995) Immunitv 2: 129-135. Moreover, antibodies that can be useful for determining the combination of IL-1 RD8, IL-1 RD9, or IL-1 RD10 with a functional beta subunit can be generated. Thus, for example, the epitopes characteristic of a particular alpha / beta functional combination can be identified with the appropriate antibodies.

IX. Production of fusion proteins with IL-1 Rs Several fusion constructs were prepared with IL-1 Rs. A portion of the appropriate gene was fused to an epitope tag, for example, a FLAG tag, or a construct of a two-hybrid system. See for example, Fields and Song (1989) Nature 340: 245-246. The epitope tag can be used in an expression cloning procedure with detection with anti-FLAG antibodies to detect the binding partner, eg, ligand for the respective IL-1 R. The two-hybrid system can also be used to isolate proteins that specifically bind, for example, to IL-1 RD9.

X. Relationship of the activity of the structure The information on the critical of the particular residues, is determined using the procedures and standard analysis. The standard mutagenesis analysis was carried out for example, generating many different variants in determined positions, for example, in the positions identified above, and evaluating the biological activities of the variants. This can be done to the point of determining the positions that modify the activity or focusing on the specific positions to determine the residues that can be substituted to retain, block or modulate the biological activity. Alternatively, the analysis of natural variants can indicate which positions tolerate natural mutations. This can result from the analysis of population variation among individuals, or through strains or species. The samples of the selected individuals were analyzed, for example, by PCR and sequencing analysis. This allows the evaluation of population polymorphisms.

XI. Isolation of a ligand for IL-1 Rs An IL-1 R can be used as a specific binding reagent to identify its binding partner, taking advantage of its binding specificity, most likely an antibody would be used. Typically, the binding receptor is a heterodimer of receptor subunits. A binding reagent is labeled as described above, for example, fluorescence or other method, or immobilized on a substrate for panning methods. The binding composition is used to classify an expression library prepared from a cell line expressing the binding partner, eg, ligand, preferably the associated membrane. Standard staining techniques are used to detect or classify the ligand expressed on the surface, or transformed cells that are expressed on the surface were sorted by panning. The classification of the intracellular expression was carried out by means of several staining or immunofluorescence procedures. See also, McMahan, et al. (1991) EMBO J. 10: 2821-2832. For example, on day 0, pre-coat permanox 2-chamber slides with 1 ml per fibronectin chamber, 10 ng / ml in PBS, for 30 min at room temperature. Rinse once by PBS. Then, place the COS cells in plates at 2-3 x 10 5 cells per chamber in 1.5 ml of the growth medium. Incubate overnight at 37 ° C. On the first day of each sample, prepare 0.5 ml of a solution of 66 μg / ml DEAE-dextran, 66 μM of chloroquine, and 4 μg of DNA in serum-free DME. For each group, a positive control was prepared, for example, of the IL-1 R-FLAG cDNA at a dilution at 1 and 1/200, and a negative model. Rinse the cells with serum-free DME. Add the DNA solution and incubate for 5 hours at 37 ° C. Remove the medium and add 0.5 ml of 10% DMSO in DME for 2.5 min. Stir and wash once with DME: Add 1.5 ml of growth medium and incubate overnight. On the second day, change the medium. On the third or fourth day, the cells were fixed and stained. Rinse the cells twice with the Hank's regulated saline solution (HBSS) and fix in 4% paraformaldehyde (PFA) / glucose for 5 minutes. Wash 3X with HBSS. The slides can be stored at -80 ° C after removing all the liquid. For each camera, incubations of 0.5 ml were carried out in the following manner. Add HBSS / saponin (0.1%) with 32 μl / ml of 1 M NaN3 for 20 minutes. The cells were then washed with HBSS / 1X saponin. Add the IL-1 R or IL-1 R / antibody complex to the cells and incubate for 30 minutes. Wash the cells twice with HBSS / saponin. If appropriate, add the first antibody for 30 min. Add the second antibody, for example, the anti-mouse antibody Vector, at a dilution of 1/200, and incubate for 30 min. Prepare the ELISA solution, for example, the Vector Elite ABC horseradish peroxidase solution, and pre-incubate for 30 min. Use, for example, 1 drop of solution A (avidin) and 1 drop of solution B (biotin) for every 2.5 ml of HBSS / saponin. Wash the cells twice with HBSS / saponin. Add the ABC HRP solution and incubate for 30 minutes. Wash the cells twice with HBSS, the second wash for 2 min, which closes the cells. Then add the Vector diaminobenzoic acid (DAB) for between 5 and 10 min. Use two drops of pH regulator plus 4 DAB drops plus 2 drops of H2O2 per 5 ml of distilled water. Carefully remove from the chamber and wash the slide in water. Air dry for a few minutes, then add 1 drop of Crystal Mount and a lid. Bake for 5 minutes at 85-90 ° C. Evaluate the positive staining of the groups and progressively sub-clone until isolating the single genes that are responsible for the binding. Alternatively, IL-1 R reagents were used to affinity purify or classify cells expressing a putative ligand. See, for example, Sambrook et al., Or Ausubel et al. Another strategy is to classify by a receptor bound to the membrane by panning. The receptor cDNA was constructed in the manner described above. The ligand can be immobilized and used to immobilize the cells with expression. Immobilization can be achieved by the use of suitable antibodies that recognize for example a FLAG sequence of an IL-1 R fusion construct, or by the use of antibodies developed against the first antibodies. The cycles of selection and recursive amplification lead to the enrichment of the appropriate clones and the eventual isolation of the clones that express the receptor. Phage display libraries can be classified by means of mammalian IL-1 Rs. Suitable labeling techniques, eg, anti-FLAG antibodies, will allow specific labeling of suitable clones. Many modifications and variations of this invention can be used without departing from its spirit and scope, as is obvious to those skilled in the art. The specific embodiments described herein are offered by way of example only, and the invention should be limited by the terms of the appended claims, together with the full scope of the equivalents accredited by these claims; and the invention should not be limited by the specific embodiments that have been presented here by way of example.

LIST OF SEQUENCES (1) GENERAL INFORMATION: (i) APPLICANT: Schering Corporation (ii) TITLE OF THE INVENTION: Human receptor proteins; reagents and related methods (iii) NUMBER OF SEQUENCES: 33 (iv) ADDRESS TO SEND CORRESPONDENCE (TO) RECIPIENT: Shering-Plow Corporation (B) STREET: 2000 Galloping Hill Road (C) CITY: Kenilworth (D) STATE: New Jersey (E) COUNTRY: USA (F) POSTAL CODE: 07033-0530 (v) COMPUTER LEADABLE FORM: (A): TYPE OF MEDIUM: Flexible disk (B) COMPUTER: IBM COMPATIBLE PC (C) OPERATING SYSTEM: PC-DOS / MS-DOS (D) SOFTWARE: Patentln Relay # 1.0, Version # 1.30 (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: (B) SUBMISSION DATE: (C) CLASSIFICATION: (vii) (A) PREVIOUS APPLICATION DATA: (A) APPLICATION NUMBER: US 60 / 078,008 (B) DATE OF SUBMISSION: MARCH 12, 1998 (vii) (A) PREVIOUS APPLICATION DATA: (A) APPLICATION NUMBER: US 60/081, 883 (B) SUBMISSION DATE: 15-APR-1998 (vii) (A) PREVIOUS APPLICATION DATA: (A) APPLICATION NUMBER: US 60 / 095,987 (B) DATE OF SUBMISSION: 10-AUG-1998 (vii) (A) PREVIOUS APPLICATION DATA: (A) APPLICATION NUMBER: US 08/971, 635 (B) SUBMISSION DATE: NOV-17-1997 (vii) (A) PREVIOUS APPLICATION DATA: (A) APPLICATION NUMBER: US 09 / 040,714 (B) DATE OF SUBMISSION: MARCH 18, 1998 (vii) (A) PREVIOUS APPLICATION DATA: (A) APPLICATION NUMBER: US 08/951, 829 (B) SUBMISSION DATE: 15-OCT-1997 (ix) INFORMATION ABOUT TELECOMMUNICATIONS (A) TELEPHONE: (908) 298-2135 (B) TELEFAX: (908) 298-5388 (2) SEQUENCE IDENTIFICATION INFORMATION NO. 1: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 1737 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: individual (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: cDNA (iii) HYPOTHETIC: Yes (ix) TRAIT: (A) NAME / KEY: CDS (B) LOCATION: 1 ... 1737 (ix) TRAIT: (A) NAME / KEY: misc eature (B) LOCATION: 342 ... 343 (D) OTHER INFORMATION: / note = "junction joint" (Ix) RASGO: (A) NAME / KEY: miscjeature (B) LOCATION: 453 ... 454 (D) OTHER INFORMATION: / note = "splice junction" (ix) TRAIT: (A) NAME / KEY: miscjeature (B) LOCATION: 756 ... 757 (d) OTHER INFORMATION: / note = "junction joint" (ix) TRAIT: (A) NAME / KEY: miscjeature (B) LOCATION: 885 ... 886 (d) OTHER INFORMATION: / note = "splice junction" (ix) TRAIT: (A) NAME / KEY: miscjeature (B) LOCATION: 1033 ... 1034 (D) OTHER INFORMATION: / note = "junction joint" (ix) TRAIT: (A) NAME / KEY: miscjeature (B) LOCATION: 1 177 ... 1 178 (D) OTHER INFORMATION: / note = "junction joint" (ix) RASGO: (A) NAME / KEY: miscjeature (B) LOCATION: 1350 ... 1351 (D) OTHER INFORMATION: / note = "splice junction" (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 1: TTA CTG CTC ACA CTA TTA GTG TCA ACA ATG CTC ACT GTA TCT TAT ACC 48 Leu Leu Leu Thu Leu Leu Val Ser Thr Met Leu Thr Val Ser Tyr Thr 1 5 10 15 TCT TCT GAT TTT CTT TCA GTG GAT GGC TGC ATT GAC TGG TCA GTG GAT 96 Ser Ser Asp Phe Leu Ser Val Asp Gly Cys lie Asp Trp Ser Val Asp 20 25 30 CTC AAG ACÁ TAC ATG GCT TTG GCA GGT GAA CCA GTC CGA GTG AAA TGT 144 Leu Lys Thr Tyr Met Ala Leu Wing Gly Glu Pro Val Arg Val Lys Cys 35 40 45 GCC CTT TTC TAC AGT TAT ATT CGT ACC AAC TAT AGC ACG GCC CAG AGC 192 Wing Leu Phe Tyr Ser Tyr lie Arg Thr Asn Tyr Ser Thr Ala. GIJI Ser 50 55 60 ACT GGG CTC AGG CTT ATG TGG TAC AAA AAC AAA GGT GAT TTG GAA GAG 240 Thr Gly Leu Arg Leu Met Trp Tyr Lys Asn Lys Gly Asp Leu Glu Glu 65 70 75 80 CCC ATC ATC TTT TCA GAG GTC AGG ATG AGC AAA GAG GAA GAT TCA ATA 288 Pro lie He Phe Ser Glu Val Arg Met Ser Lys Glu Glu Asp Ser He 85 90 95 TGG TTT CAC TCA GCT GAG GAC CAA GAC AGT GGA TTC TAC ACT TGT GTT 336 Trp Phe His Ser Wing Glu Wing Gln Asp Ser Gly Phe Tyr Thr Cys Val 100 105 110 TTA AGG AAC TCA AA TAT TGC ATG AAG GTG TCA ATG TCC TTG ACT GTT 384 Leu Arg Asn Ser Thr Tyr Cys Met Lys Val Ser Met Ser Leu Thr Val 115 120 125 GCA GAG AAT GAA TCA GGC CTG TGC TAC AAC AGC AGG ATC csc TAT TTA 432 Wing Glu Asn Glu Ser Gly Leu Cys Tyr Asn Ser Arg He Arg Tyr Leu 130 135 140 GAA AAA TCT GAA GTC ACT AAA AGA AAG GAG ATC CC TGT CCA CAC ATG 480 Glu Lys Ser Glu Val Thr Lys Arg Lys Glu He Ser Cys Pro Asp Met 145 150 155 160 GAT GAC TTT AAA AAG TCC GAT CAG GAG CCT GAT GTT GTG Cough TAT AAG 528 Asp Asp Phe Lys Lys Ser Asp Gln Glu Pro Asp Val Val Trp Tyr Lys 165 170 175 GAA TGC AAG CCA AAA ATG TGG AGA AGC ATA ATA ATA CAG AAA COA AAT 576 Glu Cys Lys Pro Lys Met Trp Arg Ser He He He Gln Lys Gly Asn 180 185 190 GCT CTT CTG ATC CAA GAA GTT CAA GAA GAA GAT GGA GGA AAT TAC ACÁ 624 Wing Leu Leu He Gln Glu Val Gln Glu Glu Asp Gly Gly Asn Tyr Thr 195 200 205 TGT GAA CTT AAA TAT GAA GGA AAA CTT GTA AGA CGA ACT ACT GAA TTG 672 Cys Glu Leu Lys Tyr Glu Gly Lys Leu Val Arg Arg Thr Thr Glu Leu 210 215 220 AAA GTT ACÁ GCT TTA CTC ACÁ GAC AAG CCT CCC AAO CCA TTG TTC CCC 720 Lys Val Thr Ala Leu Leu Thr Asp Lys Pro Pro Lys Pro Leu Phe Pro 225 230 235 240 ATG GAG AAT CAG CCA AGT GTT ATA GAT GTC CAG CTC GGT AAG CCT CTG 768 Met Glu Asn Gln Pro Ser Val He Asp Val Gln Leu Gly Lys Pro Leu 245 250 255 AAC ATC CCC TGC AAA GCA TTC TC GGA TTC AGT GGA GAO TCT GGG CCA 816 Asn He Pro Cys Lys Wing Phe Phe Gly Phe Ser Gly Glu Ser Gly Pro 260 265 270 ATG TAC TGG ATG AAA GGA GAA AAG TTT ATT GAA GAA CTG GCA GOT 864 Met He Tyr Trp Met Lys Gly Glu Lys Phe He Glu Glu Leu Wing Gly 275 280 285 CAC ATT AGA GAA GGT GAA ATA AGG CTT CTC AAA GAG CAT CTT GOA GAA 912 His He Arg Glu Glu Glu He Arg Leu Leu Lys Glu His Leu Gly Glu 290 295 300 AAA GAA GTT GAA TTG GCA CTC ATC TT GAC TCA GTT GTG GAA GCT GAC 960 Lys Glu Val Glu Leu Ala Leu He Phe Asp Ser Val Val Olu Wing Asp 305 310 315 320 CTG GCG AAT TAT ACC TGC CAT GTT GAA AAC CGA AAT GGA CGG AAA CAT 1008 Leu Ala Asn Tyr Thr Cys His Val siu Asn Arg Asn Gly Arg Lys His 325 330 335 GCC AGT GTT TTG CTG CGT AAA AAG OAT TTA ATC TAT AAA ATT GAG CTT 1056 Wing Ser Val Leu Leu Arg Lys Lys Asp Leu He Tyr Lys He Glu Leu 340 345 350 GCA sss GGC CTG GOA GCA ATC TTC CTC CTC CTT GTA CTG CTG GTG GTC 1104 Ala sly sly Leu Gly Ala He Phe Leu Leu Leu Val Leu Leu Val Val 355 360 365 ATT AC AAA TGC TAC AAC ATT GAA TTG ATG CTC TTC TAC Asa CAG CAC 1152 He Tyr Lys Cys Tyr Asn He Glu Leu Met Leu Phe Tyr Arg Gln His 370 375 380 TTT GGA GCT GAT GAA ACT AAT GAT GAC AAC AAG GAA TAT GAT GCC TAT 1200 Phe Gly Wing Asp Glu Thr Asn Asp Asp Asn Lys siu Tyr Asp Wing Tyr 385 390 395 400 CTC TCT TAC ACA AAA GTO GAC CAA GAT ACT TTA GAC TGT OAC AAT CCT 1248 Leu Ser Tyr Thr Lys Val Asp Gln Asp Thr Leu Asp Cys Asp Asn Pro 405 410 415 GAA GAA GAG CAG TTT scT CTT GAA GTA CTG CCA GAT GTC CTG GAA AAA 1296 Glu Glu Glu Gln Phe Ala Leu Glu Val Leu Pro Asp Val Leu Glu Lys 420 425 430 CAC TAT GGA TAT AAA CTC TTC ATC CCA GAA AGA GAC CTG ATT CCA AGT 1344 His Tyr Gly Tyr Lys Leu Phe He Pro Glu Arg Asp Leu He Pro Ser 435 440 445 GGA AGT GCA TAC ATG GAA GAT CTC ACA AGA TAT GTT GAA CAA AGC AGA 1392 Gly Ser Wing Tyr Met Glu Asp Leu Thr Arg Tyr Val Glu Gln Ser Arg 450 455 460 AGA CTT ATT ATC GTO CTA ACT CCA OAC TAT ATT CTC AGA CGG GGA TGG 1440 Arg Leu He He Val Leu Thr Pro Asp Tyr He Leu Arg Arg Gly Trp 465 470 475 480 AGT ATT TC GAA CTO GAA AGC AGA CTC CAT AAC ATG CTA GTC AGT GGA 1488 Be He Phe Glu Leu Glu Be Arg Leu His Asn Met Leu Val Ser Gly 485 490 495 GAA ATC AAA GTG ATT TTG ATT GAG TGT ACÁ GAA TTA AAA GGG AAA GTG 1536 Glu He Lys Val He Leu He Glu Cys Thr Glu Leu Lys Gly Lys Val 500 505 510 AAT TGC CAG GAA OTO GAA TCA CTA AAG CGT AGC ATC AAA CTT CTG TCC 1584 Asn Cys Gln Glu Val Glu Ser Leu Lys Arg Ser He Lys Leu Leu Ser 515 520 525 CTG ATC AAG TGG AAO GGA TCC AAA AGC AGC AAA TTA AAT TCT AAG TTT 1632 Leu He Lys Trp Lys Gly Ser Lys Ser Ser Lys Leu Asn Ser Lys Phe 530 535 540 TGG AAG CAC TTA OTA TAT GAA ATG CCC ATC AAA AAA AAA CAA ATG CTA 1680 Trp Lys His Leu Val Tyr Glu Met Pro He Lys Lys Lys Glu Met Leu 545 550 555 560 CCT CGG TGC CAT GTT CTG GAC TCC GCA GAA CAA GGA CTT TTT GGA GAA 1728 Pro Arg Cys His Val Leu Asp Ser Ala Glu Gln Gly Leu Phe Gly Glu 565 570 575 CTC CAG CCT 1737 Leu without Pro (2) SEQUENCE IDENTIFICATION INFORMATION NO. 2: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 579 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 2: Leu Leu Leu Thr Leu Leu Val Ser Thr Met Leu Thr Val Ser Tyr Thr 1 5 10 15 Ser Ser Asp Phe Leu Ser Val Asp Gly Cys He Asp Trp Ser Val Asp 20 25 30 Leu Lys Thr Tyr Met Ala Leu Wing Gly Glu Pro Val Arg Val Lys Cys 35 40 45 Wing Leu Phe Tyr Ser Tyr He Arg Thr Asn Tyr Ser Thr Wing Gln Ser 50 55 60 Thr Gly Leu Arg Leu Met Trp Tyr Lys Asn Lys Gly Asp Leu Glu Glu 65 70 75 80 Pro He He Phe Ser Olu Val Arg Met Ser Lys Glu Olu Asp Ser He 85 90 95 Trp Phe His Ser Wing Siu Wing Oln Asp Ser sly Phe Tyr Thr Cys Val 100 105 110 Leu Arg Asn Ser Thr Tyr Cys Met Lys Val Ser Met Ser Leu Thr Val 115 120 125 Wing Olu Asn Olu Ser sly Leu Cys Tyr Asn Ser Arg He Arg Tyr Leu 130 135 140 Olu Lys Ser siu Val Thr Lys Arg Lys siu He Ser Cys Pro Asp Met 145 150 155 160 Asp Asp Phe Lys Lys Ser Asp Gln Glu Pro Asp Val Val Trp Tyr Lys 165 170 175 Glu Cys Lys Pro Lys Met Trp Arg Ser He He Gln Lys Gly Asn 180 185 190 Wing Leu Leu He Gln Glu Val Gln Glu Asp Gly Gly Asn Tyr Thr 195 200 205 Cys Glu Leu Lys Tyr Glu Gly Lys Leu Val Arg Arg Thr Thr Glu Leu 210 215 220 Lys Val Thr Ala Leu Leu Thr Asp Lys Pro Pro Lys Pro Leu Phe Pro 225 230 235 240 Met Glu Asn Gln Pro Ser Val He Asp Val Gln Leu Gly Lys Pro Leu 245 250 255 Asn He Pro Cys Lys Wing Phe Phe Gly Phe Ser Gly Glu Ser Gly Pro 260 265 270 Met He Tyr Trp Met Lys Gly Olu Lys Phe He slu Olu Leu Ala sly 275 280 285 His He Arg slu Oly slu He Arg Leu Leu Lys Glu His Leu Gly Glu 290 295 300 Lys Glu Val Glu Leu Ala Leu He Phe Asp Ser Val Val Olu Ala Asp 305 310 315 320 Leu Ala Asn Tyr Thr Cys His Val slu Asn Arg Asn Oly Arg Lys His 325 330 335 Ala Ser Val Leu Leu Arg Lys Lys Asp Leu He Tyr Lys He Glu Leu 340 345 350 Wing Gly Gly Leu Gly Wing He Phe Leu Leu Leu Val Leu Leu Val Val 355 360 365 He Tyr Lys Cys Tyr Asn He Glu Leu Met Leu Phe Tyr Arg Gln His 370 375 380 Phe Oly Wing Asp Glu Thr Asn Asp Asp Asn Lys Glu Tyr Asp Wing Tyr 385 390 395 400 Leu Ser Tyr Thr Lys Val Asp Gln Asp Thr Leu Asp Cys Asp Asn Pro 405 410 415 Clu Olu Olu Oln Phe Ala Leu slu Val Leu Pro Asp Val Leu Glu Lys 420 425 430 His Tyr Gly Tyr Lys Leu Phe He Pro slu Arg Asp Leu He Pro Ser 435 440 445 sly Ser Ala Tyr Met slu Asp Leu Thr Arg Tyr Val Glu Gln Ser Arg 450 455 460 Arg Leu He He Val Leu Thr Pro Asp Tyr He Leu Arg Arg Gly Trp 465 470 475 480 Be He Phe Glu Leu Glu Be Arg Leu His Asn Met Leu Val Ser Gly 485 490 495 Glu He Lys Val He Leu He Glu Cys Thr Glu Leu Lys Gly Lys Val 500 505 510 Asn Cys Gln Olu Val slu Ser Leu Lys Arg Ser He Lys Leu Leu Ser 515 520 525 Leu He Lys Trp Lys sly Ser Lys Ser Ser Lys Leu Asn Ser Lys Phe 530 535 540 Trp Lys His Leu Val Tyr slu Met Pro He Lys Lys Lys Olu Met Leu 545 550 555 560 Pro Arg Cys His Val Leu Asp Ser Ala Olu Gln Gly Leu Phe Gly Glu 565 570 575 Leu Gln Pro (2) SEQUENCE IDENTIFICATION INFORMATION NO. 3: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 2061 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: individual (D) TOPOLOGY: linear (I) TYPE OF MOLECULE: cDNA (¡X) RASGO: (A) NAME / KEY: CDS (B) LOCATION: 1 ... 2058 (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 3: ATO AAO CCA CCA TTT CTT TTC GCC CTT GTO GTC TOT TCT GTA GTC AGC 48 Met Lys Pro Pro Phe Leu Leu Ala Leu Val Val Cys Ser Val Val Ser 1 5 10 15 ACÁ AAT CTG AAG ATG GTO TCA AAC ACÁ AAT TCT sto GAT ssc TOC ATT 96 Thr Asn Leu Lys Met Val Ser Lys Arg Asn Ser Val Asp sly Cys He 20 25 30 OAC TGG TCA GTO GAT CTC AAO ACÁ TAC ATO GCT TTG GCA GGT OAA CCA 144 Asp Trp Ser Val Asp Leu Lys Thr Tyr Met Wing Leu Wing Gly slu Pro 35 40 45 OTC CGA OTO AAA TGT scc CTT TTC TAC AOT TAT ATT CGT ACC AAC TAT 192 Val Arg Val Lys Cys Ala Leu Phe Tyr Ser Tyr He Arg Thr Asn Tyr 50 55 60 AOC ACG scc CAG AGC ACT sss CTC ACO CTT ATG TOG TAC AAA AAC AAA 240 Be Thr Wing Gln Ser Thr sly Leu Arg Leu Met Trp Tyr Lys Asn Lys 65 70 75 80 GGT GAT TTG GAA GAG CCC ATC ATC TT TCA GAG GTC AGG ATG AOC AAA 288 Gly Asp Leu Glu Glu Pro He He Phe Ser Glu Val Arg Met Ser Lys 85 90 95 GAO GAA GAT TCA ATA TOO TTT CAC TCA sct GAO GCA CAA GAC AOT GOA 336 Glu Glu Asp Ser He Trp Phe His Ser Ala slu Ala Gln Asp Ser Gly 100 105 110 TTC TAC ACT TGT GTT TTA Aaa AAC TCA ACAT TAT TGC ATG AAG GTG TCA 384 Phe Tyr Thr Cys Val Leu Arg Asn Ser Thr Tyr Cys Met Lys Val Ser 115 120 125 ATG TCC TTG ACT GTT OCA OAO AAT OAA TCA ssc CTG TGC TAC AAC AOC 432 Met Ser Leu Thr Val Ala Glu Asn Glu Ser aiy Leu Cys Tyr Asn Ser 130 135 140 AOG ATC CGC TAT TTA CAA AAA TCT CAA OTC ACT AAA ACA AAO GAG ATC 480 Arg He Arg Tyr Leu Glu Lys Ser Glu Val Thr Lys Arg Lys Glu He 145 150 155 160 TCC TGT CCA GAC ATG GAT GAC TTT AAA AAO TCC OAT CAO GAO CCT CAT 528 Ser Cys Pro Asp Met Asp Asp Phe Lys Ser Asp Oln slu Pro Asp 165 170 175 OTT OTO cough TAT AAO OAA TOC AAO CCA AAA ATG TGO AOA AOC ATA ATA 576 Val Val Trp Tyr Lys Glu Cys Lys Pro Lys Met Trp Arg Ser He He 180 185 190 ATA CAO AAA OA AAT s CTT CTC ATC CAA OAA GTT CAA CAA OAA OAT 624 He Oln Lys sly Asn Wing Leu Leu He Oln slu Val without slu siu Asp 195 200 205 GGA GOA AAT TAC ACE TGT OAA CTT AAA TAT GAA GGA AAA CTT GTA AGA 672 Gly Gly Asn Tyr Thr Cys Glu Leu Lys Tyr Glu Gly Lys Leu Val Arg 210 215 220 CGA ACA ACT GAA TTG AAA GTT ACÁ GCT TTA CTC ACÁ GAC AAG CCT CCC 720 Arg Thr Thr Glu Leu Lys Val Thr Ala Leu Leu Thr Asp Lys Pro Pro 225 230 235 -240 AAG CCA TTG TTC CCC ATO OAO AAT CAC CCA AGT OTT ATA GAT GTC CAG 768 Lys Pro Leu Phe Pro Met slu Asn Cln Pro Ser Val He Asp Val Gln 245 250 255 CTC GGT AAG CCT CTG AAC ATC CCC TCC AAA OCA TTC TTC GGA TTC AGT 816 Leu Gly Lys Pro Leu Asn He Pro Cys Lys Wing Phe Phe Ghe Phe Ser 260 265 270 GGA GAG TCT GGG CCA ATG ATC TAC TGG ATG AAA GGA OAA AAG TTT ATT 864 Gly Glu Gly Ser Pro Met He Tyr Trp Met Lys Gly Glu Lys Phe He 275 280 285 GAA GAA CTG GCA GOT CAC ATT AGA GAA GOT OAA ATA AGO CTT CTC AAA 912 Glu Glu Leu Wing Gly His He Arg Glu Oly Olu He Arg Leu Leu Lys 290 295 300 GAO CAT CTT COA OAA AAA OAA OTT GAA TTG OCA CTC ATC TTT GAC TCA 960 Olu His Leu sly slu Lys Glu Val Glu Leu Ala Leu He Phe Asp Ser 305 310 315 ^ 20 CTT OTG OAA sCT GAC CTC GCG AAT TAT ACC TGC CAT CTT GAA AAC CGA 1008 Val Val Olu Wing Asp Leu Wing Asn Tyr Thr Cys His Val Glu Asn Arg 325 330 335 AAT OOA CGO AAA CAT GCC AGT OTT TTO CTO AAA AAA OTA TTA ATC 1056 Asn sly Arg Lys His Wing Ser Val Leu Leu Arg Lys Lys Asp Leu He 340 345 350 TAT AAA ATT OAO CTT OCA sss ssc cto GGA GCA ATC TTC CTC CTC CTT 1104 Tyr Lys He slu Leu Ala Oly sly Leu Gly Ala He Phe Leu Leu Leu 355 360 365 GTA CTC GTC GTC ATT TAC AAA TOC TAC AAC ATT GAA TTG ATG CTC 1152 Val Leu Leu Val Val He Tyr Lys Cys Tyr Asn He Glu Leu Met Leu 370 375 380 TTC TAC AOG CAO CAC TTT GGA CCT OAT GAA ACT AAT GAT GAC AAC AAG 1200 Phe Tyr Arg without His Phe Gly Wing Asp Glu Thr Asn Asp Asp Asn Lys 385 390 395 400 GAA TAT GAT OCC TAT CTC CT TAC AC AAA OTG OAC CAA GAT ACT TTA 1248 Glu Tyr Asp Wing Tyr Leu Ser Tyr Thr Lys Val Asp Gln Asp Thr Leu 405 410 415 GAC TOT GAC AAT CCT GAA GAA OAO CAO TTT GCT CTT GAA GTA CTO CCA 1296 Asp Cys Asp Asn Pro Olu Glu slu Oln Phe Ala Leu Glu Val Leu Pro 420 425 430 OAT GTC CTG CAA AAA CAC TAT OOA TAT AAA CTC TTC ATC CCA OAA AGA 1344 Asp Val Leu Olu Lys His Tyr a and Tyr Lys Leu Phe He Pro Olu Arg 435 440 445 OAC CTG ATT CCA AGT OGA ACÁ TAC ATG GAA GAT CTC AC AGA TAT GTT 1392 Asp Leu He Pro Ser Gly Thr Tyr Met Glu Asp Leu Thr Arg Tyr Val 450 455 460 OAA CAA AOC ACA AGA CTT ATT ATC GTG CTA ACT CCA GAC TAT ATT CTC 1440 Olu Gln Ser Arg Arg Leu He He Val Leu Thr Pro Asp Tyr He Leu 465 470 475 480 AOA CGG GGA TOO AOT ATT TTC OAA CTG GAA AGC ACÁ CTC CAT AAC ATO 1488 Arg Arg Gly Trp Ser He Phe slu Leu Glu Be Arg Leu His Asn Met 485 490 495 CTA GTC AGT SAA OAA ATC AAA OTO ATT TTG ATT OAO TCT ACÁ OAA TTA 1536 Leu Val Ser sly siu He Lys Val He Leu He siu Cys Thr Olu Leu 500 505 510 AAA GGG AAA GTG AAT TGC CAG GAA GTG GAA TCA CTA AAO CGT AOC ATC 1584 Val Asn Cys Cln Glu Val Glu Ser Leu Lys Arg Ser He 515 520 525 AAA CTT CTG TCC CTC ATC AAO TGO AAG GOA TCC AAA AOC AGC AAA TTA 1632 Lys Leu Leu Ser Leu He Lys Trp Lys Gly Ser Lys Ser Ser Lys Leu 530 535 540 AAT CT AAG TTT TGG AAG CAC TTA GTA TAT OAA ATO CCC ATC AAO AAA 1680 Asn Ser Lys Phe Trp Lys His Leu Val Tyr Siu Met Pro He Lys Lys 545 550 555 560 AAA OAA ATG CTA CCT css TCC CAT GTT CTO OAC TCC GCA GAA CAA OGA 1728 Lys slu Met Leu Pro Arg Cys His Val Leu Asp Ser Wing Glu Oln Gly 565 570 575 CTT TT GGA GAA CTC CAO CCT ATA CCC TCT ATT GCC ATG ACC AGT ACT 1776 Leu Phe Gly Glu Leu Gln Pro He Pro Be He Wing Met Thr Ser Thr 580 585 590 TCA scc ACT CTC GTO TCA TCT CAO OCT GAT CTC CCT OAA TTC CAC CCT 1824 Be Ala Thr Leu Val Ser Ser Oln Ala Asp Leu Pro Glu Phe His Pro 595 600 605 TCA OAT TCA ATG CAA ATC AGG CAC TGT TGC AGA GGT TAT AAA CAT GAG 1872 Be Asp Ser Met without He Arg His Cys Cys Arg Gly Tyr Lys His Glu 610 615 620 ATA CCA scc ACG ACC TTO CCA CTA CCT TCC TTA ssc AAC CAC CAT ACT 1920 He Pro Wing Thr Thr Leu Pro Val Pro Ser Leu siy Asn His His Thr 625 630 635 640 TAT OT AAC CTG CCT CTC ACG CTA CTC AAC GOA CAO CTA CCC CTT AAT 1968 Tyr Cys Asn Leu Pro Leu Thr Leu Leu Asn Gly without Leu Pro Leu Asn 645 650 655 AAC ACC CTO AAA CAT ACC CAG CAA TTT CAC AGO AAC AGT TCT TTO CTG 2016 Asn Thr Leu Lys Asp Thr without Olu Phe His Arg Asn Ser Ser Leu Leu 660 665 670 CCT TTA CC TCC AAA CAO CTT AOC TTT ACC AOT CAT ATT tso 2058 Pro Leu Ser Ser Lys slu Leu Ser Phe Thr Ser Asp He Trp 675 680 685 TAG_2061_(2) SEQUENCE IDENTIFICATION INFORMATION NO. 4: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 686 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (I) TYPE OF MOLECULE: protein (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 4: Met Lys Pro Pro Phe Leu Leu Ala Leu Val Val Cys Ser Val Val Ser 1 5 10 15 Thr Asn Leu Lys Met Val Ser Lys Arg Asn Ser Val Asp Cly Cys He 20 25 30 Asp Trp Ser Val Asp Leu Lys Thr Tyr Met Wing Leu Wing Gly Glu Pro 35 40 45 Val Arg Val Lys Cys Wing Leu Phe Tyr Ser Tyr He Arg Thr Asn Tyr 50 55 60 Ser Thr Wing Gln Ser Ttur Gly Leu Arg Leu Met Trp Tyr Lys Asn Lys 65 70 75 80 Gly Asp Leu Glu Glu Pro He He Phe Ser Glu Val Arg Met Ser Lys 85 90 95 slu Glu Asp Ser He Trp Phe His Ser Wing Glu Wing Gln Asp Ser sly 100 105 110 Phe Tyr Thr Cys Val Leu Arg Asn Ser Thr Tyr Cys Met Lys Val Ser 115 120 125 Met Ser Leu Thr Val Wing Clu Asn slu Ser Oly Leu Cys Tyr Asn Ser 130 135 140 Arg He Arg Tyr Leu Olu Lys Ser slu Val Thr Lys Arg Lys slu He 145 150 155 160 Ser Cys Pro Asp Met Asp Asp Phe Lys Lys Ser Asp Cln slu Pro Asp 165 170 175 Val Val Trp Tyr Lys slu Cys Lys Pro Lys Met Trp Arg Ser He He 180 185 190 He Oln Lys Oly Asn Ala Leu Leu He Gln slu Val Gln Glu Glu Asp 195 200 205 Gly Gly Asn Tyr Thr Cys Glu Leu Lys Tyr Glu Gly Lys Leu Val Arg 210 215 220 Arg Thr Thr Glu Leu Lys Val Thr Ala Leu Leu Thr Asp Lys Pro Pro 225 230 235 240 Lys Pro Leu Phe Pro Met Glu Asn Gln Pro Ser Val He Asp Val Gln 245 250 255 Leu Oly Lys Pro Leu Asn He Pro Cys Lys Ala Phe Phe sly Phe Ser 260 265 270 Gly Olu Ser sly Pro Met He Tyr Trp Met Lys sly Olu Lys Phe He 275 280 285 Olu Olu Leu Ala sly His He Arg Glu Gly Glu He Arg Leu Leu Lys 290 295 300 slu His Leu Gly slu Lys alu Val slu Leu Wing Leu He Phe Asp Ser 305 310 315 320 Val Val slu Ala Asp Leu Ala Asn Tyr Thr Cys His Val Glu Asn Arg 325 330 335 Asn Gly Arg Lys His Wing Ser Val Leu Leu Arg Lys Lys Asp Leu He 340 345 350 Tyr Lys He Glu Leu Wing Gly Gly Leu Gly Wing He Phe Leu Leu Leu 355 360 365 Val Leu Leu Val Val Tyr Lys Cys Tyr Asn He Glu Leu Met Leu 370 375 380 Phe Tyr Arg Gln His Phe Gly Wing Asp Glu Thr Asn Asp Asp Asn Lys 385 390 395 400 Glu Tyr Asp Ala Tyr Leu Ser Tyr Thr Lys Val Asp Gln Asp Thr Leu 405 410 415 Asp Cys Asp Asn Pro Clu Olu alu Gln Phe Ala Leu Glu Val Leu Pro 420 425 430 Asp Val Leu Glu Lys His Tyr Gly Tyr Lys Leu Phe He Pro slu Arg 435 440 445 Asp Leu He Pro Ser Oly Thr Tyr Met slu Asp Leu Thr Arg Tyr Val 450 455 460 Glu Gln Ser Arg Arg Leu He He Val Leu Thr Pro Asp Tyr He Leu 465 470 475 480 Arg Arg Gly Trp Ser He Phe Glu Leu Glu Ser Arg Leu His Asn Met 485 490 495 Leu Val Ser Gly Glu He Lys Val He Leu He Glu Cys Thr Glu Leu 500 505 510 Lys Gly Lys Val Asn Cys Gln Olu Val slu Ser Leu Lys Arg Ser He 515 520 525 Lys Leu Leu Ser Leu He Lys Trp Lys Oly Ser Lys Ser Ser Lys Leu 530 535 540 Asn Ser Lys Phe Trp Lys His Leu Val Tyr slu Met Pro He Lys Lys 545 550 555 560 Lys slu Met Leu Pro Arg Cys His Val Leu Asp Ser Ala Clu Gln sly 565 570 575 Leu Phe aiy alu Leu Cln Pro He Pro Be He Wing Met Thr Ser Thr 580 585 590 Be Wing Thr Leu Val Ser Ser Oln Wing Asp Leu Pro slu Phe His Pro 595 600 605 Ser Asp Ser Met Cln He Arg His Cys Cys Arg Cly Tyr Lys His Olu 610 615 620 He Pro Wing Thr Thr Leu Pro Val Pro Ser Leu sly Asn His His Thr 625 630 635"640 Tyr Cys Asn Leu Pro Leu Thr Leu Leu Asn Oly Oln Leu Pro Leu Asn 645 650 655 Asn Thr Leu Lys Asp Thr sln slu Phe His Arg Asn Ser Ser Leu Leu 660 665 670 Pro Leu Ser Ser Lys slu Leu Ser Phe Thr Ser Asp He Trp 675 680 685 (2) SEQUENCE IDENTIFICATION INFORMATION NO. 5: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 482 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: individual (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: cDNA (ix) TRAIT: (A) NAME / KEY: CDS (B) LOCATION: 1 ... 480 (ix) TRAIT: (A) NAME / KEY: miscjeature (B) LOCATION: 9 (D) OTHER INFORMATION: / note = "residues 9, 459, 462, 469, and 474 are indicated as C, each may be A , C, G, or T " (ix) TRAIT: (A) NAME / KEY: miscjeature (B) LOCATION: 246 (D) OTHER INFORMATION: / note = "residue 246 indicated as C, may be C, or G" (ix) TRAIT: (A) NAME / KEY: miscjeature (B) LOCATION: 321 (D) OTHER INFORMATION: / note = "residues 321, 335, 360, and 423 are indicated as C, each may be C, or T " (ix) TRAIT: (A) NAME / KEY: miscjeature (B) LOCATION: 426 (D) OTHER INFORMATION: / note = "residue 426 indicated as C, may be A, or C" (xi) SEQUENCE DESCRIPTION: ID . SEQUENCE NO: 5: AAA TAT OON TAT AOC CTO TTT TTC CTT GAA AGA AAT GTO sCT CCA COA 48 Lys Tyr Gly Tyr Ser Leu Phe Phe Leu Glu Arg Asn Val Wing Pro sly 1 5 10 15 COA GTG TAT GCA GAA GAC ATT GTA AGC ATT ATT AAG AOA AOC ACA AOA 96 sly Val Tyr Ala slu Asp He Val Ser He He Lys Arg Ser Arg Arg 20 25 30 OOA ATA TTT ATC TTA ACC CCC AAC TAT OTC AAT COA CCC ACT ATC TTT 144 Oly He Phe He Leu Thr Pro Asn Tyr Val Asn sly Pro Ser He Phe 35 40 45 CAA CTA CAA CTA OCA CCA OTO AAT CTT OCC TTC OAT OAT CAA ACA CTO AAA 192 slu Leu Oln Wing Wing Val Asn Leu Wing Leu Asp Asp sln Thr Leu Lys 50 55 60 CTC ATT TTA ATT AAC TTC TOT TAC TTC TTC CAA GAO CCA GAO TCT CTA CCT 240 Leu He Leu He Lys Phe Cys Tyr Phe aln Glu Pro Glu Ser Leu Pro 65 70 75 80 CAT CTS OTO AAA AAA OCT CTC Aaa GTT TTG CCC ACÁ GTT ACT TCO AOA 288 His Leu Val Lys Lys Wing Leu Arg Val Leu Pro Thr Val Thr Trp Arg 85 90 95 aOC TTA AAA TCA OTT CCT CCC AAT TCT AGG TTY TGG GCC AAA ATC COY 336 Oly Leu Lys Ser Val Pro Pro Asn Ser Arg Phe Trp Ala Lys Met Arg 100 105 110 TAC CAC ATO CCT CTO AAA AAT CTY TCA GGG ATT CAC GTG GOA ACC AGC 384 Tyr His Met Pro Val Lys Asn Leu Ser sly He His Val Gly Thr Ser 115 120 125 TCC AOA ATT ACC TCT ACO GAT TTT TTC AGT GOA AAG GAY TCM GTA GAA 432 Ser Arg He Thr Ser Arg Asp Phe Phe Ser Gly Lys Asp Ser Val Glu 130 135 140 CAG AAA CCA TGG GGA GGA GCT CCC AGN CTN AAG GOA NGG TGN AAT GAG 480 Gln Lys Pro Trp Gly Gly Pro Wing Pro Leu Lys Gly Arg Cys Asn Glu 145 150 155 160 CC 482 (2) SEQUENCE IDENTIFICATION INFORMATION NO. 6: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 160 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (I) TYPE OF MOLECULE: protein (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 6: Lys Tyr sly Tyr Ser Leu Phe Phe Leu alu Arg Asn Val Wing Pro Gly 1 5 10 15 Gly Val Tyr Ala slu Asp He Val Ser He He Lys Arg Ser Arg Arg 20 25 30 Oly He Phe He Leu Thr Pro Asn Tyr Val Asn Oly Pro Ser He Phe 35 40 45 Olu Leu Gln Ala Ala Val Asn Leu Ala Leu Asp Asp Gln Thr Leu Lys 50 55 60 Leu He Leu He Lys Phe Cys Tyr Phe Gln Glu Pro Glu Ser Leu Pro 65 70 75 80 His Leu Val Lys Lys Ala Leu Arg Val Leu Pro Thr Val Thr Trp Arg 85 90 95 Gly Leu Lys Ser Val Pro Pro Asn Ser Arg Phe Trp Wing Lys Met Arg 100 105 110 tYr His Met Pro Val LYS Asn Leu Ser ° l and He His Val Gly Thr Ser 115 120 125 Ser Arg He Thr Ser Arg Asp Phe Phe Ser Gly Lys Asp Ser Val Glu 130 135 140 Gln Lys Pro Trp Oly sly Pro Wing Pro Leu Lys sly Arg Cys Asn slu 145 150 155 160 (2) SEQUENCE IDENTIFICATION INFORMATION NO. 7: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 1404 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: individual (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: cDNA (ix) TRAIT: (A) NAME / KEY: CDS (B) LOCATION: 1 ... 1401 (xi) SEQUENCE DESCRIPTION: ID. SEQUENCE NO: 7: TT CCT ACO ACC CCC TAT GAT GTA GCC TCT TOT GTC AAG ATO ATT TTA 48 Phe Pro Arg Ser Pro Tyr Asp Val Wing Cys Cys Val Lys Met He Leu 1 5 10 15 CAA OTT AAO CCC CAC AC AAT GCA TCC TGT GAO TAT TCC GCA TCA CAT 96 Glu Val Lys Pro Cln Thr Asn Wing Ser Cys Clu Tyr Ser Wing His 20 25 30 AAO CAA CAC CTA CTT COO AOC ACT COC TCT ATT TCT TOC CCC ACT 144 Lys Cln Asp Leu Leu Leu sly Ser Thr Gly Ser He Ser Cys Ser Ser 35 40 45 CTC AGC TGC CAA AGT GAT GCA CAA AGT CCA OCO CTA ACC TOO TAC AAC 192 Leu Ser Cys sln Ser Asp Wing Oln Ser Pro Wing Val Thr Trp Tyr Lys 50 55 60 AAT OOA AAA CTC CTC TCT CTG OAA AGG AOC AAC COA ATC CTA OTO OA.T 240 Asn sly Lys Leu Leu Ser Val slu Arg Ser Asn Arg He Val Val Asp 65 70 75 80 OAA OTT TAT OAC TAT CAC CAO OOC ACÁ TAT OTA TOT OAT TAC ACT CAG 288 Glu Val Tyr Asp Tyr His Gln Gly Thr Tyr Val Cys Asp Tyr Thr Gln 85 90 95 TCG GAT ACT GTO AOT TCG TOO ACÁ CTC ACÁ CCT CTT OTT CAA OTO ACÁ 336 Ser Asp Thr Val Ser Ser Trp Thr Val Arg Ala Val Val sln Val Arg 100 105 110 ACC ATT sto OCA OAC ACT AAA CTC AAA CCA CAT ATT CTC OAT CCT OTC 384 Thr He Val sly Asp Thr Lys Leu Lys Pro Asp He Leu Asp Pro Val 115 120 125 GAO OAC ACÁ CTG GAA OTA OAA CTT sOA AAO CCT TTA ACT ATT ACC TOC 432 slu Asp Thr Leu Olu Val Clu Leu sly Lys Pro Leu Thr He Ser Cys 130 135 140 AAA OCA COA TTT OGC TTT CAA AOO OTC TTT AAC CCT OTC AA AAA TOO 480 Lys Ala Arg Phe Oly Phe slu Arg Val Phe Asn Pro Val He Lys Trp 145 150 155 160 TAC ATC AAA OAT TCT OAC CTA CAO TGC CAÁ OTC TCA OTA CCT OAO GCG 528 Tyr He Lys Asp Ser Asp Leu alu Trp alu Val Ser Val Pro slu Wing 165 170 175 AAA AOT ATT AAA TCC ACT TTA AAO OAT OAA ATC ATT CAO CCT AAT ATC 576 Lys Ser He Lys Ser Thr Leu Lys Asp slu He He alu Arg Asn He 180 185 190 ATC TTO GAA AAA GTC ACT CAG CGT OAT CTT csc Ass AAO TTT OTT toc 624 He Leu Glu Lys Val Thr Gln Arg Asp Leu Arg Arg Lys Phe Val Cys 195 200 205 TTT CTC CAO AAC TCC ATT COA AC ACA ACC CAG TCC GTC CAA CTO AAA 672 Phe Val Cln Asn Ser He Gly Asn Thr Thr Gln Ser Val Gln Leu Lys 210 215 220 CAA AAO AOA OOA stope CTC CTC TAC ATC CTO CTT asc ACC ATC aaa 720 slu Lys Arg Oly Val Val Leu Leu Tyr He Leu Leu Oly Thr He Gly 225 230 235 240 ACC CTG GTG GCC GTO cto aca GCG AGT GCC CTC CTC TAC ACO CAC TCC 768 Thr Leu Val Wing Val Leu Wing Wing Wing Wing Leu Leu Tyr Arg His Trp 245 250 255 ATT OAA ATA GTO CTC TTC CGG ACC TAC CAG AGC AAG GAT CAG ACG 816 He alu He Val Leu Leu Tyr Arg Thr Tyr Gln Ser Lys Asp sln Thr 260 265 270 CTT sss OAT AAA OA OAT TTT OAT OCT TTC OTA TCC TAT OCA AAA tso 864 Leu Oly Asp Lys Lys Asp Phe Asp Wing Phe Val Ser Tyr Wing Lys Trp 275 280 285 AOC TCT TTT CCA AOT OAO scc ACT TCA TCT CTC AOT OAA CAÁ CAC tto 9 2 Be Ser Phe Pro Ser slu Wing Thr Ser Ser Leu Ser alu alu His Leu 290 295 300 GCC CTG AGC CTA TTT CCT GAT GTT TTA GAA AAC AAA TAT GCA TAT ACC 960 Ala Leu Ser Leu Phe Pro Asp Val Leu alu Asn Lys Tyr sly Tyr Ser 305 310 315 320 CTC TCT TTO CTT OAA AOA OAT OTO OCT CCA GOA COA GTO TAT OCA OAA 1008 Leu Cys Leu Leu alu Arg Asp Val Wing Pro Gly Gly Val Tyr Ala slu 325 330 335 OAC ATT GTG AGC ATT ATT AAG AOA ACC AGA GAO GTA ATA TTT ATC TTO 1056 Asp He Val Ser He He Lys Arg Ser Arg Glu Val He Phe He Leu 340 345 350 AOC CCC AAC TAT OTC AAT COA CCC AOT ATC TTT GAA CTA CAA OCA CCA 1104 Ser Pro Asn Tyr Val Asn sly Pro Pro Be He Phe Glu Leu Cln Ala Wing 355 360 365 sto AAT CTT GCC TTC OAT OAT CAA ACA CTC AAA CTC ATT TTA ATT AAO 1152 Val Asn Leu Wing Leu Asp Asp Oln Thr Leu Lys Leu He Leu He Lys 370 375 380 TTC TOT TAC TTC CA CAO CAO C OAO CT CTA CCT CAT CTC OTO AAA AAA 1200 Phe Cys Tyr Phe Oln alu Pro alu Ser Leu Pro His Leu Val Lys Lys 385 390 395 400 GCT CTC AGG GTT TTO CCC ACA GTT ACT TGG AGA GGC TTA AAA TCA OTT 1248 Wing Leu Arg Val Leu Pro Thr Val Thr Trp Arg Gly Leu Lys Ser Val 405 410 415 CCT CCC AAT TCT Ass TTC toa GCC AAA ATG CGC TAC CAC ATO CCT ato 1296 Pro Pro Asn Ser Arg Phe Trp Wing Lys Met Arg Tyr His Met Pro Val 420 425 430 AAA AAC TCT CAG COA TTC ACO TGO AAC CAG CTC AGA ATT ACC TCT AGG 1344 Lys Asn Ser Gln sly Phe Thr Trp Asn ain Leu Arg He Thr Ser Arg 435 440 445 ATT TTT CAG TGC AAA COA CTC AOT AGA ACÁ GAA ACC ACT asa CAO GAO 1392 He Phe Gln Trp Lys sly Leu Ser Arg Thr Olu Thr Thr sly slu alu 450 455 460 CTC CCA scc TAA 1404 Leu Pro Ala 465 (2) SEQUENCE IDENTIFICATION INFORMATION NO. 8: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 467 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 8: Phe Pro Arg Ser Pro Tyr Asp Val Wing Cys Cys Val Lys Met He Leu 1 5 10 15 alu Val Lys Pro sln Thr Asn Wing Ser Cys Clu Tyr Ser Wing Ser His 20 25 30 Lys Oln Asp Leu Leu Leu Oly Ser Thr sly Ser He Ser Cys Pro Ser 35 40 45 Leu Ser Cys sln Ser Asp Ala ain Ser Pro Ala Val Thr Trp Tyr Lys 50 55 60 Asn Gly Lys Leu Leu Ser Val Glu Arg Ser Asn Arg He Val Val Asp 65 70 75 80 Glu Val Tyr Asp Tyr His Gln sly Thr Tyr Val Cys Asp Tyr Thr Oln 85 90 95 Ser Asp Thr Val Ser Ser Trp Thr Val Arg Ala Val Val Sln Val Arg 100 105 110 Tnr I1e Val Gly Asp Thr Lys Leu Lys Pro Asp He Leu Asp Pro Val 115 120 125 slu Asp Thr Leu slu Val alu Leu aly Lys Pro Leu Thr He Ser Cys 130 135 140 Lys Wing Arg Phe sly Phe slu Arg Val Phe Asn Pro Val He Lys Trp 145 150 155 _160 Tyr He Lys Asp Ser Asp Leu alu Trp alu Val Ser Val Pro Clu Ala 165 170 175 Lys Ser He Lys Ser Thr Leu Lys Asp slu He He alu Arg Asn He 180 185 190 He Leu Olu Lys Val Thr sln Arg Asp Leu Arg Arg Lys Phe Val Cys 195 200 205 Phe Val sln Asn Ser He Oly Asn Thr Thr Cln Ser Val sln Leu Lys 210 215 220 slu Lys Arg Oly Val Val Leu Leu Tyr He Leu Leu sly Thr He sly 225 230 235 240 Thr Leu Val Wing Val Leu Wing Wing Being Wing Leu Leu Tyr Arg His Trp 245 250 255 He Olu He Val Leu Leu Tyr Arg Thr Tyr Oln Ser Lys Asp Sln Thr 260 265 270 Leu sly Asp Lys Lys Asp Phe Asp Wing Phe Val Ser Tyr Wing Lys Trp 275 280 285 Ser Ser Phe Pro Ser Olu Wing Thr Ser Ser Leu Ser Clu Olu His Leu 290 295 300 Wing Leu Ser Leu Phe Pro Asp Val Leu Olu Asn Lys Tyr a and Tyr Ser 305 310 315 320 Leu Cys Leu Leu Clu Arg Asp Val Ala Pro Oly sly Val Tyr Ala Glu 325 330 335 Asp He Val Ser He He He Lys Arg Ser Arg Glu Val He Phe He Leu 340 345 350 Ser Pro Asn Tyr Val Asn Gly Pro Ser He Phe Glu Leu Gln Ala Wing 355 360 365 Val Asn Leu Ala Leu Asp Asp sln Thr Leu Lys Leu He Leu He Lys 370 375 380 Phe Cys Tyr Phe Gln Glu Pro Glu Ser Leu Pro His Leu Val Lys Lys 385 390 395 400 Ala Leu Arg Val Leu Pro Thr Val Thr Trp Arg Gly Leu Lys Ser Val 405 410 415 Pro Pro Asn Ser Arg Phe Trp Wing Lys Met Arg Tyr His Met Pro Val 420 425 430 Lys Asn Ser sln ai Phe Thr Trp Asn Cln Leu Arg He Thr Ser Arg 435 440 445 He Phe Gln Trp Lys sly Leu Ser Arg Thr Clu Thr Thr Gly Glu Glu 450 455 460 Leu Pro Wing 465 (2) SEQUENCE IDENTIFICATION INFORMATION NO. 9: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 2314 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: individual (D) TOPOLOGY: linear (I) TYPE OF MOLECULE: cDNA (ix) TRAIT: (A) NAME / KEY: CDS (B) LOCATION: 109 ... 1905 (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 9: ccAsccTssT caAATTcasA TACTCACOOC ACAOTTCTOA ATCTCAAAAC ACTTTAATCT 60 GGCAAAGGAA TGAAGTTATT GGAGTGATGA CAGGAACACG GGAGAACA ATG CTC TGT 117 Met Leu Cys 1 TTG aac tao ATA TTT CTT TOO CTT OCA COA OAO CCA ATT AAA COA l65 Leu Gly Trp He Phe Leu Trp Leu Val Wing Gly Glu Arg He Lys Gly 5 10 15 TTT AAT ATT TCA GOT TGT TCC AA AAA AAA CTC CTT TGG TATA TCT 213 Phe Asn He Ser Gly Cys Ser Thr Lys Lys Leu Leu Trp Thr Tyr Ser 20 25 30 35 AGA AGO GAA GAO GAA TTT GTC TTA TTT TGT GAT TTA CCA CAO CCA 261 Thr Arg Be alu alu Glu Phe Val Leu Phe Cys Asp Leu Pro Glu Pro 40 45 50 CAG AAA TCA CAT TTC TGC CAC AGA AAT CGA CCA TCA CCA AAA CAA GTC 309 Cln Lys Ser His Phe Cys His Arg Asn Arg Leu Ser Pro Lys Cln Val 55 60 65 CCT OAO CAC CTO CCC TTC ATO ost AOT AAC OAC CTA TCT OAT GTC CAA 357 Pro slu His Leu Pro Phe Met Cly Ser Asn Asp Leu Ser Asp Val ain 70 75 80 tao TAC CAA CAA CCT TCO AAT COA OAT CCA TTA CAO CAC ATT AGO AAA 405 Trp Tyr sln Cln Pro Ser Asn Oly Asp Pro Leu slu Asp He Arg Lys 85 90 95 AOC TAT CCT CAC ATC ATT CAO sAC AAA TCT ACC CTT CAC TTT TTO ACC 453 Ser Tyr Pro His He He Cln Asp Lys Cys Thr Leu His Phe Leu Thr 100 105 110 115 CCA sas OTO AAT AAT TCT sas TCA TAT ATT TCT ACÁ CCC AAO ATO ATT 501 Pro sly Val Asn Asn Ser aiy Ser Tyr He Cys Arg Pro Lys Met He 120 125 130 AAO AOC CCC TAT CAT OTA scc TCT TGT OTC AAC ATO ATT TTA OAA CTT 549 Lys Ser Pro Tyr Asp Val Wing Cys Cys Val Lys Met He Leu alu Val 135 140 145 AAO CCC CAO ACÁ AAT GCA TCC TOT CAO TAT TCC GCA TCA CAT AAa CAA 597 Lys Pro sln Thr Asn Wing Ser Cys Clu Tyr Ser Wing His Lys sln 150 155 160 GAC CTA CTT GGG AGC ACT GGC TCT ATT CT TGC CCC AGT CTC AOC 645 Asp Leu Leu Leu Gly Be Thr Gly Ser Be Ser Cys Pro Ser Leu Ser 165 170 175 TGC CAA AOT GAT CAV CAA AOT CCA scs OTA ACC TGG TAC AAG AAT GOA 693 Cys Cln Ser Asp Wing Gln Ser Pro Wing Val Thr Trp Tyr Lys Asn Oly 180 185 190 195 AAA CTC CTC TCT GTO CAA Ass AGC AAC CCA ATC GTA OTO GAT CA GTT 741 Lys Leu Leu Ser Val alu Arg Ser Asn Arg He Val Val Asp Olu Val 200 205 210 TAT CAC TAT CAC CAC aoc ACÁ TAT OTA TCT OAT TAC ACT CAC TCO GAT 789 Tyr Asp Tyr His Cln Cly Thr Tyr Val Cys Asp Tyr Thr Cln As Asp 215 220 225 ACT OTO AOT TCG toa ACÁ OTC AGA oct OTT OTT CAA GTC AGA ACC ATT 837 Thr Val Ser Ser Trp Thr Val Arg Wing Val Val Gln Val Arg Thr He 230 235 240 GTO ssA OAC ACT AAA CTC AAA CCA CAT ATT CTO OAT CCT GTC CAO GAC 885 Val sly Asp Thr Lys Leu Lys Pro Asp He Leu Asp Pro Val alu Asp 245 250 255 ACÁ CTC OAA OTA OAA CTT OCA AAG CCT TTA ACT ATT AOC TGC AAA GCA 933 Thr Leu slu Val Clu Leu sly Lys Pro Leu Thr He Ser Cys Lys Wing 260 265 270 275 COA TTT oac TTT CAA Aaa OTC TTT AAC CCT CTC ATA AAA TGG TAC ATC 981 Arg Phe siy Phe alu Arg Val Phe Asn Pro Val He Lys Trp Tyr He 280 285 290 AAA OAT TCT CAC CTA OAO toa GAA CTC TCA CTA CCT CAO GCG AAA ACT 1029 Lys Asp Ser Asp Leu siu Trp Olu Val Ser Val Pro alu Ala Lys Ser 295 300 305 ATT AAA TCC ACT TTA AAG CAT OAA ATC ATT OAG CGT AAT ATC ATC TC 1077 He Lys Ser Thr Leu Lys Asp slu He He slu Arg Asn He He Leu 310 315 320 GAA AAA CTC ACT CAC CGT OAT CTT CGC AOG AAG TTT GTT TGC TT GTC 1125 Glu Lys Val Thr sln Arg Asp Leu Arg Arg Lys Phe Val Cys Phe Val 325 330 335 CAG AAC TCC ATT OCA AAC ACA ACC CAG TCC OTC CAA CTG AAA GAA AAG 1173 Gln Asn Ser He sly Asn Thr Thr Gln Ser Val Gln Leu Lys Glu Lys 340 345 350 355 ACA COA ote CTG CTC CTG TAC ATC CTG CTT ACC ACC ATC GGG ACC CTG 1221 Arg aiy Val Val Leu Leu Tyr He Leu Leu al and Thr He a and Thr Leu 360 365 370 OTO scc ato CTO sca GCG ACT CCC CTC CTC TAC ACO CAC tso ATT GAA 1269 Val Ala Val Leu Ala Ala Be Ala Leu Leu Tyr Arg His Trp He Glu 375 380 385 ATA OTO CTO CTO TAC CGC ACC TAC CAG AGC AAC OAT CAG Acs CTT sss 1317 He Val Leu Leu Tyr Arg Thr Tyr ain Ser Lys Asp Gln Thr Leu Oly 390 395 400 CAT AAA AAO OAT TTT OAT CCT TTC OTA TCC TAT OCA AAA TGG AGC TCT 1365 Asp Lys Lys Asp Phe Asp Wing Phe Val Ser Tyr Wing Lys Trp Ser Ser 405 410 415 TTT - CCA AOT OAO acc ACT TCA TCT CTG AGT OAA OAA CAC TTG GCC CTO 1413 Phe Pro Ser slu Ala Thr Ser Ser Leu Ser alu alu His Leu Ala Leu 420 425 430 435 AGC CTA TTT CCT CAT ott TTA GAA AAC AAA TAT COA TAT AGC CTG TOT 1461 Ser Leu Phe Pro Asp val Leu Glu Asn Lys Tyr sly Tyr Ser Leu Cys 440 445 450 TTG CTT OAA ACÁ OAT OTC CCT CCA COA OCA ato TAT CCA GAA GAC ATT 1509 Leu Leu slu Arg Asp Val Wing Pro aiy sly Val Tyr Wing Glu Asp He 455 460 465 GTO AOC ATT ATT AAO AOA AOC AGA ACA GOA ATA TTT ATC TTG AGC CCC 1557 Val Ser He He Lys Arg Ser Arg Arg Gly He Phe He Leu Ser Pro 470 475 480 AAC TAT CTC AAT OCA CCC AOT ATC TTT GAA CTA CAA OCA GCA GTO AAT 1605 Asn Tyr Val Asn sly Pro Ser He He Phe Clu Leu sln Ala Ala Val Asn 485 490 495 CTT CCC TTO CAT CAT CAA ACA CTG AAA CTC ATT TTA ATT AAG TTC TCT 1653 Leu Ala Leu Asp Asp sln Thr Leu Lys Leu He Leu He Lys Phe Cys 500 505 510 515 TAC TTC CA CAO CA CA CA CT TCT CTA CCT CAT CTC CTO AAA AAA CCT CTC 1701 Tyr Phe Cln Clu Pro alu Ser Leu Pro His Leu Val Lys Lys Ala Leu 520 525 530 Years ott TTO ccc ACÁ CTT ACT toa ACÁ sac TTA AAA TCA CTT CCT CCC 1749 Arg Val Leu Pro Thr Val Thr Trp Arg sly Leu Lys Val Val Pro Pro 535 540 545 AAT TCT Aas TTC Tcs acc AAA ATO CCC TAC CAC ATO CCT ato AAA AAC 1797 Asn Ser Arg Phe Trp Wing Lys Met Arg Tyr His Met Pro Val Lys Asn 550 555 560 TCT CAC GOA TTC ACG TGO AAC CAO CTC AOA ATT ACC TCT ACO ATT TTT 1845 Ser ain sly Phe Thr Trp Asn aln Leu Arg He Thr Ser Arg He Phe 565 570 575 CAO TOO AAA OCC CTC ACT ACA ACA CA ACC ACT COO AOO AOC TCC CAO 1893 Cln Trp Lys Cly Leu Ser Arg Thr alu Thr Thr Cly Arg Ser Ser 580 585 590 595 CCT AAO OAA toa TsAAATaAac CCTCCAOCCC CCTCCACTCC Aatccctaoa 1945 Pro Lys slu Trp ATAsAOATCT TGCTCOACAa AACTCACAGC tctotatsts TOTOTTCAGO CTGATACaAA 2005 ATTCAAAOAa TCTCCTGCCA GCACCAACCA AOCTTOATOO ACAATGOAAT GGGATTGAGA 2065 CTsTaa TTA GAaCCTTTCA TTTCCTGOAC TGGACAGACG aCOAOTOAAT TCTCTAGACC 2125 TTsasTACTT TCAOTACACA ACACCCCTAA sATTTCCCAO TGCTCCaAOC ACAATCAOAA 2185 AATACAGCTA CTTCTCCCTT ATGscTAaac AACTCTCATC TCTACCATGT ATTOTACATA 2245 TGACTTTATC TATACTTOCA ATCAAATAAA TATTATTTTA TTAsAAAAAA AAAAAAAAAO 2305 aacGaccsc 2314 (2) SEQUENCE IDENTIFICATION INFORMATION NO. 10: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 599 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 10: Met Leu Cys Leu Gly Trp He Phe Leu Trp Leu Val Wing Gly Glu Arg 1 5 10 15 He Lys Gly Phe Asn He Ser Gly Cys Ser Thr Lys Lys Leu Leu Trp 20 25 30 Thr Tyr Ser Thr Arg Ser slu slu Olu Phe Val Leu Phe Cys Asp Leu 35 40 45 Pro alu Pro sln Lys Ser His Phe Cys His Arg Asn Arg Leu Ser Pro 50 55 60 Lys Oln Val Pro Clu His Leu Pro Phe Met Sly Ser Asn Asp Leu Ser 65 70 75 80 Asp Val Cln Trp Tyr Gln Gln Pro Ser Asn Gly Asp Pro Leu Glu Asp 85 90 95 He Arg Lys Ser Tyr Pro His He He Gln Asp Lys Cys Thr Leu His 100 105 110 Phe Leu Thr Pro Gly Val Asn Asn Ser Gly Ser Tyr He Cys Arg Pro 115 120 125 Lys Met He Lys Ser Pro Tyr Asp Val Ala Cys Cys Val Lys Met He 130 135 140 Leu Glu Val Lys Pro Gln Thr Asn Wing Ser Cys Glu Tyr Ser Wing Ser 145 150 155 160 His Lys Oln Asp Leu Leu Leu Gly Ser Thr Gly Ser He Ser Cys Pro 165 170 175 Ser Leu Ser Cys Gln Ser Asp Wing Gln Ser Pro Wing Val Thr Trp Tyr 180 185 190 Lys Asn aiy Lys Leu Leu Ser Val Clu Arg Ser Asn Arg He Val Val 195 200 205 Asp alu Val Tyr Asp Tyr His Oln sly Thr Tyr Val Cys Asp Tyr Thr 210 215 220 Oln Ser Asp Thr Val Ser Ser Trp Thr Val Arg Ala Val Val Oln Val 225 230 235 240 Arg Thr He Val sly Asp Thr Lys Leu Lys Pro Asp He Leu Asp Pro 245 250 255 Val alu Asp Thr Leu Clu Val alu Leu Cly Lys Pro Leu Thr He Ser 260 265 270 Cys Lys Wing Arg Phe Gly Phe Glu Arg Val Phe Asn Pro Val He Lys 275 280 285 Trp Tyr He Lys Asp Ser Asp Leu Glu Trp Glu Val Ser Val Pro Glu 290 295 300 Wing Lys Ser He Lys Ser Thr Leu Lys Asp Glu He He slu Arg Asn 305 310 315 320 He He Leu alu Lys Val Thr Cln Arg Asp Leu Arg Arg Lys Phe Val 325 330 335 Cys Phe Val Gln Asn Ser He Gly Asn Thr Thr Gln Ser Val Valn Leu 340 345 350 Lys Olu Lys Arg aly Val Val Leu Leu Tyr He Leu Leu sly Thr He 355 360 365 aly Thr Leu Val Ala Val Leu Ala Ala Ser Ala Leu Leu Tyr Arg His 370 375 380 Trp He alu He Val Leu Leu Tyr Arg Thr Tyr Cln Ser Lys Asp sln 385 390 395 400 Thr Leu Cly Asp Lys Lys Asp Phe Asp Wing Phe Val Ser Tyr Wing Lys 405 410 415 Trp Ser Ser Phe Pro Ser Clu Wing Thr Ser Ser Leu Ser Olu slu His 420 425 430 Leu Ala Leu Ser Leu Phe Pro Asp Val Leu alu Asn Lys Tyr Oly Tyr 435 440 445 Ser Leu Cys Leu Leu alu Arg Asp Val Ala Pro aly Val Tyr Ala 450 455 460 alu Asp He Val Ser He He Lys Arg Ser Arg Arg aly He Phe He 465 470 475 480 Leu Ser Pro Asn Tyr Val Asn sly Pro Be He Phe alu Leu Oln Wing 485 490 495 Wing Val Asn Leu Wing Leu Asp Asp sln Thr Leu Lys Leu He Leu He 500 505 510 Lys Phe Cys Tyr Phe Oln alu Pro Olu Ser Leu Pro His Leu Val Lys 515 520 525 Lys Ala Leu Arg Val Leu Pro Thr Val Thr Trp Arg sly Leu Lys Ser 530 535 540 Val Pro Pro Asn Ser Arg Phe Trp Wing Lys Met Arg Tyr His Met Pro 545 550 555 560 Val Lys Asn Being sln sly Phe Thr Trp Asn Oln Leu Arg He Thr Ser 565 570 575 Arg He Phe Gln Trp Lys sly Leu Ser Arg Thr alu Thr alr Arg 580 585 590 Ser Ser sln Pro Lys alu Trp 595 (2) SEQUENCE IDENTIFICATION INFORMATION NO. eleven : (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 768 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: individual (D) TOPOLOGY: linear (I) TYPE OF MOLECULE: cDNA (ix) TRAIT: (A) NAME / KEY: CDS (B) LOCATION: 1 ... 360 (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 1 1: G A GCA GTG AAT tt OOC TTG GTT GAT CAG ACÁ CTG AAG TTG ATT TTA 48 Wing Wing Val Asn Leu Wing Leu Val Asp Cln Thr Leu Lys Leu He Leu 1 5 10 15 ATT AAO TTC TOT TCC TTC CAA OAC CCA OAA TCT CTT CCT TAC CTT CTC 96 He Lys Phe Cys Ser Phe Oln slu Pro Olu Ser Leu Pro Tyr Leu Val 20 25 30 AAA OCT CTC CCG GTT CTC CCC ACÁ GTC ACÁ TAG AAA OOC TTO AAO 144 Lys Lys Ala Leu Arg Val Leu Pro Thr Val Thr Trp Lys Gly Leu Lys 35 40 45 Tca otc CAC scc AGT TCC ACÓ TTC TOO ACC CAA ATT COT AC CAC ATO 192 Ser Val His Wing Ser Arg Phe Trp Thr Cln He Arg Tyr His Met 50 55 60 CCT OTO AAO AAC TCC AAC ACO TTT ATO TTC AAC COO CTC AOA ATT TTC 240 Pro Val Lys Asn Ser Asn Arg Phe Met Phe Asn aly Leu Arg He Phe 65 70 75 80 CTO AAO OaC TTT TCC CCT CAA AAO OAC CTA CTG AA CAG AAA CCC CTG 288 Leu Lys Gly Phe Ser Pro Glu Lys Asp Leu Val Thr Gln Lys Pro Leu 85 90 95 OAA OCA ATC CCC AAC TCT COO AAT OAC CAC COA CCT CAC AAC CTC CTT 336 Glu Gly Met Pro Lys Ser aly Asn Asp His sly Ala sln Asn Leu Leu 100 105 110 CTC TAC AGT GAC CAG AAG AGO TGC TGATCsGTAG AACTTCCTOT OTOCAT CAOO 390 Leu Tyr Ser Asp sln Lys Arg Cys 115 120 CTaATACAAA TTGAGCCTTT CTGCTCTCAO TGCCAACCAA OCTTOACACa CAaTssAATs 450 AAacaacATC tstosttttA aaatctsaot TCCTCOAACA OACACACAOC AATACTCCAO 510 ACCTCTCCCG TOTCCTTAOC ACACATTTCC CTaAOAsTTC CCAAOTAOCC TOAACACAAT 570 CAACAGAAAT AGCTCCATGG CCTGTCCAAC ATTCATGCAC GCATGCCTOT TTTCCACTAT 630 ATATATOAAT TTATCATACC TTIOTOTOTa TATATOCATT CAGATAAATA GGATTTTATT 690 TTGTTCGATA CGAOTOATTa AAACTCCATT TAAAGCCCTT CTGTAAAGAA ATTTTGCTsC 750 AAAAAAAAAA AAAAAAAA 768 (2) SEQUENCE IDENTIFICATION INFORMATION NO. 12: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 120 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 12: Wing Wing Val Asn Leu Wing Leu Val Asp Gln Thr Leu Lys Leu He Leu 1 5 10 15 He Lys Phe Cys Ser Phe Gln Glu Pro Glu Ser Leu Pro Tyr Leu Val 20 25 30 Lys Lys Wing Leu Arg Val Leu Pro Thr Val Thr Trp Lys Gly Leu Lys 35 40 45 Ser Val His Wing Being Ser Arg Phe Trp Thr Gln He Arg Tyr His Met 50 55 60 Pro Val Lys Asn Ser Asn Arg Phe Met Phe Asn sly Leu Arg He Phe 65 70 75 80 Leu Lys Oly Phe Ser Pro slu Lys Asp Leu Val Thr sln Lys Pro Leu 85 90 95 slu sly Met Pro Lys Ser sly Asn Asp His sly Ala ala Asn Leu Leu 100 105 110 Leu Tyr Ser Asp Cln Lys Arg Cys 115 120 (2) SEQUENCE IDENTIFICATION INFORMATION NO. 13: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 1833 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: individual (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: cDNA (ix) TRAIT: (A) NAME / KEY: CDS (B) LOCATION: 1 ... 1830 (ix). RUNNING: (A) NAME / KEY: mat_peptide (B) LOCATION: 52 ... 1830 (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 13: ATG TCT GTT TOO CTO OTO TTC TTG OTT CT OCA COA GAG AAO ACC ACÁ 48 Met Ser Val Trp Leu Val Phe Leu Val Cys Ala aly Glu Lys Thr Thr -17 -15 -10 -5 OGA TTT AAT CAT TCA scT TGT GCC ACC AAA AAT TCT GTO OAC ATA TTC 96 Gly Phe Asn His Ser Wing Cys Wing Thr Lys Asn Ser Val Asp He Phe 1 5 10 15 OCA AGa aot GCA CAC AAT TTT GTC TAT TTT GTC ACT TAC AAO AGC TTC 144 Wing Arg sly Wing slu Asn Phe Val Tyr Phe Val Thr Tyr Lys Ser Phe 20 25 30 AOO AGC AAA AAT TCT CCC ATG CAA GTC AAC TGT CAC CAA CAC AAA GTC 192 Arg Ser Lys Asn Ser Pro Met Gln Val Asn Cys His sln His Lys Val 35 40 45 TOC TCA CAA ACT TOC AGT GOC AOT CAG AAO GAC TTA TCT GAT GTC CAG 240 Cys Ser aln Thr Cys Ser Gly Ser Gln Lys Asp Leu Ser Asp Val Gln 50 55 60 TGC TAC ATO CAA CCT caa AGT COA AGT CCA CTA GAC CAO ATC AGT AGA 288 Trp Tyr Met Gln Pro Arg Be aly Ser Pro Leu Glu slu He Ser Arg 65 70 75 AAC TCT CCC CAT ATO CAG AGT OAA ssc ATO CTG CAT ATA TTG GCC CCA 336 Asn Ser Pro His Met Gln Ser alu Cly Met Leu His He Leu Wing Pro 80 85 90 95 CAO ACG AAC AOC ATT TOG TCA TAT ATT TOT AGA CCC AOA ATT AGO AOC 384 sln Thr Asn Ser He Trp Ser Tyr He Cys Arg Pro Arg He Arg Ser 100 105 110 CCC CAG OAT ATO acc TGT TGT ATC AAG ACA GTC TTA GAA GTT AAG CCT 432 Pro Gln Asp Met Wing Cys Cys He Lys Thr Val Leu Glu Val Lys Pro 115 120 125 CAO ACÁ AAC OTO TCC TCT ssa AAC ACA GCA CAA CAT GAA CAA GTC CTA 480 sln Arg Asn Val Ser Cys Gly Asn Thr Wing Gln Asp Glu Gln Val Leu 130 135 140 CTT CTT GGC AGT ACT GGC TCC ATT CAT TGT CCC AGT CTC AGC TGC CAA 528 Leu Leu Gly Be Thr Gly Be He His Cys Pro Be Leu Be Cys Gln 145 150 155 ACT GAT GTA CAG AGT CCA GAG ATG ACC TGO TAC AAG GAT GGA AGA CTA 576 Ser Asp Val Gln Ser Pro Olu Met Thr Trp Tyr Lys Asp Gly Arg Leu 160 165 170 175 CTT CCT GAG CAC AAG AAA AAT CCA ATT GAO ATO CCA OAT ATT TAT OTT 624 Leu Pro Glu His Lys Lys Asn Pro He Olu Met Wing Asp He Tyr Val 180 185 190 TTT AAT CAA acc TTG TAT CTA TOT CAT TAC ACA CAG TCA GAT AAT GTG 672 Phe Asn Gln aly Leu Tyr Val Cys Asp Tyr Thr Gln As As Asn Asn Val 195 200 205 AOT TCC Tas ACA OTC CGA GCT GTO GTT AAA GTG AGA ACC ATT GGT AAO 720 Ser Ser Trp Thr Val Arg Ala Val Val Lys Val Arg Thr He Gly Lys 210 215 220 GAC ATC AAT GTC AAO CCC OAA ATT CTG CAT CCC ATT ACÁ GAT ACÁ CTG 768 Asp He Asn Val Lys Pro Glu He Leu Asp Pro He Thr Asp Thr Leu 225 230 235 GAC GTA GTA GTA AAO CCT TA ACT CTC CCC TOC AGA GTA CAG TTT 816 Asp Val Glu Leu Gly Lys Pro Leu Thr Leu Pro Cys Arg Val Gln Phe 240 245 250 255 GGC TTC CAA AGA CTT TCA AAO CCT OTO ATA AAO TGG TAT GTC AAA GAA 864 Gly Phe Gln Arg Leu Ser Lys Pro Val He Lys Trp Tyr Val Lys Glu 260 265 270 TCT ACÁ CAG GAG TGG CAÁ ATO TCA OTA TTT OAO OAO AAA AOA ATT CAA 912 Ser Thr Gln Olu Trp slu Met Ser Val Phe alu slu Lys Arg He Cln 275 280 285 TCC ACT TTC AAC AAT OAA GTC ATT GAA CGT ACC ATC TTC TTG AGA GAA 960 Ser Thr Phe Lys Asn slu Val He Glu Arg Thr He Phe Leu Arg Glu 290 295 300 CTT ACC CAG AGA GAT CTC ACC AGA AAG TTT GTT TGC TTT sCC CAG AAC 1008 Val Thr Gln Arg Asp Leu Ser Arg Lys Phe Val Cys Phe Wing Gln Asn 305 310 315 TCC ATT GGG AAC ACA ACA CGO ACC ATA CGG CTG ACC AAa AAG GAA GAG 1056 Ser He Gly Asn Thr Thr Arg Thr He Arg Leu Arg Lys Lys Glu Glu 320 325 330 335 GTG GTG TTT GTA TAC ATC CTT CTC GGC ACG GCC TTG ATG CTC GTG GGC 1104 Val Val Phe Val Tyr He Leu Leu Gly Thr Ala Leu Met Leu Val Gly 340 345 350 GTT CTG GTG GCA GCT GCT TTC CTC TAC TGO TAC TGO ATT CAA CTT GTC 1152 Val Leu Val Ala Ala Ala Phe Leu Tyr Trp Tyr Trp He slu Val __Val 355 360 365 CTG CTC TGT CGA ACC TAC AAC AAC AAA OAT GAC ACT CTG oaa OAT AAG 1200 Leu Leu Cys Arg Thr Tyr Lys Asn Lys Asp Glu Thr Leu sly Asp Lys 370 375 380 AAG GAA TTC GAT GCA TTT OTA TCC TAC Tca AAT TGG AGC TCT CCT GAG 1248 Lys Glu Phe Asp Wing Phe Val Ser Tyr Ser Asn Trp Ser Ser Glu 385 390 395 ACT GAC scc GTO GOA TCT CTG AOT GAG aAA CAC CTG GCT cTa AAT CTT 1296 Thr Asp Wing Val Gly Ser Leu Ser Glu slu His Leu Wing Leu Asn Leu 400 405 410 415 TTC CCG CAG GTG CTA GAA GAC ACC TAT scs TAC AGA TTG TOT TTG CTT 1344 Phe Pro slu Val Leu Glu Asp Thr Tyr sly Tyr Arg Leu Cys Leu Leu 420 425 430 GAC CGA OAT OTO ACC CCA GGA COA GTG TAT GCA GAT GAC ATT GTC AGC 1392 Asp Arg Asp Val Thr Pro Gly sly Val Tyr Wing Asp Asp He Val Ser 435 440 445 ATC ATT AAa AAA AGC CGA ACA OOA ATA TTT ATC CTG AGT CCC AOC TAC 1440 He He Lys Lys Ser Arg Arg Gly He Phe He Leu Ser Pro Ser Tyr 450 455 460 CTC AAT COA CCC CGT GTC TTT GAO CTA CAA GCA GCA GTG AAT CTT GCC 1488 Leu Asn Cly Pro Arg Val Phe Glu Leu Gln Wing Wing Val Asn Leu Wing 465 470 475 TTG GTT GAT CAO ACÁ CTG AAO TTG ATT TTA ATT AAG TTC TOT TCC TC 1536 Leu Val Asp sln Thr Leu Lys Leu He Leu He Lys Phe Cys Ser Phe 480 485 490 495 CAA GAG CCA GAA TCT CTT CCT TAC CTT GTC AAA AAG GCT CTG CGG GTT 1584 Gln Glu Pro Glu Ser Leu Pro Tyr Leu Val Lys Lys Wing Leu Arg Val 500 505 510 CTC CCC ACÁ GTC ACÁ TGC AAA GGC TTG AAG TCG GTC CAC acc AGT TCC 1632 Leu Pro Thr Val Thr Trp Lys Gly Leu Lys Ser Val His Wing Ser Ser 515 520 525 ACO TTC TGG ACC CAA ATT CCT TAC CAC ATG CCT GTG AAG CC AAC 1680 Arg Phe Trp Thr Gln He Arg Tyr His Met Pro Val Lys Asn Ser Asn 530 535 540 Aaa TTT ATO TTC AAC ssa CTC AGA ATT TC CTG AAG ssc TTT TCC CCT 1728 Arg Phe Met Phe Asn Oly Leu Arg He Phe Leu Lys Cly Phe Ser Pro 545 550 555 CAA AAG GAC CTA GTG ACA CAG AAA CCC CTG GAA GGA ATG CCC AAG TCT 1776 Glu Lys Asp Leu Val Thr Gln Lys Pro Leu Glu Gly Met Pro Lys Ser 560 565 570 575 saa AAT OAC CAC COA OCT CAC AAC CTC CTT CTC TAC AOT OAC CAO AAO 1824 sly Asn Asp His Gly Wing Gln Asn Leu Leu Leu Tyr Ser Asp Gln Lys 580 585 590 Handle Tac TCA 1833 Arg Cys (2) SEQUENCE IDENTIFICATION INFORMATION NO. 14: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 610 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 14: Met Ser Val Trp Leu Val Phe Leu Val Cys Ala sly alu Lys Thr Thr -17 -15 -10 -5 Oly Phe Asn His Ser Wing Cys Wing Thr Lys Asn Ser Val Asp He Phe 1 5 10 15 Wing Arg Cly Ala slu Asn Phe Val Tyr Phe Val Thr Tyr Lys Ser Phe 20 25 30 Arg Ser Lys Asn Ser Pro Met sln Val Asn Cys His sln His Lys Val 35 40 45 Cys Ser Cln Thr Cys Ser aly Ser aln Lys Asp Leu Ser Asp Val sln 50 55 60 Trp Tyr Met sln Pro Arg Ser sly Ser Pro Leu alu Clu He Ser Arg 65 70 75 Asn Ser Pro His Met aln Ser Olu aly Met Leu His He Leu Ala Pro 80 85 90 95 aln Thr Asn Ser He Trp Ser Tyr He Cys Arg Pro Arg He Arg Ser 100 105 110 Pro Oln Asp Met Wing Cys Cys He Lys Thr Val Leu slu Val Lys Pro 115 120 125 Oln Arg Asn Val Ser Cys Cly Asn Thr Ala sln Asp slu aln Val Leu 130 135 140 Leu Leu Oly Ser Thr sly Ser He His Cys Pro Ser Leu Ser Cys Cln 145 150 155 Ser Asp Val Cln Ser Pro Glu Met Thr Trp Tyr Lys Asp Gly Arg Leu 160 165 170 175 Leu Pro Glu His Lys Lys Asn Pro He Glu Met Wing Asp He Tyr Val 180 185 190 Phe Asn sln sly Leu Tyr Val Cys Asp Tyr Thr sln Ser Asp Asn Val 195 200 205 Ser Ser Trp Thr Val Arg Wing Val Val Lys Val Arg Thr He sly Lys 210 215 220 Asp He Asn Val Lys Pro alu He Leu Asp Pro He Thr Asp Thr Leu 225 230 235 Asp Val Clu Leu sly Lys Pro Leu Thr Leu Pro Cys Arg Val Oln Phe 240 245 250 255 sly Phe sln Arg Leu Ser Lys Pro Val He Lys Trp Tyr Val Lys alu 260 265 270 Be Thr Cln alu Trp Clu Met Ser Val Phe Glu Glu Lys Arg He Gln 275 280 285 Be Thr Phe Lys Asn alu Val He slu Arg Thr He Phe Leu Arg Glu 290 295 300 Val Thr Gln Arg Asp Leu Ser Arg Lys Phe Val Cys Phe Ala Gln Asn 305 310 315 Ser He Gly Asn Thr Thr Arg Thr He Arg Leu Arg Lys Lys Glu Glu 320 325 330 335 Val Val Phe Val Tyr He Leu Leu Gly Thr Ala Leu Met Leu Val Gly 340 345 350 Val Leu Val Ala Ala Ala Phe Leu Tyr Trp Tyr Trp He Glu Val Val 355 360 365 Leu Leu Cys Arg Thr Tyr Lys Asn Lys Asp Glu Thr Leu Gly Asp Lys 370 375 380 Lys Olu Phe Asp Wing Phe Val Ser Tyr Ser Asn Trp Be Ser Pro slu 385 390 395 Thr Asp Ala Val Oly Ser Leu Ser Clu alu His Leu Ala Leu Asn Leu 400 405 410 415 Phe Pro Olu Val Leu alu Asp Thr Tyr aly Tyr Arg Leu Cys Leu Leu 420 425 430 Asp Arg Asp Val Thr Pro sly sly Val Tyr Wing Asp Asp He Val Ser 435 440 445 He He Lys Lys Ser Arg Arg sly He Phe He Leu Ser Pro Ser Tyr 450 455 460 Leu Asn Oly Pro Arg Val Phe slu Leu Oln Ala Wing Val Asn Leu Wing 465 470 475 Leu Val Asp sln Thr Leu Lys Leu He Leu He Lys Phe Cys Ser Phe 480 485 490 495 aln alu Pro alu Ser Leu Pro Tyr Leu Val Lys Lys Ala Leu Arg Val 500 505 510 Leu Pro Thr Val Thr Trp Lys Gly Leu Lys Ser Val His Wing Ser 515 520 525 Arg Phe Trp Thr Gln He Arg Tyr His Met Pro Val Lys Asn Ser Asn 530 535 540 Arg Phe Met Phe Asn Gly Leu Arg He Phe Leu Lys Gly Phe Ser Pro 545 550 555 Glu Lys Asp Leu Val Thr Gln Lys Pro Leu Glu Gly Met Pro Lys Ser 560 565 570 575 Gly Asn Asp His Gly Ala Gln Asn Leu Leu Leu Tyr Ser Asp Gln Lys 580 585 590 Arg Cys (2) SEQUENCE IDENTIFICATION INFORMATION NO. fifteen: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 2259 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: individual (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: cDNA (ix) TRAIT: (A) NAME / KEY: CDS (B) LOCATION: 22 ... 1863 (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 15: TGAC _AGGI -GC i = __ Aac -GOAi _C C ATO CTC TGT TTC drops TOO OTG TTT CTT TCO 51 Met Leu Cys Leu Cly Trp Val Phe Leu Trp 1 5 10 TTT OTT GCA OGA CAO AAO ACC ACA GGA TTT AAT CAT TCA GCT TOT GCC 99 Phe Val Wing Gly slu Lys Thr Thr Gly Phe Asn His Ser Wing Cys Wing 15 20 25 ACC AAA AAA CTT CTO toa ACA TAT TCT OCA AOG sot GCA GAG AAT TTT 147 Thr Lys Lys Leu Leu Trp Thr Tyr Ser Wing Arg sly Wing Glu Asn Phe 30 35 40 OTC CTA TTT TGT OAC TTA CAA CAO CTT CAO GAG CAA AAA TTC TCC CAT 195 Val Leu Phe Cys Asp Leu Gln Glu Leu Gln Glu sln Lys Phe Ser His 45 50 55 OCA ACT CAA CTG TCA CCA ACA CAA AGT CCT OCT CAC AAA CCT TCC AGT 243 Wing Ser Gln Leu Ser Pro Thr Gln Pro Pro Wing His Lys Pro Cys Ser 60 65 70 sac AOT CAG AAG CAC CTA TCT GAT GTC CAO tso TAC ATG CAA CCT CGG 291 Cly Ser Gln Lys Asp Leu Ser Asp Val sln Trp Tyr Met Gln Pro Arg 75 80 85 90 AOT OCA ACT CCA CTA CAO GAO ATC ACT AOA AAC TCT CCC CAT ATO CAG 339 Be aly Ser Pro Leu alu alu He Ser Arg Asn Ser Pro His Met Gln 95 100 105 AOT OAA sac ATG CTC CAT ATA TTG acc CCA CAO Aca AAC AOC ATT TGG 387 Be alu sly Met Leu His He Leu Wing Pro Slender Thr Asn Ser He Trp 110 115 120 TCA TAT ATT TOT ACA CCC AGA ATT AGO AGC CCC CAG GAT ATC OCC TCT 435 Ser Tyr He Cys Arg Pro Arg He Arg Ser Pro aln Asp Met Ala Cys 125 130 135 TCT ATC AAO ACÁ OTC TTA OAA OTT AAO CCT CAO AGA AAC GTO TCC TGT 483 Cys He Lys Thr Val Leu Clu Val Lys Pro Gln Arg Asn Val Ser Cys 140 145 150 GCG AAC ACÁ GCA CAA GAT CAA CAA CA CT CTA CTT GOC AGT ACT GGC 531 Gly Asn Thr Ala Gln Asp Glu Gln Val Leu Leu Leu Gly Ser Thr Gly 155 160 165 170 TCC ATT CAT TGT CCC AGT CTC AGC TGC CAA AGT OAT OTA CAG AGT CCA 579 Ser He His Cys Pro Ser Leu Ser Cys Gln Ser Asp Val Gln Ser Pro 175 180 185 GAO ATO ACC TCO TAC AAC GAT GCA AGA CTA CTT CCT GAG CAC AAG AAA 627 Olu Met Thr Trp Tyr Lys Asp Gly Arg Leu Leu Pro Glu His Lys Lys 190 195 200 AAT CCA ATT GAG ATG GCA GAT ATT TAT GTT TTT AAT CAA GOC TTC TAT 675 Asn Pro He Glu Met Wing Asp He Tyr Val Phe Asn Gln sly Leu Tyr 205 210 215 OTA TGT GAT TAC ACA CAG TCA GAT AAT GTG AGT TCC TGO ACA GTC COA 723 Val Cys Asp Tyr Thr Gln Ser Asp Asn Val Ser Ser Trp Thr Val Arg 220 225 230 acT ote CTT AAA OTO AOA ACC ATT GOT AAG GAC ATC AAT sto AAa CCG 771 Wing Val Val Lys Val Arg Thr He Gly Lys Asp He Asn Val Lys Pro 235 240 245 250 GAA ATT CTG GAT CCC ATT ACÁ GAT ACA CTG GAC GTA GAG CTT GGA AAG 819 Glu He Leu Asp Pro He Thr Asp Thr Leu Asp Val Glu Leu Gly Lys 255 260 265 CCT TTA ACT CTC CCC TGC AGA GTA CAG TTT GGC TTC CAA AGA CTT TCA 867 Pro Leu Thr Leu Pro Cys Arg Val Gln Phe Gly Phe Gln Arg Leu Ser 270 275 280 AAG CCT GTG ATA AAG TGG TAT GTC AAA GAA TCT ACÁ CAG CAO TOO OAA 915 Lys Pro Val He Lys Trp Tyr Val Lys Glu Ser Thr Gln slu Trp slu 285 290 295 ATO TCA OTA TTT CAO OAO AAA ACÁ ATT CAA TCC ACT TTC AAO AAT CAÁ 963 Met Ser Val Phe aiu aiu Lys Arg He Oln Ser Thr Phe Lys Asn slu 300 305 310 OTC ATT CAA CGT ACC ATTC TTC AGA GAA GTT ACC CAG AOA OAT CTC 1011 Val He Glu Arg Thr He Phe Leu Arg Glu Val Thr Gln Arg Asp Leu 315 320 325 330 AOC AGA AAG TTT GTT TGC TTT GCC CAG AAC TCC ATT GGs AAC ACÁ ACÁ 1059 Ser Arg Lys Phe Val Cys Phe Wing Gln Asn Ser He Oly Asn Thr Thr 335 340 345 CGC ACC ATA CGG CTO ACC AAG AAG GAA CAC GTC ota TTT GTA TAC ATC 1107 Arg Thr He Arg Leu Arg Lys Lys Glu slu Val Val Phe Val Tyr He 350 355 360 CTT CTC GGC ACG acc TTO ATO CTG GTG sac GTT CTC GTO GCA OCT GCT 1155 Leu Leu Gly Thr Ala Leu Met Leu Val Cly Val Leu Val Ala Wing Wing 365 370 375 TTC CTC TAC TGC TAC tao ATT GAA GTT OTC CTG CTC TGT COA ACC TAC 1203 Phe Leu Tyr Trp Tyr Trp He Glu Val Val Leu Leu Cys Arg Thr Tyr 380 385 390 AAG AAA OAT CAO ACT CTO Gss GAT AAO AAG CAAT TTC OAT OCA TTT 1251 Lys Asn Lys Asp Olu Thr Leu aly Asp Lys Lys Olu Phe Asp Wing Phe 395 400 405 410 GTA TCC TAC Tcs AAT tso AOC TCT CCT CAO ACT OAC GCC OTO ssA TCT 1299 Val Ser Tyr Ser Asn Trp Ser Ser Pro Clu Thr Asp Wing Val Oly Ser 415 420 425 CTG AGT GAO CAÁ CAC CTO CCT CTG AAT CTT TTC cca GAA OTO CTA GAA 1347 Leu Ser Glu slu His Leu Ala Leu Asn Leu Phe Pro Glu Val Leu Glu 430 435 440 GAC ACC TAT CGC TAC ACTION TTC TGT TTG CTT GAC CCA GAT ota ACC CCA 1395 Asp Thr Tyr Gly Tyr Arg Leu Cys Leu Leu Asp Arg Asp Val Thr Pro 445 450 455 CGA GGA GTG TAT OCA GAT GAC ATT GTO ACC ATC ATT AAC AAA AGC CGA 1443 Gly Gly Val Tyr Wing Asp Asp He Val Ser He He Lys Lys Ser Arg 460 465 470 ACÁ GGA ATA TTT ATC CTG AGT CCC AOC TAC CTC AAT GOA CCC CGT GTC 1491 Arg Gly He Phe He Leu Ser Pro Be Tyr Leu Asn Gly Pro Arg Val 475 480 485 490 TT -GAG CTA CAA CCA GCA GTG AAT CTT acc TTG OTT GAT CAO ACÁ CTC 1539 Phe Glu Leu Gln Wing Wing Val Asn Leu Wing Leu Val Asp Oln Thr Leu 495 500 505 AAG TTO ATT TTA ATT AAG TTC TGT TCC TTC CAA CAO CCA OAA CT CTT 1587 Lys Leu He Leu He Lys Phe Cys Ser Phe Gln Olu Pro Clu Ser Leu 510 515 520 CCT TAC CTT CTC AAA AAG GCT CTG CAS OTT CTC CCC ACÁ OTC ACÁ TOO 1635 Pro Tyr Leu Val Lys Lys Wing Leu Arg Val Leu Pro Thr Val Thr Trp 525 530 535 AAA GOC TTG AAG TCC GTC CAC GCC ACT TCC AGC TTC TGG ACC CAA ATT 1683 Lys Gly Leu Lys Ser Val His Wing Being Ser Arg Phe Trp Thr Gln He 540 545 550 CGT TAC CAC ATG CCT GTG AAG AAC TCC AAC AGO TTT ATG TTC AAC GGC 1731 Arg Tyr His Met Pro Val Lys Asn Ser Asn Arg Phe Met Phe Asn Gly 555 560 565 570: 9I- ON VI0N3n03S 30 Ol: VI0N3fr33S 30 NOI0dl-JOS30 (¡x) eui? xid: vin03101 I 30 Odll (ü) 03 | BTU || : vi0010d01 (?) OPPBOUJLUB Odll (a) soppBOUjLUB H9 ODIIONOI (V): VI0N3n03S VI 30 SV0llSI_.310Vi_V0 (i) 91- : 9I- ON VI0N3n03S 3Q NOI0V0ldllN3ai V Vd NOlOVI? IdOdNI (z) Www 6se_ wvwwvw DVWXOXD eeee XXDDDDVWX DXVDDXDVW DXXVDXDVOD VXVDDXXDXX XXVXXXXVDD VXVWXVOVD 01-XX e_t_ DOXVXVX oxoxoxoxxx ODVXVDXVXX XWDXVXVXV VXDVDOXXX XDXDDDXVDD et? _ DVDOXVDXXV DWDDXDXDD DDXVDDXDDV VWDVDWD XWDVDWDX DDDVXOWDD eS0- DXXDVDVDXD DDXXXVDVDV DDVXXDDXDX DDDDXDXDDV DVDDXDVXW DDVDVDVDVD e66T VDWDDXDDX XDODXDXDDD VXXXXDDXDX DXVDDODDW DXWDDXDVD DDVDVDXXDD ? ZZ6X WDDWDDDX DVDXDXDDXD XXXDDDVDXX VWOVXVDXD DDVDXVDDXD XDXDDXXDW 019 S09 SÃO ssaV SAQ or you as 3- &? Z naq naq naq USV u or ZL8T OVXDDDXVOX DDX DDV DW OVD DVD XOV DVX DXD XXD DXD DW DVD 009 S6S 06S BTV ATO STH DSV USV AO aas sAq od aw A? On? 3 n3q oad sAq u? 3 LZ8X XDD VDD DVD DVD XW DDD XDX DW DDD DXV VOD WD DXD DDD VW DVD S8S 08S S_S aqx XB? naq dsv sAq nd oad aas sqd s? aqd naq aqd 3? i? nsq 6LLX VDV DXD VXD DVD DW WD XDD DDX XXX DDD DW DXD DXX XXV VDV DXD M Met Leu Cys Leu aly Trp Val Phe Leu Trp Phe Val Wing Gly Glu Lys 1 5 10 15 Thr Thr sly Phe Asn His Ser Wing Cys Wing Thr Lys Lys Leu Leu Trp 20 25 30 Thr Tyr Ser Wing Arg Cly Wing slu Asn Phe Val Leu Phe Cys Asp Leu 35 40 45 Oln alu Leu sln alu aln Lys Phe Ser His Wing Ser Cln Leu Ser Pro 50 55 60 Thr Gln Ser Pro Wing His Lys Pro Cys Ser Cly Ser Gln Lys Asp Leu 65 70 75 80 Ser Asp Val aln Trp Tyr Met aln Pro Arg Ser sly Ser Pro Leu slu 85 90 95 Glu He Ser Arg Asn Ser Pro His Met Gln Ser Glu Gly Met Leu His 100 105 110 He Leu Ala Pro Gln Thr Asn Ser He Trp Ser Tyr He Cys Arg Pro 115 120 125 Arg He Arg Ser Pro sln Asp Met Ala Cys Cys He Lys Thr Val Leu 130 135 140 Olu Val Lys Pro aln Arg Asn Val Ser Cys Gly Asn Thr Ala Gln Asp 145 150 155 160 Glu Gln Val Leu Leu Leu Oly Ser Thr aly Ser He His Cys Pro Ser 165 170 175 Leu Ser Cys sln Ser Asp Val sln Ser Pro alu Met Thr Trp Tyr Lys 180 185 190 Asp Oly Arg Leu Leu Pro slu His Lys Lys Asn Pro He slu Met Wing 195 200 205 Asp He Tyr Val Phe Asn aln Cly Leu Tyr Val Cys Asp Tyr Thr Cln 210 215 220 As As Asn Val Ser Ser Trp Thr Val Arg Ala Val Val Lys Val Arg 225 230 235 240 Thr He Cly Lys Asp He Asn Val Lys Pro alu He Leu Asp Pro He 245 250 255 Thr Asp Thr Leu Asp Val slu Leu Oly Lys Pro Leu Thr Leu Pro Cys 260 265 270 Arg Val Cln Phe Gly Phe Gln Arg Leu Ser Lys Pro Val He Lys Trp 275 280 285 Tyr Val Lys Glu Ser Thr Gln Glu Trp Glu Met Ser Val Phe Glu Glu 290 295 300 Lys Arg He Gln Ser Thr Phe Lys Asn Glu Val He Glu Arg Thr He 305 310 315 320 Phe Leu Arg slu Val Thr aln Arg Asp Leu Ser Arg Lys Phe Val Cys 325 330 335 Phe Ala Gln Asn Ser He Gly Asn Thr Thr Arg Thr He Arg Leu Arg 340 345 350 Lys Lys Glu Val Val Phe Val Tyr He Leu Leu Gly Thr Ala Leu 355 360 365 Met Leu Val Gly Val Leu Val Ala Ala Wing Phe Leu Tyr Trp Tyr Trp 370 375 380 He Glu Val Val Leu Leu Cys Arg Thr Tyr Lys Asn Lys Asp Glu Thr 385 390 395 400 Leu Gly Asp Lys Lys Olu Phe Asp Wing Phe Val Ser Tyr Ser Asn Trp 405 410 415 Be Ser Pro slu Thr Asp Wing Val sly Ser Leu Ser slu slu His Leu 420 425 430 Wing Leu Asn Leu Phe Pro slu Val Leu Clu Asp Thr Tyr Cly Tyr Arg 435 440 445 LeuT-ys Leu Leu Asp Arg Asp Val Thr Pro aly sly Val Tyr Ala Asp 450 455 460 Asp He Val Ser He He Lys Lys Ser Arg Arg aly He Phe He Leu 465 470 475 480 Be Pro Pro Tyr Leu Asn sly Pro Arg Val Phe alu Leu Cln Ala Wing 485 490 495 Val Asn Leu Ala Leu Val Asp sln Thr Leu Lys Leu He Leu He Lys 500 505 510 Phe Cys Ser Phe Gln Glu Pro Glu Ser Leu Pro Tyr Leu Val Lys Lys 515 520 525 Ala Leu Arg Val Leu Pro Thr Val Thr Trp Lys Gly Leu Lys Ser Val 530 535 540 His Wing Being Ser Arg Phe Trp Thr Gln He Arg Tyr His Met Pro Val 545 550 555 560 Lys Asn Being Asn Arg Phe Met Phe Asn Gly Leu Arg He Phe Leu Lys 565 570 575 Gly Phe Ser Pro Glu Lys Asp Leu Val Thr Gln Lys Pro Leu Glu Gly 580 585 590 Met Pro Lys Ser Gly Asn Asp His Gly Wing Gln Asn Leu Leu Leu Tyr 595 600 605 Ser Asp Cln Lys Arg Cys 610 (2) SEQUENCE IDENTIFICATION INFORMATION NO. 17: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 516 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: individual (D) TOPOLOGY: linear (I) TYPE OF MOLECULE: cDNA (ix) TRAIT: (A) NAME / KEY: CDS (B) LOCATION: 2 ... 514 (ix) TRAIT: (A) NAME / KEY: miscjeature (B) LOCATION: 374 (D) OTHER INFORMATION: / note : "nucleotides 374, 383, 396, 403, 433, 458, 459, 483, and 515 are indicated as C, each can be A, C, G, or T" (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 17: C TOT GAA TTA AAA TAT GGA GOC TTT GTT GTG AGA ACA ACT ACT GAA 46 Cys Glu Leu Lys Tyr Gly Gly Phe Val Val Arg Arg Thr Thr Glu 1 5 10 15 TTA ACT GTT ACÁ GCC CCT CTG ACT GAT AAG CCA CCC AAG CTT TTG TAT 94 Leu Thr Val Thr Ala Pro Leu Thr Asp Lys Pro Pro Lys Leu Leu Tyr 20 25 30 CCT ATG GAA ACT AAA CTG ACA ATT CAC CAO ACC CAO CTO OOT OAC TCT 142 Pro Met Clu Ser Lys Leu Thr He aln slu Thr sln Leu aly Asp Ser 35 40 45 OCT AAT CTA ACC TGC AGA GCT TTC TTT GOO TAC ACC GOA GAT CTC ACT 190 Wing Asn Leu Thr Cys Arg Wing Phe Phe Cly Tyr Sery and Asp Val Ser 50 55 60 CCT TTA ATT TAC TOO ATG AAA GCA OAA AAA TTT ATT CAA CAT CTO OAT 238 Pro Leu He Tyr Trp Met Lys sly Clu Lys Phe He slu Asp Leu Asp 65 70 75 CAA AAT COA OTT TOO OAA AOT OAC ATT ACA ATT CTT AAO OAO CAT CTT 286 Glu Asn Arg Val Trp Glu Ser Asp He Arg He Leu Lys Glu His Leu 80 85 90 95 CGG GAA CAG GAA GTT TCC ATC TCA TTA ATT GTG GAC TCT GTG CAA CAA 334 Cly Clu sln alu Val Ser He Ser Leu He Val Asp Ser Val Olu slu 100 105 110 OGT CAC TTC OCA AAT TAC TCC TGT TAT GTT GAA AAA TGG CAA TGO ACG 382 Gly Asp Leu Gly Asn Tyr Ser Cys Tyr Val Glu Lys Trp Gln Trp Thr 115 120 125 CCG ACÁ CGC CAG CCG TCC CCC TTC ATA AAC GAO AGC CTA ATC TAC ACA 430 Pro Thr Arg Gln Pro Ser Pro Phe He Asn Olu Ser Leu Met Tyr Thr 130 135 140 GTC COA ACT TOC cto OAO scc CTT ass CCA AAA CCT TOO tao tto AAT 478 Val aly Thr Cys Leu slu Ala Leu aly Pro Pro Lys Pro Trp Leu Asn 145 150 155 OTT TCC OCA CCA CCT TCA AAO TOT ACC AAC OTT COA ce 516 Val Ser aly Pro Pro Ser Lys Cys Thr Lys Val Oly 160 165 170 (2) SEQUENCE IDENTIFICATION INFORMATION NO. 18: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 171 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 18: Cys Glu Leu Lys Tyr Gly Gly Phe Val Val Arg Arg Thr Thr alu Leu 1 5 10 15 Thr Val Thr Ala Pro Leu Thr Asp Lys Pro Pro Lys Leu Leu Tyr Pro 20 25 30 - | Q Met Clu Ser Lys Leu Thr He aln alu Thr Cln Leu sly Asp Ser Ala 35 40 45 Asn Leu Thr Cys Arg Wing Phe Phe Cly Tyr Ser Gly Asp Val Ser Pro 50 55 60 Leu He Tyr Trp Met Lys Gly Glu Lys Phe He Glu Asp Leu Asp alu 65 70 75 80 Asn Arg Val Trp slu Ser Asp He Arg He Leu Lys Clu His Leu aly 85 90 95 alu Cln alu Val Ser Be Leu He Val Asp Ser Val slu Olu sly 100 105 110 Asp Leu aly Asn Tyr Ser Cys Tyr Val Olu Lys Trp Cln Trp Thr Pro 115 120 125 Thr Arg Gln Pro Ser Pro Phe He Asn Glu Ser Leu Met Tyr Thr Val 130 135 140 Gly Thr Cys Leu Glu Wing Leu Gly Pro Lys Pro Trp Trp Leu Asn Val 145 150 155 160 Ser Oly Pro Pro Ser Lys Cys Thr Lys Val aly 0 165 170 (2) SEQUENCE IDENTIFICATION INFORMATION NO. 19: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 1991 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: individual (D) TOPOLOGY: linear (I) TYPE OF MOLECULE: cDNA (ix) TRAIT: (A) NAME / KEY: CDS (B) LOCATION: 1 ... 1458 (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 19: GAA TTC sac ACO AOC TCT CAÁ TTA AAA TAT GOA ssc TTT OTT OTO ACÁ 48 Olu Phe Cly Thr Ser Cys Olu Leu Lys Tyr aly aly Phe Val Val Arg 1 5 10 15 AOA ACT ACT CATA TTA ACT CTT ACA OCC CCT CTO ACT OAT AAO CCA CCC 96 Arg Thr Thuu alu Leu Thr Val Thr Wing Pro Leu Thr Asp Lys Pro Pro 20 25 30 AAC CTT TTO TAT CCT ATO CAA AOT AAA CTa ACA ATT CAO CAO ACC CAG 144 Lys Leu Leu Tyr Pro Met Glu Ser Lys Leu Thr He Gln Glu Thr Gln 35 40 45 CTG GGT GAC TCT GCT AAT CTA ACC TGC AGA GCT TTC TTT GGG TAC AGC 192 Leu Gly Asp Ser Wing Asn Leu Thr Cys Arg Wing Phe Phe Oly Tyr Ser 50 55 60 OCA OAT OTC AOT CCT TTA ATT TAC tao ATO AAA OCA OAA AAA TTT ATT 240 and Asp Val Ser Pro Leu He Tyr Trp Met Lys Oly Olu Lys Phe He 65 70 75 80 GAA GAT CTG GAT GAA AAT CGA GTT TGC GAA AGT GAC ATT AGA ATT CTT 288 Glu Asp Leu Asp slu Asn Arg Val Trp Olu Ser Asp He Arg He Leu 85 90 95 AAO OAG CAT CTT GCG GAA CAG GAA GTT TCC ATC TCA TTA ATT OTO CAC 336 Lys Glu His Leu Gly Glu Gln Olu Val Ser Ser Leu He Val Val 100 100 110 TCT GTG GAA GAA GOT GAC TTG GGA AAT TAC TCC TGT TAT GTT GAA AAT 384 Ser Val Glu Glu Gly Asp Leu Gly Asn Tyr Ser Cys Tyr Val Glu Asn 115 120 125 GOA AAT OOA CGT CGA CAC GCC AGC GTT CTC CTT CAT AAA CGA GAG CTA 432 Gly Asn Gly Arg Arg His Wing Ser Val Leu Leu His Lys Arg Glu Leu 130 135 140 ATG TAC ACA GTO GAA CTT GCT GOA GCC CTT GGT GCT ATA CTC TTG CTG 480 Met Tyr Thr Val Glu Leu Ala Gly sly Leu aly Ala He Leu Leu Leu 145 150 155 160 CTT GTA TGT TTG GTG ACC ATC TAC AAG TGT TAC AAG ATA GAA ATC ATG 528 Leu Val Cys Leu Val Thr He Tyr Lys Cys Tyr Lys He Glu He Met 165 170 175 CTC TTC TAC AGG AAT CAT TTT GGA GCT GAA GAG CTC GAT GOA GAC AAT 576 Leu Phe Tyr Arg Asn His Phe Cly Ala alu Clu Leu Asp sly Asp Asn 180 185 190 AAA OAT TAT GAT CCA TAC TTA TCA TAC ACC AAA GTC GAT CCT GAC CAG 624 Lys Asp Tyr Asp Ala Tyr Leu Ser Tyr Thr Lys Val Asp Pro Asp Gln 195 200 205 TGG AAT CAA GAG ACT GGG GAA GAA GAA CGT TTT GCC CTT GAA ATC CTA 672 Trp Asn Gln Glu Thr Gly Glu Glu alu Arg Phe Ala Leu alu He Leu 210 215 220 CCT GAT ATG CTT GAA AAG CAT TAT GGA TAT AAG TTC TTT ATA CCA CAT 720 Pro Asp Met Leu Olu Lys His Tyr Gly Tyr Lys Leu Phe He Pro Asp 225 230 235 240 AGA OAT TTA ATC CCA ACT GGA ACA TAC ATT OAA OA T ato OCA ACA TGT 768 Arg Asp Leu He Pro Thr Gly Thr Tyr He slu Asp Val Wing Arg Cys 245 250 255 GTA GAT CAA AGC AAG CGG CTG ATT ATT GTC ATG ACC CCA AAT TAC GTA 816 Val Asp Gln Ser Lys Arg Leu He He Val Met Thr Pro Asn Tyr Val 260 265 270 GTT ACA Aaa soc tso AOC ATC TTT CAO CTO CAA ACC AOA CTT COA AAT 864 Val Arg Arg sly Trp Ser He Phe alu Leu alu Thr Arg Leu Arg Asn 275 280 285 ATO CTT GTG ACT GGA GAA ATT AAA GTG ATT CTA ATT GAA TGC AGT GAA 912 Met Leu Val Thr Gly Glu He Lys Val He Leu He Glu Cys Ser Glu 290 295 300 CTG AGA GGA ATT ATG AAC TAC CAG GAG OTO GAC OCC CTC AAO CAC ACC 960 Leu Arg aly He Met Asn Tyr aln slu Val Olu Ala Leu Lys His Thr 305 310 315 320 ATC AAC CTC CTO ACG GTC ATT AAA TGG CAT GGA CCA AAA TGC AAC AAG 1008 He Lys Leu Leu Thr Val He Lys Trp His sly Pro Lys Cys Asn Lys 325 330 335 TTO AAC TCC AAG TTC TOO AAA CGT TTA CAG TAT GAA ATG CCT TTT AAG 1056 Leu Asn Ser Lys Phe Trp Lys Arg Leu Gln Tyr alu Met Pro Phe Lys 340 345 350 ACO ATA CAA CCC ATT ACA CAT GAO CAG GCT TTA GAT AGT GAO CAA 1104 Arg He Clu Pro He Thr His alu sln Ala Leu Asp Val Ser slu sln 355 360 365 sss CCT TTT sas CAO CTO CAO ACT OTC TCO acc ATT TCC ATC acc scs 1152 aly Pro Phe aly alu Leu Gln Thr Val Ser Wing He Ser Met Wing Wing 370 375 380 aCC ACC TCC ACA GCT CTA GCC ACT GCC CAT CCA GAT CTC CGT TCT ACC 1200 Wing Thr Ser Thr Wing Leu Wing Thr Wing Pro Asp Leu Arg Ser Thr 385 390 395 400 TTT CAC AAC TAC CAT TCA CAT CABLE ATG CGT CAG AAA CAC TAC TAC TGA CGA 1248 Phe His Asn Thr Tyr His Ser Gln Met Arg Gln Lys His Tyr Tyr Arg 405 410 415 AOC TAT GAO TAC GAC GTA CCT CCT ACC GGC ACC CTG CCT CTT ACC TCC 1296 Ser Tyr Glu Tyr Asp Val Pro Pro Thr Gly Thr Leu Pro Leu Thr Ser 420 425 430 ATA GsC AAT CAC CAT ACC TAC TCT AAC ATC CCT ATC ACA CTC ATC AAC 1344 He Gly Asn Gln His Thr Tyr Cys Asn He Pro Met Thr Leu He Asn 435 440 445 ssc CAO cao CCA CAO ACA AAA TCC AOC Aaa CAO CAO AAT CCA CAT CAO 1392 Oly Cln Arg Pro Cln Thr Lys Ser Ser Arg Clu Gln Asn Pro Asp Glu 450 455 460 GCC CAC ACA AAC AGT GCC ATC CTG CCG CTG TTG CCA AGO GAO ACC AGT 1440 Ala His Thr Asn Ser Ala He Leu Pro Leu Leu Pro Arg Glu Thr Ser 465 470 475 480 ATA TCC AGT GTO ATA TOO TGACAaAAAA GCAAGGGACA TCCCGTCCCT 1488 He Ser Ser Val He Trp 485 GGGAGaTTCA aTGCAATCTC CACTCCAOTa CCTCOAACTA AATCCTCOAC TCCTCCTCTT 1548 AAAAAACATG CATTAGAATC TTTAGAACAC GAGGAAAAAC AGGOTCTTGT ACATATGTTT 1608 TTTOGAATTT CTTTGTAGCA TCAGTOTCCT CCTOTTTTAC CATOTCTTTT ACCATTACAT 1668 TTTTTCACTT TCTTTTATAT GTCGTTCGAA TTTGTAAATT TACATTTTTT TTAAAGAAOA 1728 aACTOATOTa TAsATAaAAA ACCCTTTTTT TGCTTCATTA GTTTAOTTTT AOAATGCOTT 1788 TTTATTTTAT TTCCTTTTTT AAAATTTTAC TTTCCTTTTA ACATTTCCTT GCGaTaCTTG 1848 AACAAATCTA TCCGATGOsA CAAOCAaCAC CGGATTCTTT CTCGOOTTCT GCCTAGCATC 1908 AACTGascCA CGTCGGCCTT CAGAGAACAG TGCAACAAAT GCCAGCATTG CCATTCGGGG 1968 GOAAAAAAAA AAAAAAAAAA AAA 1991 (2) SEQUENCE IDENTIFICATION INFORMATION NO. twenty: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 486 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 20: slu Phe sly Thr Ser Cys Clu Leu Lys Tyr sly Oly Phe Val Val Arg 1 5 10 15 Arg Thr Thu alu Leu Thr Val Thr Wing Pro Leu Thr Asp Lys Pro Pro 20 25 30 Lys Leu Leu Tyr Pro Met alu Ser Lys Leu Thr He Gln Glu Thr Gln 35 40 45 eu G1y AsP Ser Wing Asn Leu Thr Cys Arg Wing Phe Phe Gly Tyr Ser 50 55 60 Gly Asp Val Ser Pro Leu He Tyr Trp Met Lys Oly Olu Lys Phe He 65 70 75 80 alu Asp Leu Asp slu Asn Arg Val Trp Olu Ser Asp He Arg He Leu 85 90 95 Lys alu His Leu alu alu Cln Glu Val Ser He Ser Leu He Val Asp 100 105 110 Ser Val Glu Glu sly Asp Leu Oly Asn Tyr Ser Cys Tyr Val alu Asn 115 120 125 Cly Asn Gly Arg Arg His Wing Ser Val Leu Leu His Lys Arg Glu Leu 130 135 140 Met Tyr Thr Val Glu Leu Ala Gly Gly Leu Gly Ala He Leu Leu Leu 145 150 155 160 Leu Val Cys Leu Val Thr He Tyr Lys Cys Tyr Lys He Glu He Met 165 170 175 Leu Phe Tyr Arg Asn His Phe Gly Wing Glu Glu Leu Asp Gly Asp Asn 180 185 190 Lys sp Tyr Asp Wing Tyr Leu Ser Tyr Thr Lys Val Asp Pro Asp Gln 195 200 205 Trp Asn sln slu Thr Oly alu alu Clu Arg Phe Ala Leu alu He Leu 210 215 220 Pro Asp Met Leu Clu Lys His Tyr sly Tyr Lys Leu Phe He Pro Asp 225 230 235 240 Arg Asp Leu He Pro Thr aly Thr Tyr He alu Asp Val Wing Arg Cys 245 250 255 Val Asp Cln Ser Lys Arg Leu He He Val Met Thr Pro Asn Tyr Val 260 265 270 Val Arg Arg aly Trp Ser He Phe slu Leu alu Thr Arg Leu Arg Asn 275 280 285 Met Leu Val Thr sly slu He Lys Val He Leu He slu Cys Ser Clu 290 295 300 Leu Arg Cly He Met Asn Tyr sln alu Val Glu Ala Leu Lys His Thr 305 310 315 -320 He Lys Leu Leu Thr Val He Lys Trp His Gly Pro Lys Cys Asn Lys 325 330 335 Leu Asn Ser Lys Phe Trp Lys Arg Leu Gln Tyr Glu Met Pro Phe Lys 340 345 350 Arg He Glu Pro He Thr His Glu Gln Ala Leu Asp Val Ser Glu Gln 355 360 365 Oly Pro Phe sly slu Leu aln Thr Val Ser Wing He Ser Met Wing Wing 370 375 380 Wing Thr Ser Thr Wing Leu Wing Thr Wing His Pro Asp Leu Arg Ser Thr 385 390 395 400 Phe His Asn Thr Tyr His Ser sln Met Arg sln Lys His Tyr Tyr Arg 405 410 415 Ser Tyr Olu Tyr Asp Val Pro Pro Thr sly Thu Leu Pro Leu Thr Ser 420 425 430 He Oly Asn Cln His Thr Tyr Cys Asn He Pro Met Thr Leu He Asn 435 440 445 aly aln Arg Pro aln Thr Lys Ser Ser Arg Olu sln Asn Pro Asp Olu 450 455 460 Wing His Thr Asn Be Wing He Leu Pro Leu Leu Pro Arg Clu Thr Ser 465 470 475 480 He Ser Ser Val Val Trp 485 (2) SEQUENCE IDENTIFICATION INFORMATION NO. twenty-one : (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 570 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: not relevant (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 21: Met Cly Leu Leu Trp Tyr Leu Met Ser Leu Ser Phe Tyr Gly He Leu 1 5 10 15 Gln Ser His Wing Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met 20 25 30 Arg Gln He Gln Val Phe Glu Asp Glu Pro Wing Arg He Lys Cys Pro 35 40 45 Leu Phe Glu His Phe Leu Lys Tyr Asn Tyr Ser Thr Ala His Ser Ser 50 55 60 Gly Leu Thr Leu He Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu slu 65 70 75 80 slu Pro He Asn Phe Arg Leu Pro alu Asn Arg He Ser Lys slu Lys 85 90 95 Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr sly Asn Tyr 100 105 110 Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Wing Phe Pro 115 120 125 Leu Clu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Wing Met Arg Phe 130 135 140 Pro Val His Lys Met Tyr He Clu His sly He His Lys He Thr Cys 145 150 155 160 Pro Asn Val Asp aly Tyr Phe Pro Ser Ser Val Lys Pro Ser Val Thr 165 170 175 Trp Tyr Lys Gly Cys Thr Glu Hep Val Asp Phe His Asn Val Leu Pro 180 185 190 Glu Gly Met Asn Leu Ser Phe Phe He Pro Leu Val Ser Asn Asn sly 195 200 205 Asn Tyr Thr Cys Val Val Thr Tyr Pro Clu Asn Arg Leu Phe His 210 210 210 Leu Thr Arg Thr Val Thr Val Lys Val Val aly Ser Pro Lys Asp Ala 225 230 235 240 Leu Pro Pro Gln He Tyr Ser Pro Asn Asp Arg Val Val Tyr Glu Lys 245 250 255 alu Pro Cly alu Clu Leu Val He Pro Cys Lys Val Tyr Phe Ser Phe 260 265 270 He Met Asp Ser His Asn alu Val Trp Trp Thr He Asp sly Lys Lys 275 280 285 Pro Asp Asp Val Thr Val Asp He Thr He Asn slu Ser Val Ser Tyr 290 295 300 Ser Ser Thr Glu Asp Glu Thr Arg Thr Gln He Leu Ser He Lys Lys 305 310 315 320 Val Thr Pro Glu Asp Leu Arg Arg Asn Tyr Val Cys His Wing Arg Asn 325 330 335 Thr Lys Gly Glu Ala alu Gln Ala Ala Lys Val Lys Oln Lys Val He 340 345 350 Pro Pro Arg Tyr Thr Val Glu Leu Ala Cys Gly Phe Gly Ala Thr Val 355 360 365 Phe Leu Val Val Val Leu He Val Val Tyr His Val Tyr Trp Leu Glu 370 375 380 Met Val Leu Phe Tyr Arg Ala His Phe sly Thr Asp slu Thr He Leu 385 390 395 400 Asp aly Lys slu Tyr Asp He Tyr Val Ser Tyr Wing Arg Asn Val alu 405 410 415 Olu alu alu Phe Val Leu Leu Thr Leu Arg aly Val Leu Olu Asn Glu 420 425 430 Phe Cly Tyr Lys Leu Cys He Phe Asp Arg Asp Ser Leu Pro Oly sly 435 440 445 He Val Thr Asp Olu Thr Leu Ser Phe He Cln Lys Ser Arg Arg Leu 450 455 460 Leu Val Val Leu Ser Pro Asn Tyr Val Leu sln Oly Thr aln Ala Leu 465 470 475 480 Leu Glu Leu Lys Wing Gly Leu Glu Asn Met Wing Being Arg sly Asn He 485 490 495 Asn Val He Leu Val Gln Tyr Lys Wing Val Lys Asp Met Lys Val Lys 500 505 510 Glu Leu Lys Arg Wing Lys Thr Val Leu Thr Val He Lys Trp Lys Gly 515 520 525 Glu Lys Ser Lys Tyr Pro aln Oly Arg Phe Trp Lys sln Leu Cln Val 530 535 540 Wing Met Pro Val Lys Lys Ser Pro Arg Trp Ser Ser As Asp Lys sln 545 550 555 560 Gly Leu Ser Tyr Ser Ser Leu Lys Asn Val 565 570 (2) SEQUENCE IDENTIFICATION INFORMATION NO. 22: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 562 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: not relevant (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 22: Met Trp Ser Leu Leu Leu Cys sly Leu Ser He Ala Leu Pro Leu Ser 1 5 10 15 Val Thr Ala Asp aly Cys Lys Asp He Phe Met Lys Asn slu He Leu 20 25 30 Be Ala Be sln Pro Phe Ala Phe Asn Cys Thr Phe Pro Pro He Thr 35 40 45 Ser Cly Glu Val Ser Val Thr Trp Tyr Lys Asn Ser Ser Lys He Pro 50 55 60 Val Ser Lys He He Gln Ser Arg He His Gln Asp Olu Thr Trp He 65 70 75 80 Leu Phe Leu Pro Met alu Trp Cly Asp Ser aly Val Tyr Oln Cys Val 85 90 95 He Lys aly Arg Asp Ser Cys His Arg He His Val Asn Leu Thr Val 100 105 110 Phe Glu Lys His Trp Cys Asp Thr Ser He Gly Gly Leu Pro Asn Leu 115 120 125 Ser Asp Glu Tyr Lys Gln He Leu His Leu Gly Lys Asp Asp Ser Leu 130 135 140 Thr Cys His Leu His Phe Pro Lys Ser Cys Val Leu Gly Pro He Lys 145 150 155 160 Trp Tyr Lys Asp Cys Asn Glu He Lys Gly Glu Arg Phe Thr Val Leu 165 170 175 Glu Thr Arg Leu Leu Val Ser Asn Val Ser Wing Glu Asp Arg Gly Asn 180 185 190 Tyr Wing Cys Gln Wing He Leu Thr His Ser Gly Lys Gln Tyr slu Val 195 200 205 Leu Asn sly He Thr Val Ser He Thr slu Arg Ala aly Tyr Cly sly 210 215 220 Ser Val Pro Lys He He Tyr Pro Lys Asn His Ser He alu Val sln 225 230 235 240 Leu Gly Thr Thr Leu He Val Asp Cys Asn Val Thr Asp Thr Lys Asp 245 250 255 Asn Thr Asn Leu Arg Cys Trp Arg Val Asn Asn Thr Leu Val Asp Asp 260 265 270 Tyr Tyr Asp slu Ser Lys Arg He Arg slu aly Val Clu Thr His Val 275 280 285 Ser Phe Arg alu His Asn Leu Tyr Thr Val Asn He Thr Phe Leu alu 290 295 300 Val Lys Met Olu Asp Tyr aly Leu Pro Phe Met Cys His Ala sly Val 305 310 315 320 Be Thr Wing Tyr He He Leu sln Leu Pro Wing Pro Asp Phe Arg Wing 325 330 335 Tyr Leu He Gly Gly Leu He Wing Leu Val Wing Val Wing Val Ser Val 340 345 350 Val Tyr He Tyr Asn He Phe Lys He Asp He Val Leu Trp Tyr Arg 355 360 365 Being Wing Phe His Ser Thr Glu Thr He Val Asp Gly Lys Leu Tyr Asp 370 375 380 Wing Tyr Val Leu Tyr Pro Lys Pro His Lys Glu Ser Gln Arg His Wing 385 390 395 400 Val Asp Ala Leu Val Leu Asn He Leu Pro slu Val Leu slu Arg Oln 405 410 415 Cys Cly Tyr Lys Leu Phe He Phe aly Arg Asp Clu Phe Pro aly aln 420 425 430 Wing Val Wing Asn Val He Asp alu Asn Val Lys Leu Cys Arg Arg Leu 435 440 445 He Val He Val Val Pro alu Ser Leu aly Phe aly Leu Leu Lys Asn 450 455 460 Leu Ser Olu alu sln He Wing Val Tyr Ser Wing Leu He Oln Asp sly 465 470 475 480 Met Lys Val He Leu He alu Leu Clu Lys He alu Asp Tyr Thr Val 485 490 495 Met Pro Pro alu Ser He Gln Tyr He Lys Gln Lys His sly Ala He Arg 500 505 510 Trp His aly Asp Phe Thr Clu aln Ser aln Cys Met Lys Thr Lys Phe 515 520 525 Trp Lys Thr Val Arg Tyr His Met Pro Pro Arg Arg Cys Arg Pro Phe 530 535 540 Leu Arg Ser Thr Cys Arg Ser Thr His Leu Cys Thr Ala Pro Cln Ala 545 550 555 560 aln Asn (2) INFORMATION FOR IDENTIFICATION OF SEQUENCE NO. 2. 3: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 561 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: not relevant (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) SEQUENCE DESCRIPTION: ID. SEQUENCE NO: 23: Met Gly Met Pro Pro Leu Leu Phe Cys Trp Val Ser Phe Val Leu Pro 1 5 10 15 Leu Phe Val Wing Wing Gly Asn Cys Thr Asp Val Tyr Met His His Glu 20 25 30 Met He Ser Glu Gly Oln Pro Phe Pro Phe Asn Cys Thr Tyr Pro Pro 35 40 45 Val Thr Asn aly Wing Val Asn Leu Thr Trp His Arg Thr Pro Ser Lys 50 55 60 Ser Pro He Ser He Asn Arg His Val Arg He His sln Asp sln Ser 65 70 75 80 Trp He Leu Phe Leu Pro Leu Ala Leu slu Asp Ser sly He Tyr aln 85 90 95 Cys Val He Lys Asp Wing His Ser Cys Tyr Arg He Wing He Asn Leu 100 105 110 Thr Val Phe Arg Lys His Trp Cys Asp Ser Ser Asn alu alu Ser Ser 115 120 125 He Asn Ser Ser Asp alu Tyr sln aln Trp Leu Pro He Cly Lys Ser 130 135 140 Cly Ser Leu Thr Cys His Leu Tyr Phe Pro Glu Ser Cys Val Leu Asp 145 150 155 160 Ser He Lys Trp Tyr Lys Cly Cys Glu Glu He Lys Val Ser Lys Lys 165 170 175 Phe Cys Pro Thr Gly Thr Lys Leu Leu Val Asn Asn He Asp Val Glu 180 185 190 Asp Ser Gly Ser Tyr Wing Cys Ser Wing Arg Leu Thr His Leu sly Arg 195 200 205 He Phe Thr Val Arg Asn Tyr He Wing Val Asn Thr Lys slu Val Oly 210 215 220 Ser Oly aly Arg He Pro Asn He Thr Tyr Pro Lys Asn Asn Ser He 225 230 235 240 Olu Val Cln Leu Oly Ser Thr Leu He Val Asp Cys Asn He Thr Asp 245 250 255 Thr Lys Clu Asn Thr Asn Leu Arg Cys Trp Arg Val Asn Asn Thr Leu 260 265 270 Val Asp Asp Tyr Tyr Asn Asp Phe Lys Arg He Oln slu aly He slu 275 280 285 Thr Asn Leu Ser Leu Arg Asn His He Leu Tyr Thr Val Asn He Thr 290 295 300 Phe Leu slu Val Lys Met Clu Asp Tyr Gly His Pro Phe Thr Cys His 305 310 315 320 Wing Wing Val Wing Wing Tyr He He Leu Wing Arg Pro Wing Pro Asp 325 330 335 Phe Arg Ala Tyr Leu He Gly Gly Leu Met Ala Phe Leu Leu Leu Ala 340 345 350 Val Ser He Leu Tyr He Tyr Asn Thr Phe Lys Val Asp He Val Leu 355 360 365 Trp Tyr Arg Ser Thr Phe His Thr Ala Gln Ala Pro Asp Asp Clu Lys 370 375 380 Leu Tyr Asp Ala Tyr Val Leu Tyr Pro Lys Tyr Pro Arg Glu Ser Gln 385 390 395 400 Oly His Asp Val Asp Thr Leu Val Leu Lys He Leu Pro Glu Val Leu 405 410 _- - -415 Glu Lys Gln Cys Gly Tyr Lys Leu Phe He Phe Gly Arg Asp Glu Phe 420 425 430 Pro Gly Gln Ala Val Ala Ser Val He Asp slu Asn He Lys Leu Cys 435 440 445 Arg Arg Leu Met Val Leu Val Ala Pro Clu Thr Ser Ser Phe Ser Phe 450 455 460 Leu Lys Asn Leu Thr Glu Glu Gln He Wing Val Tyr Asn Wing Leu Val 465 470 475 480 sln Asp aly Met Lys Val He Leu He Clu Leu alu Arg Val Lys Asp 485 490 495 Tyr Ser Thr Met Pro Olu Ser He sln Tyr He Arg Oln Lys His Oly 500 505 510 Wing He sln Trp Asp sly Asp Phe Thr Olu sln Wing sln Cys Wing Lys 515 520 525 Thr Lys Phe Trp Lys Lys Val Arg Tyr His Met Pro Pro Arg Arg Tyr 530 535 540 Pro Ala Ser Pro Pro Val sln Leu Leu sly His Thr Pro Arg He Pro 545 550 555 560 sly (2) SEQUENCE IDENTIFICATION INFORMATION NO. 24: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 567 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: not relevant (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 24: Met He Asp Arg sln Arg Met Oly Leu Trp Ala Leu Ala He Leu Thr 1 5 10 - - 15 Leu Pro Met Tyr Leu Thr Val Thr alu Cly Ser Lys Ser Ser Trp Gly 20 25 30 Leu Glu Asn Glu Ala Leu He Val Arg Cys Pro Cln Arg Oly Arg Ser 35 40 45 Thr Tyr Pro Val Olu Trp Tyr Tyr Ser Asp Thr Asn Olu Ser He Pro 50 55 60 Thr sln Lys Arg Asn Arg He Phe Val Ser Arg Asp Arg Leu Lys Phe 65 70 75 80 Leu Pro Ala Arg Val slu Asp Ser sly He Tyr Ala Cys Val He Arg 85 90 95 Ser Pro Asn Leu Asn Lys Thr sly Tyr Leu Asn Val Thr He His Lys 100 105 110 Lys Pro Pro Ser Cys Asn He Pro Asp Tyr Leu Met Tyr Ser Thr Val 115 120 125 Arg sly Ser Asp Lys Asn Phe Lys He Thr Cys Pro Thr He Asp Leu 130 135 140 Tyr Asn Trp Thr Wing Pro Val Gln Trp Phe Lys Asn Cys Lys Ala Leu 145 150 155 160 Gln Clu Pro Arg Phe Arg Wing His Arg Ser Tyr Leu Phe He Asp Asn 165 170 175 Val Thr His Asp Asp slu sly Asp Tyr Thr Cys Gln Phe Thr His Wing 180 185 190 Glu Asn Gly Thr Asn Tyr He Val Thr Wing Thr Arg Ser Phe Thr Val 195 200 205 Glu Glu Lys Gly Phe Ser Met Phe Pro Val He Thr Asn Pro Pro Tyr 210 215 220 Asn His Thr Met Glu Val Glu He sly Lys Pro Wing Ser He Wing Cys 225 230 235 240 Be Ala Cys Phe aly Lys Cly Ser His Phe Leu Wing Asp Val Leu Trp 245 250 255 sln He Asn Lys Thr Val Val aly Asn Phe sly slu Ala Arg He sln 260 265 270 slu Olu alu sly Arg Asn slu Ser Ser As Asn Asp Met Asp Cys Leu 275 280 285 Thr Ser Val Leu Arg He Thr sly Val Thr alu Lys Asp Leu Ser Leu 290 295 300 Glu Tyr Asp Cys Leu Ala Leu Asn Leu His Gly Met He Arg His Thr 305 310 315 320 He Arg Leu Arg Arg Lys Gln Pro He Asp His Arg Ser He Tyr Tyr 325 330 335 He Val Wing Oly Cys Ser Leu Leu Leu Met Phe He Asn Val Leu Val 340 345 350 He Val Leu Lys Val Phe Trp He Glu Val Wing Leu Phe Trp Arg Asp 355 360 365 He Val Thr Pro Tyr Lys Thr Arg Asn Asp Gly Lys Leu Tyr Asp Wing 370 375 380 Tyr He He Tyr Pro Arg Val Phe Arg Gly Ser Wing Wing Gly Thr His 385 390 395 400 Ser Val Glu Tyr Phe Val His His Thr Leu Pro Asp Val Leu Glu Asn 405 410 415 Lys Cys Gly Tyr Lys Leu Cys He Tyr Gly Arg Asp Leu Leu Pro Gly 420 425 430 Gln Asp Wing Wing Thr Val Val Olu Ser Ser He Gln Asn Ser Arg Arg 435 440 445 Gln Val Phe Val Leu Pro Wing His Met Met Met Ser Lys Glu Phe Wing 450 455 460 Tyr alu aln slu He Wing Leu His Ser Wing Leu He aln Asn Asn Ser 465 470 475 480 Lys Val He Leu He alu Met alu Pro Leu Cly Glu Ala Ser Arg Leu 485 490 495 Gln Val sly Asp Leu sln Asp Ser Leu sln His Leu Val Lys He sln 500 505 510 sly Thr He Lys Trp Arg alu Asp His Val Wing Asp Lys Gln Ser Leu 515 520 525 Ser Ser Lys Phe Trp Lys His Val Arg Tyr Gln Met Pro Val Pro Glu 530 535 540 Arg Wing Ser Lys Thr Wing Ser Val Wing Wing Pro Leu Ser Gly Lys Wing 545 550 555 560 Cys Leu Asp Leu Lys His Phe 565 (2) SEQUENCE IDENTIFICATION INFORMATION NO. 25: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 328 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: not relevant (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 25: Met sly Phe Trp He Leu Wing He Leu Thr lie Leu Met Tyr Ser Thr 1 5 10 15 Ala Ala Lys Phe Ser Lys Gln Ser Trp Gly Leu Glu Asn Glu Ala Leu 20 25 30 He Val Arg Cys Pro Arg Gln Gly Lys Pro Ser Tyr Thr Val Asp Trp 35 40 45 Tyr Tyr Ser Gln Thr Asn Lys Ser He Pro Thr sln alu Arg Asn Arg 50 55 60 Val Phe Ala Ser Oly sln Leu Leu Lys Phe Leu Pro Ala alu Val Ala 65 70 75 80 Asp Ser aly He Tyr Thr Cys He Val Arg Ser Pro Thr Phe Asn Arg 85 90 95 Thr Gly Tyr Wing Asn Val Thr He Tyr Lys Lys Gln Ser Asp Cys Asn 100 105 110 Val Pro Asp Tyr Leu Met Tyr Ser Thr Val Ser aly Ser Olu Lys Asn 115 120 125 Ser Lys He Tyr Cys Pro Thr He Asp Leu Tyr Asn Trp Thr Ala Pro 130 135 140 Leu Clu Trp Phe Lys Asn Cys aln Ala Leu aln aly Ser Arg Tyr Arg 145 150 155 160 Ala His Lys Ser Phe Leu Val As Asn Asn Val Met Thr Clu Asp Ala 165 170 175 Cly Asp Tyr Thr Cys Lys Phe He His Asn Glu Asn Gly Wing Asn Tyr 180 185 190 Ser Val Thr Wing Thr Arg Ser Phe Thr Val Lys Asp Glu Gln Gly Phe 195 200 205 Ser Leu Phe Pro Val He Gly Pro Wing Gln Asn alu He Lys alu 210 215 220 Val alu He sly Lys Asn Wing Asn Leu Thr Cys Ser Wing Cys Phe Gly 225 230 235 240 Lys Gly Thr Gln Phe Leu Ala Wing Val Leu Trp Cln Leu Asn sly Thr 245 250 255 Lys He Thr Asp Phe aly alu Pro Arg He sln Cln slu alu sly sln 260 265 270 Asn sln Ser Phe Ser Asn Cly Leu Ala Cys Leu Asp Met Val Leu Arg 275 280 285 He Wing Asp Val Lys Glu Glu Asp Leu Leu Leu Gln Tyr Asp Cys Leu 290 295 300 Wing Leu Asn Leu His aly Leu Arg Arg His Thr Val Arg Leu Ser Arg 305 310 315 320 Lys Asn Pro Ser Lys slu Cys Phe 325 (2) SEQUENCE IDENTIFICATION INFORMATION NO. 26: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 398 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: not relevant (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 26: Met Leu Arg Leu Tyr Val Leu Val Met sly Val Ser Ala Phe Thr Leu 1 5 10 15 sln Pro Ala Ala His Thr sly Ala Ala Arg Ser Cys Arg Phe Arg Gly 20 25 30 Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val Wing Leu 35 40 45 Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Wing Ser Val Ser Pro Arg 50 55 60 He Asn Leu Thr Trp His Lys Asn Asp Ser Wing Arg Thr Val Pro Gly 65 70 75 80 Glu Glu Glu Thr Arg Met Trp Wing Gln Asp Oly Wing Leu Trp Leu Leu 85 90 95 Pro Ala Leu aln 01u Asp Ser sly Thr Tyr Val Cys Thr Thr Arg Asn 100 105 no Wing Ser Tyr Cys Asp Lys Met Ser He Glu Leu Arg Val Phe Clu Asn 115 120 125 Thr Asp Ala Phe Leu Pro Phe He Ser Tyr Pro Gln He Leu Thr Leu 130 135 140 Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe Thr Arg 145 150 155 160 Asp Lys Thr Asp Val Lys He Gln Trp Tyr Lys Asp Ser Leu Leu Leu 165 170 175 Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr His Leu 180 185 190 Leu Val His Asp Val Ala Leu Glu Asp Wing Gly Tyr Tyr Arg Cys Val 195 200 205 Leu Thr Phe Wing His Glu Gly Cln Gln Tyr Asn He Thr Arg Ser He 210 215 220 Glu Leu Arg He Lys Lys Lys Lys Glu Glu Thr He Pro Val He He 225 230 235 240 Be Pro Leu Lys Thr Be Ser Wing Be Leu Gly Be Arg Leu Thr He 245 250 255 Pro Cys Lys Val Phe Leu Cly Thr sly Thr Pro Leu Thr Thr Met Leu 260 265 270 Trp Trp Thr Wing Asn Asp Thr His He alu Ser Wing Tyr Pro sly aly 275 280 285 Arg Val Thr slu sly Pro Arg aln Glu Tyr Ser Glu Asn Asn Glu Asn 290 295 300 Tyr He Glu Val Pro Leu He Phe Asp Pro Val Thr Arg Glu Asp Leu 305 310 315 320 His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe Gln Thr 325 330 335 Leu Arg Thr Thr Val Lys Glu Wing Ser Ser Thr Phe Ser Trp Gly He 340 345 350 Val Leu Wing Pro Leu Ser Leu Wing Phe Leu Val Leu Gly Gly He Trp 355 360 365 Met His Arg Arg Cys Lys His Arg Thr Gly Lys Wing Asp Gly Leu Thr 370 375 380 Val Leu Trp Pro His His Gln Asp Phe Oln Ser Tyr Pro Lys 385 390 395 (2) SEQUENCE IDENTIFICATION INFORMATION NO. 27: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 410 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: not relevant (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 27: Met Phe He Leu Leu Val Leu Val Thr Gly Val Ser Wing Phe Thr Thr 1 5 10 15 Pro Thr Val Val His Thr Gly Lys Val Ser Glu Pro Pro He Thr Ser 20 25 30 Glu Lys Pro Thr Val His Gly Asp Asn Cys Gln Phe Arg sly Arg Clu 35 40 45 Phe Lys Ser Clu Leu Arg Leu Olu sly slu Pro Val Val Leu Arg Cys 50 55 60 Pro Leu Ala Pro His Ser Asp He Ser Ser Ser Ser Ser His Ser Phe Leu 65 70 75 80 Thr Trp Ser Lys Leu Asp Ser Ser Gln Leu Pro Pro Arg Asp Glu Pro 85 90 95 Arg Met Trp Val Lys Gly Asn He Leu Trp He Leu Pro Wing Val Gln 100 105 110 Gln Asp Ser Gly Thr Tyr He Cys Thr Phe Arg Asn Ala Ser His Cys 115 120 125 Glu Gln Met Ser Val slu Leu Lys Val Phe Lys Asn Thr Glu Wing Ser 130 135 140 Leu Pro His Val Ser Tyr Leu Gln Be Ser Wing Leu Ser Thr Thr Gly 145 150 155 160 Leu Leu Val Cys Pro Asp Leu Lys Glu Phe He Ser Ser Asn Ala Asp 165 170 175 Gly Lys He Gln Trp Tyr Lys Cly Wing He Leu Leu Asp Lys Gly Asn 180 185 190 Lys Glu Phe Leu Ser Wing Gly Asp Pro Thr Arg Leu Leu He Ser Asn 195 200 205 Thr Ser Met Asp Asp Wing Gly Tyr Tyr Arg Cys Val Met Thr Phe Thr 210 215 220 Tyr Asn Gly Gln Glu Tyr Asn He Thr Arg Asn He Glu Leu Arg Val 225 230 235 240 Lys Gly Thr Thr Glu Pro He Pro Val He He Ser Pro Glu Leu 245 250 255 Thr He Pro Wing Being Leu sly Being Arg Leu He Val Pro Cys Lys Val 260 265 270 Phe Leu sly Thr sly Thr Ser Being Asn Thr He Val Trp Trp Leu Wing 275 280 285 Asn Being Thr Phe He Being Wing Wing Tyr Pro Arg sly Arg Val Thr slu 290 295 300 Cly Leu His His Gln Tyr Ser Glu Asn Asp Glu Asn Tyr Val slu Val 305 310 315 320 Ser Leu He Phe Asp Pro Val Thr Arg Glu Asp Leu His Thr Asp Phe 325 330 335 Lys Cys Val Wing Ser Asn Pro Arg Ser Ser Gln Ser Leu His Thr Thr 340 345 350 Val Lys Clu Val Ser Ser Thr Phe Ser Trp Ser He Ala Leu Ala Pro 355 360 365 Leu Ser Leu He He Leu Val Val Gly Ala He Trp Met Arg Arg Arg 370 375 380 Cys Lys Arg Arg Wing Gly Lys Thr Tyr Gly Leu Thr Lys Leu Arg Thr 385 390 395 400 Asp Asn Cln Asp Phe Pro Ser Ser Pro Asn 405 410 (2) SEQUENCE IDENTIFICATION INFORMATION NO. 28: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 541 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: not relevant (D) TOPOLOGY: linear (I) TYPE OF MOLECULE: peptide (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 28: Met Asn Cys Arg slu Leu Pro Leu Thr Leu Trp Val Leu He Ser Val 1 5 10 15 Be Thr Wing Olu Ser Cys Thr Ser Arg Pro His He Thr Val Val alu 20 25 30 Cly slu Pro Phe Tyr Leu Lys His Cys Ser Cys Ser Leu Wing His Glu 35 40 45 He Glu Thr Thr Thr Lys Ser Trp Tyr Lys Ser Ser Gly Ser Oln alu 50 55 60 His Val alu Leu Asn Pro Arg Ser Ser Ser Arg He Ala Leu His Asp 65 70 75 80 Cys Val Leu Olu Phe Trp Pro Val alu Leu Asn Asp Thr aly Ser Tyr 85 90 95 Phe Phe Oln Met Lys Asn Tyr Thr Oln Lys Trp Lys Leu Asn Val He 100 105 110 Arg Arg Asn Lys His Ser Cys Phe Thr Clu Arg Svn Val Thr Ser Lys 115 120 125 He Val slu Val Lys Lys Phe Phe sln He Thr Cys slu Asn Ser Tyr 130 135 140 Tyr Cln Thr Leu Val Asn Ser Thr Ser Leu Tyr Lys Asn Cys Lys Lys 145 150 155 160 Leu Leu Leu alu Asn Asn Lys Asn Pro Thr He Lys Lys Asn Ala slu 165 170 175 Phe slu Asp Oln sly Tyr Tyr Ser Cys Val His Phe Leu His His Asn 180 185 190 Gly Lys Leu Phe Asn He Thr Lys Thr Phe Asn He Thr He Val Glu 195 200 205 Asp Arg Ser Asn He Val Pro Val Leu Leu Gly Pro Lys Leu Asn His 210 215 220 Val Wing Val Glu Leu Gly Lys Asn Val Arg Leu Asn Cys Ser Wing Leu 225 230 235 240 Leu Asn Glu alu Asp Val He Tyr Trp Met Phe Cly Clu Glu Asn Gly 245 250 255 Be Asp Pro Asn He His Glu Glu Lys Glu Met Arg He Met Thr Pro 260 265 270 slu sly Lys Trp His Wing Ser Lys Val Leu Arg He slu Asn He aly 275 280 285 alu Ser Asn Leu Asn Val Leu Tyr Asn Cys Thr Val Wing Ser Thr aly 290 295 300 Gly Thr Asp Thr Lys Ser Phe He Leu Val Arg Lys Wing Asp Met Wing 305 310 315 320 Asp He Pro Gly His Val Phe Thr Arg Gly Met He He Wing Val Leu 325 330 335 He Leu Val Wing Val Val Cys Leu Val Thr Val Cys Val He Tyr Arg 340 345 350 Val Asp Leu Val Leu Phe Tyr Arg His Leu Thr Arg Arg Asp slu Thr 355 360 365 Leu Thr Asp sly Lys Thr Tyr Asp Wing Phe Val Ser Tyr Leu Lys slu 370 375 380 Cys Arg Pro slu Asn aly Olu slu His Thr Phe Wing Val slu He Leu 385 390 395 400 Pro Arg Val Leu slu Lys His Phe Cly Tyr Lys Leu Cys He Phe Glu 405 410 415 Arg Asp Val Val Pro Gly Gly Ala Val Val Asp Glu He His Ser Leu 420 425 430 He Glu Lys Ser Arg Arg Leu He He Val Leu Ser Lys Ser Tyr Met 435 440 445 Ser Asn Glu Val Arg Tyr Glu Leu Glu Ser Gly Leu His Glu Ala Leu 450 455 460 Val Glu Arg Lys He Lys He He Leu He Glu Phe Thr Pro Val Thr 465 470 475 480 Asp Phe Thr Phe Leu Pro Gln Ser Leu Lys Leu Leu Lys Ser His Arg 485 490 495 Val Leu Lys Trp Lys Wing Asp Lys Ser Leu Ser Tyr Asn Ser Arg Phe 500 505 510 Trp Lys Asn Leu Leu Tyr Leu Met Pro Wing Lys Thr Val Lys Pro Oly 515 520 525 Arg Asp alu Pro alu Val Leu Pro Val Leu Ser Clu Ser 530 535 540 (2) SEQUENCE IDENTIFICATION INFORMATION NO. 29: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 537 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: not relevant (D) TOPOLOGY: linear (I) TYPE OF MOLECULE: peptide (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 29: Met His His Glu Glu Leu He Leu Thr Leu Cys He Leu He Val Lys 1 5 10 15 Being Wing Being Lys Being Cys Being His Arg Being Gln He His Val Val Glu 20 25 30 Gly Glu Pro Phe Tyr Leu Lys Pro Cys Gly He Ser Wing Pro Val His 35 40 45 Arg Asn Glu Thr Wing Thr Met Arg Trp Phe Lys Cly Ser Ala Ser His 50 55 60 Glu Tyr Arg Glu Leu Asn Asn Arg Ser Ser Pro Arg Val Thr Phe His 65 70 75 80 Asp His Thr Leu Glu Phe Trp Pro Val Glu Met Glu Asp Glu Gly Thr 85 90 95 Tyr He Ser Gln Val aly Asn Asp Arg Arn Asn Trp Thr Leu Asn Val 100 105 110 Thr Lys Arg Asn Lys His Ser Cys Phe Ser Asp Lys Leu Val Thr Ser 115 120 125 Arg Asp Val Glu Val Asn Lys Ser Leu His He Thr Cys Lys Asn Pro 130 135 140 Asn Tyr Glu Glu Leu He Gln Asp Thr Trp Leu Tyr Lys Asn Cys Lys 145 150 155 - 160 Glu He Ser Lys Thr Pro Arg He Leu Lys Asp Wing Glu Phe Gly Asp 165 170 175 Glu aly Tyr Tyr Ser Cys Val Phe Ser Val His His Asn sly Thr Arg 180 185 190 Tyr Asn He Thr Lys Thr Val Asn He Thr Val He alu Oly Arg Ser 195 200 205 Lys Val Thr Pro Ala He Leu sly Pro Lys Cys Glu Lys Val Cly Val 210 215 220 Glu Leu Gly Lys Asp Val Glu Leu Asn Cys Ser Wing Ser Leu Asn Lys 225 230 235 240 Asp Asp Leu Phe Tyr Trp Ser He Arg Lys Glu Asp Ser Ser Asp Pro 245 250 255 Asn Val Gln alu Asp Arg Lys slu Thr Thr Thr Trp He Ser alu Gly 260 265 270 Lys Leu His Wing Ser Lys He Leu Arg Phe Gln Lys He Thr Glu Asn 275 280 285 Tyr Leu Asn Val Leu Tyr Asn Cys Thr Val Wing Asn Glu Glu Wing He 290 295 300 Asp Thr Lys Ser Phe Val Leu Val Arg Lys Glu He Pro Asp He Pro 305 310 315 320 Gly His Val Phe Thr Gly Gly Val Thr Val Leu Val Leu Ala Ser Val 325 330 335 Wing Wing Val Cys He Wing He Leu Cys Val He Tyr Lys Val Asp Leu 340 345 350 Val Leu Phe Tyr Arg Arg He Wing Glu Arg Asp Glu Thr Leu Thr Asp 355 360 365 Gly Lys Thr Tyr Asp Wing Phe Val Ser Tyr Leu Lys slu Cys His Pro 370 375 380 Olu Asn Lys slu alu Tyr Thr Phe Wing Val Olu Thr Leu Pro Arg Val 385 390 395 400 Leu slu Lys aln Phe aly Tyr Lys Leu Cys He Phe Glu Arg Asp Val 405 410 415 Val Pro Gly Gly Wing Val Val Glu Glu He His Ser Leu He Glu Lys 420 425 430 Ser Arg Arg Leu He He Val Leu Ser Gln Ser Tyr Leu Thr Asn aly 435 440 445 Wing Arg Arg alu Leu alu Ser Oly Leu His Olu Wing Leu Val slu Arg 450 455 460 Lys He Lys He He Leu He slu Phe Thr Pro Wing Ser Asn He Thr 465 470 475 480 Phe Leu Pro Pro Ser Leu Lys Leu Leu Lys Ser Tyr Arg Val Leu Lys 485 490 495 Trp Arg Wing Asp Ser Pro Ser Met Asn Ser Arg Phe Trp Lys Asn Leu 500 505 510 Val Tyr Leu Met Pro Wing Lys Wing Val Lys Pro Trp Arg slu alu Ser 515 520 525 alu Ala Arg Ser Val Leu Ser Ala Pro 530 535 (2) SEQUENCE IDENTIFICATION INFORMATION NO. 30: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 576 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: not relevant (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 30: Met slu Asn Met Lys Val Leu Leu Cly Leu He Cys Leu Met Val Pro 1 5 10 15 Leu Leu Ser Leu Glu He Asp Val Cys Thr Glu Tyr Pro Asn Gln He 20 25 30 Val Leu Phe Leu Ser Val Asn Olu He Asp He Arg Lys Cys Pro Leu 35 40 45 Thr Pro Asn Lys Met His Oly Asp Thr He He Trp Tyr Lys Asn Asp 50 55 60 Ser Lys Thr Pro He Ser Wing Asp Arg Asp Ser Arg He His aln aln 65 70 75 80 Asn Clu His Leu Trp Phe Val Pro Wing Lys Val alu Asp Ser Cly Tyr 85 90 95 Tyr Tyr Cys He Val Arg Asn Ser Thr Tyr Cys Leu Lys Thr Lys Val 100 105 110 Thr Val Thr Val Leu alu Asn Asp Pro aly Leu Cys Tyr Ser Thr Gln 115 120 125 Wing Thr Phe Pro Gln Arg Leu His He Wing Cly Asp sly Ser Leu Val 130 135 140 Cys Pro Tyr Val Ser Tyr Phe Lys Asp Glu Asn Asn Glu Leu Pro Glu 145 150 155 160 Val Gln Trp Tyr Lys Asn Cys Lys Pro Leu Leu Leu Asp Asn Val Ser 165 170 175 Phe Phe Gly Val Lys Asp Lys Leu Leu Val Arg Asn Val Wing Glu Glu 180 185 190 His Arg Gly Asp Tyr He Cys Arg Met Ser Tyr Thr Phe Arg Gly Lys 195 200 205 Gln Tyr Pro Val Thr Arg Val He aln Phe He Thr He Asp alu Asn Lys Arg Asp Arg Pro Val lie Leu Ser Pro Arg Asn slu Thr He slu 225 230 235 240 Wing Asp Pro sly Ser Met He aln Leu He Cys Asn Val Thr Gly Gln 245 250 255 Phe Ser Asp Leu Val Tyr Trp Lys Trp Asn sly Ser slu He slu Trp 260 265 270 Asn Asp Pro Phe Leu Ala alu Asp Tyr aln Phe Val slu His Pro Ser 275 280 285 Thr Lys Arg Lys Tyr Thr Leu He Thr Thr Leu Asn He Ser alu Val 290 295 300 Lys Ser aln Phe Tyr Arg Tyr Pro Phe He Cys Val Val Lys Asn Thr 305 310 315 320 Asn He Phe Glu Be Wing His Val Gln Leu He Tyr Pro Val Pro Asp 325 330 335 Phe Lys Asn Tyr Leu He Gly Gly Phe He He Leu Thr Ala Thr He 340 345 350 Val Cys Cys Val Cys He Tyr Lys Val Phe Lys Val Asp He Val Leu 355 360 365 Trp Tyr Arg Asp Ser Cys Ser Gly Phe Leu Pro Ser Lys Wing Ser Asp 370 375 380 Gly Lys Thr Tyr Asp Wing Tyr He Leu Tyr Pro Lys Thr Leu Gly Glu 385 390 395 400 Gly Ser Phe Ser Asp Leu Asp Thr Phe Val Phe Lys Leu Leu Pro Glu 405 410 415 Val Leu Glu Gly Gln Phe Gly Tyr Lys Leu Phe He Tyr Gly Arg Asp 420 425 430 Asp Tyr Val aly alu Asp Thr He Glu Val Thr Asn Glu Asn Val Lys 435 440 445 Lys Ser Arg Arg Leu He He He Leu Val Arg Asp Met Gly Gly Phe 450 455 460 Ser Trp Leu Gly Gln Be Ser Clu Clu sln He Wing He Tyr Asn Wing 465 470 475 480 Leu He aln Olu aly He Lys He Val Leu Leu Clu Leu alu Lys He 485 490 495 aln Asp Tyr slu Lys Met Pro Asp Ser He sln Phe He Lys aln Lys 500 505 510 His Oly Val He Cys Trp Ser Gly Asp Phe Gln alu Arg Pro Oln Ser 515 520 525 Wing Lys Thr Arg Phe Trp Lys Asn Leu Arg Tyr sln Met Pro Wing 5n 530 535 540 Arg Arg Ser Pro Leu Ser Lys His Arg Leu Leu Thr Leu Asp Pro Val 545 550 555 560 Arg Asp Thr Lys alu Lys Leu Pro Wing Wing Thr His Leu Pro Leu aly 565 570 575 (2) SEQUENCE IDENTIFICATION INFORMATION NO. 31: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 569 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: not relevant (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 31: Met Lys Val Leu Leu Arg Leu He Cys Phe He Ala Leu Leu He Ser 1 5 10 15 Ser Leu Glu Wing Asp Lys Cys Lys Glu Arg Glu Glu Lys He He Leu 20 25 30 Val Ser Ser Wing Asn Glu He Asp Val Arg Pro Cys Pro Leu Asn Pro 35 40 45 Asn Glu His Lys Gly Thr He Thr Trp Tyr Lys Asp Asp Ser Lys Thr 50 55 60 Pro Val Ser Thr Glu Gln Ala Ser Arg He His Cln His Lys slu Lys 65 70 75 80 Leu Trp Phe Val Pro Ala Lys Val alu Asp Ser Oly His Tyr Tyr Cys 85 90 95 Val Val Arg Asn Be Ser Tyr Cys Leu Arg He Lys He Be Wing Lys 100 105 110 Phe Val slu Asn Olu Pro Asn Leu Cys Tyr Asn Wing Gln Wing He Phe 115 120 125 Lys Gln Lys Leu Pro Val Wing sly Asp Oly Cly Leu Val Cys Pro Tyr 130 135 140 Met Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp 145 150 155 160 Tyr Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn He His Phe Ser Gly 165 170 175 Val Lys Asp Arg Leu He Val Met Asn Val Ala Glu Lys His Arg aly 180 185 190 Asn Tyr Thr Cys His Wing Ser Tyr Thr Tyr Leu sly Lys sln Tyr Pro 195 200 205 He Thr Arg Val He alu Phe He Thr Leu Olu Glu Asn Lys Pro Thr 210 215 220 Arg Pro Val He Val Ser Pro Wing Asn Glu Thr Met Glu Val Asp Leu 225 230 235 240 Gly Ser Gln He Gln Leu He Cys Asn Val Thr Gly Gln Leu Ser Asp 245 250 255 He Wing Tyr Trp Lys Trp Asn Gly Ser Val He Asp Glu Asp Asp Pro 260 265 270 Val Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Wing Asn Lys Arg 275 280 285 Arg Ser Thr Leu He Thr Val Leu Asn He Ser Glu He Glu Ser Arg 290 295 300 Phe Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly He 305 310 315 320 Asp Ala Ala Tyr He Gln Leu He Tyr Pro Val Thr Asn Phe Gln Lys 325 330 335 His Met He Gly He Cys Val Thr Leu Thr Val He He Val Cys Ser 340 345 350 Val Phe He Tyr Lys He Phe Lys He Asp He Val Leu Trp Tyr Arg 355 360 365 Asp Ser Cys Tyr Asp Phe Leu Pro He Lys Wing Ser Asp Gly Lys Thr 370 375 380 Tyr Asp Wing Tyr He Leu Tyr Pro Lys Thr Val Gly Glu Gly Ser Thr 385 390 395 400 Be Asp Cys Asp He Phe Val Phe Lys Val Leu Pro Glu Val Leu Glu 405 410 415 Lys Gln Cys Cly Tyr Lys Leu Phe He Tyr aly Arg Asp Asp Tyr Val 420 425 430 aly slu Asp He Val alu Val He Asn Glu Asn Val Lys Lys Ser Arg 435 440 445 Arg Leu He He He Leu Val Arg Glu Thr Ser Gly Phe Ser Trp Leu 450 455 460 Gly Gly Ser Ser Glu Glu Gln He Wing Met Tyr Asn Ala Leu Val Gln 465 470 475 480 Asp Gly He Lys Val Val Leu Leu Glu Leu Glu Lys He Gln Asp Tyr 485 490 495 Glu Lys Met Pro Glu Be He Lys Phe He Lys Gln Lys His Gly Wing 500 505 510 He Arg Trp Ser Gly Asp Phe Thr Gln Gly Pro Gln Ser Ala Lys Thr 515 520 525 Arg Phe Trp Lys Asn Val Arg Tyr His Met Pro Val Gln Arg Arg Ser 530 535 540 Pro Ser Ser Lys His Gln Leu Leu Ser Pro Wing Thr Lys slu Lys Leu 545 550 555 560 sln Arg slu Wing His Val Pro Leu sly 565 (2) SEQUENCE IDENTIFICATION INFORMATION NO. 32: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 555 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: not relevant (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 32: Met His Lys Met Thr Ser Thr Phe Leu Leu He sly His Leu He Leu 1 5 10 15 Leu He Pro Leu Phe Ser Wing Clu slu Cys Val He Cys Asn Tyr Phe 20 25 30 Val Leu Val sly alu Pro Thr Ala He Ser Cys Pro Val He Thr Leu 35 40 45 Pro Met Leu His Ser Asp Tyr Asn Leu Thr Trp Tyr Arg Asn sly Ser 50 55 60 Asn Met Pro Pro Th Thr alu Arg Arg Ala Arg He His Cln Arg Lys 65 70 75 80 sly Leu Leu Trp Phe He Pro Ala Ala Leu Olu Asp Ser Cly Leu Tyr 85 90 95 Olu Cys Clu Val Arg Ser Leu Asn Arg Ser Lys Cln Lys He He Asn 100 105 110 Leu Lys Val Phe Lys Asn Asp Asn Oly Leu Cys Phe Asn Cly slu Met 115 120 125 Lys Tyr Asp aln He Val Lys Ser Ala Asn Ala aly Lys He He Cys 130 135 140 Pro Asp Leu Clu Asn Phe Lys Asp Glu Asp Asn He Asn Pro Glu He 145 150 155 160 His Trp Tyr Lys Glu Cys Lys Ser Gly Phe Leu Glu Asp Lys Arg Leu 165 170 175 Val Leu Wing Glu Gly Glu Asn Wing He Leu He Leu Asn Val Thr He 180 185 190 Gln Asp Lys sly Asn Tyr Thr Cys Arg Met Val Tyr Thr Tyr Met aly 195 200 205 Lys Gln Tyr Asn Val Ser Arg Thr Met Asn Leu Glu Val Lys Glu Ser 210 215 220 Pro Leu Lys Met Arg Pro Glu Phe He Tyr Pro Asn Asn Asn Thr He 225 230 235 240 Glu Val Glu Leu Gly Ser His Val Val Met Glu Cys Asn Val Ser Ser 245 250 255 Gly Val Tyr Gly Leu Leu Pro Tyr Trp Gln Val Asn Asp Glu Asp Val 260 265 270 Asp Ser Phe Asp Ser Thr Tyr Arg Glu Gln Phe Tyr alu Alu Oly Met 275 280 285 Pro His aly He Ala Val Ser Cly Thr Lys Phe Asn He Ser slu Val 290 295 300 Lys Leu Lys Asp Tyr Wing Tyr Lys Phe Phe Cys His Phe He Tyr Asp 305 310 315 320 Ser Gln Glu Phe Thr Ser Tyr He Lys Leu Glu His Pro Val Gln Asn 325 330 335 He Arg aly Tyr Leu He sly ally sly He Ser Leu He Phe Leu Leu 340 345 350 Phe Leu He Leu He Val Tyr Lys He Phe Lys He Asp He Val Leu 355 360 365 Trp Tyr Arg Ser Ser Cys His Pro Leu Leu Gly Lys Lys Val Ser Asp 370 375 380 Gly Lys He Tyr Asp Ala Tyr Val Leu Tyr Pro Lys Asn Arg Glu Ser 385 390 395 400 Cys Leu Tyr Ser Ser Asp He Phe Ala Leu Lys He Leu Pro alu Val 405 410 415 Leu alu Arg sln Cys Cly Tyr Asn Leu Phe He Phe Oly Arg Asn Asp 420 425 430 Leu Ala sly Olu Ala Val As Asp Val Thr Asp Glu Lys He His Gln 435 440 445 Ser Arg Arg Val He He He Leu Val Pro Glu Pro Ser Cys Tyr Gly 450 455 460 He Leu alu Asp Ala Ser alu Lys His Leu Ala Val Tyr Asn Ala Leu 465 470 475 480 He aln Asp aly He Lys He He Leu He slu Leu slu Lys He Olu 485 490 495 Asp Tyr Wing Asn Met Pro Glu Ser He Lys Tyr Val Lys Gln Lys Tyr 500 505 510 Gly Wing He Arg Trp Thr Gly Asp Phe Ser Glu Arg Ser His Ser Wing 515 520 525 Ser Thr Arg Phe Trp Lys Lys Val Arg Tyr His Met Pro Ser Arg Lys 530 535 540 His Gly Ser Ser Ser Gly Phe His Leu Ser Ser 545 550 555 (2) SEQUENCE IDENTIFICATION INFORMATION NO. 33: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 802 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: not relevant (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) SEQUENCE DESCRIPTION: ID. OF SEQUENCE NO: 33: Met Arg Leu Leu Leu Ala Leu Leu aly Val Leu Leu Ser Val Pro Cly 1 5 10 15 Pro Pro Val Leu Ser Leu slu Ala Ser alu Clu Val slu Leu Olu Pro 20 25 30 Cys Leu Ala Pro Ser Leu alu Cln sln slu Oln Clu Leu Thr Val Ala 35 40 45 Leu aly Cln Pro Val Arg Leu Cys Cys sly Arg Ala alu Arg aly sly 50 55 60 His Trp Tyr Lys Glu Gly Ser Arg Leu Wing Pro Wing Gly Arg Val Arg 65 70 75 80 Gly Trp Arg Gly Arg Leu Glu He Wing Being Phe Leu Pro Glu Asp Wing 85 90 95 Gly Arg Tyr Leu Cys Leu Wing Arg Cly Ser Met He Val Leu Oln Asn 100 105 110 Leu Thr Leu He Thr Gly Asp Ser Leu Thr Ser Ser Asn Asp Aslu Glu 115 120 125 Asp Pro Lys Ser His Arg Asp Pro Ser Asn Arg His Ser Tyr Pro aln 130 135 140 Oln Wing Pro Tyr Trp Thr His Pro sln Arg Met alu Lys Lys Leu His 145 150 155 160 Ala Val Pro Ala sly Asn Thr Val Lys Phe Arg Cys Pro Ala Ala aly 165 170 175 Asn Pro Thr Pro Thr He Arg Trp Leu Lys Asp aly aln Wing Phe His 180 185 190 aly Clu Asn Arg He aly aly He Arg Leu Arg His Gln His Trp Ser 195 200 205 Leu Val Met Glu Ser Val Val Pro Ser Asp Arg Gly Thr Tyr Thr Cys 210 215 220 Leu Val Glu Asn Wing Val Gly Ser He Arg Tyr Asn Tyr Leu Leu Asp 225 230 235 240 Val Leu Glu Arg Pro Pro His Arg Pro He Leu Gln Ala Oly Leu Pro 245 250 255 Wing Asn Thr Thr Wing Val Val Oly As Asp Val alu Leu Leu Cys Lys 260 265 270 Val Tyr Ser Asp Ala aln Pro His He aln Trp Leu Lys His He Val 275 280 285 He Asn aly Ser Ser Phe aly Ala Val sly Phe Pro Tyr Val sln Val 290 295 300 Leu Lys Thr Wing Asp He Asn Ser Ser alu Val Clu Val Leu Tyr Leu 305 310 315 320 Arg Asn Val Ser Ala slu Asp Ala sly slu Tyr Thr Cys Leu Ala Cly 325 330 335 Asn Be He Gly Leu Be Tyr Gln Be Wing Trp Leu Thr Val Leu Pro 340 345 350 Olu slu Asp Pro Thr Trp Thr Wing Wing Pro Olu Wing Arg Tyr Thr 355 360 365 Asp He He Leu Tyr Wing Ser Cly Ser Leu Wing Leu Wing Val Leu Leu 370 375 380 Leu Leu Wing Gly Leu Tyr Arg Gly Gln Wing Leu His sly Arg His Pro 385 390 395 400 Arg Pro Pro Wing Thr Val aln Lys Leu Ser Arg Phe Pro Leu Wing Arg 405 410 415 sln Phe Ser Leu slu Ser Gly Ser Ser Gly Lys Ser Ser Ser Leu 420 425 430 Val Arg Gly Val Arg Leu Ser Ser Gly Pro Ala Leu Leu Wing Gly 435 440 445 Leu Val Ser Leu Asp Leu Pro Leu Asp Pro Leu Trp Glu Phe Pro Arg 450 455 460 Asp Arg Leu Val Leu Gly Lys Pro Leu Gly Glu Gly Cys Phe Gly Gln 465 470 475 480 Val Val Arg Ala Glu Ala Phe Gly Met Asp Pro Ala Arg Pro Asp Gln 485 490 495 Wing Ser Thr Val Wing Val Lys Met Leu Lys Asp Asn Wing Ser Asp Lys 500 505 510 Asp Leu Wing Asp Leu Val Ser Glu Met Glu Val Met Lys Leu He Gly 515 520 525 Arg His Lys Asn He He Asn Leu Leu Gly Val Cys Thr Gln_ Glu Gly 530 535 540 ~ Pro Leu Tyr Val He Val Glu Cys Ala Wing Lys Gly Asn Leu Arg Glu 545 550 555 560 Phe Leu Arg Ala Arg Arg Pro Pro Oly Pro Asp Leu Ser Pro Asp aly 565 570 575 Pro Arg Ser Ser slu sly Pro Leu Ser Phe Pro Val Leu Val Ser Cys 580 585 590 Wing Tyr aln Val Wing Arg aly Met aln Tyr Leu alu Ser Arg Lys Cys 595 600 605 He His Arg Asp Leu Ala Wing Arg Asn Val Leu Val Thr slu Asp Asn 610 615 620 Val Met Lys He Wing Asp Phe sly Leu Wing Arg sly Val His His He 625 630 635 640 Asp Tyr Tyr Lys Lys Thr Ser Asn Oly Arg Leu Pro Val Lys Trp Met 645 650 655 Wing Pro Olu Wing Leu Phe Asp Arg Val Tyr Thr His Sln Ser Asp Val 660 665 670 Trp Ser Phe aly He Leu Leu Trp slu He Phe Thr Leu sly sly Ser 675 680 685 Pro Tyr Pro sly He Pro Val alu alu Leu Phe Ser Leu Leu Arg Glu 690 695 700 Gly His Arg Met Asp Arg Pro Pro His Cys Pro Pro Glu Leu Tyr Gly 705 710 715 720 Leu Met Arg Glu Cys Trp His Wing Pro Pro Gln Arg Pro Thr Phe 725 730 735 Lys Gln Leu Val Glu Ala Leu Asp Lys Val Leu Leu Ala Val Ser Glu 740 745 750 Glu Tyr Leu Asp Leu Arg Leu Thr Phe Gly Pro Tyr Ser Pro Ser Gly 755 760 765 Gly Asp Wing Ser Ser Thr Cys Ser Ser Ser Asp Val Phe Ser His 770 775 780 Asp Pro Leu Pro Leu Gly Be Being Ser Phe Pro Phe Gly Ser Gly Val 785 790 795 800 Gln Thr

Claims (9)

1. NOVELTY OF THE INVENTION CLAIMS 1. An isolated or recombinant IL-1 RD9 polypeptide: a) formed by the Nr ID of Sec: 6, 8, 10, 12, 14 or 16; b) encoded by a polynucleotide comprising the open reading frame of the Nr ID of Sec: 5, 7, 9, 1, 13 or 15; or c) encoded by means of a natural allelic variant of a polynucleotide comprising the open reading frame of the Nr ID of Sec: 5, 7, 9, 11, 13, 0 15.
2. 2. A polypeptide of claim 1, encoded by a natural allelic variant of a polynucleotide comprising the open reading frame of the Sec ID Nr: 5, 7, 9, 11, 13 or 15.
3. 3. An isolated or recombinant IL-1 RD9 polypeptide that: a ) has an apparent molecular weight of 68.3 kD as determined by means of SDS / polyacrylamide gel electrophoresis; b) has an estimated pl of 9.04; and c) it was found in the T cells, and where said polypeptide has at least one of the following properties: i) it is a heterodimer; ii) is an IL-1 of subunit type a, or iii) when contacted with IL-1 RD5 and IL-1a, for a sufficient time, forms a receptor complex with high functional affinity that activates the construction of the informer of the transcription factor NFkB.
4. 4. An isolated or recombinant polypeptide comprising a segment of the contiguous amino acid residues selected from the following group: a) contiguous amino acid residues of said polypeptide of claim 2; b) contiguous amino acid residues of said polypeptide of claim 2; c) contiguous amino acid residues of said polypeptide of claim 2; d) contiguous amino acid residues of said polypeptide of claim 2; e) contiguous amino acid residues of said polypeptide of claim 2; or f) 40 contiguous amino acid residues of said polypeptide of claim 2.
5. 5. The polypeptide of claim 1 which is immunogenic.
6. 6. An isolated or recombinant polypeptide comprising an immunogenic peptide of said polypeptide of claim 3.
7. 7. An isolated or recombinant polypeptide comprising an immunogenic polypeptide of claim 4.
8. 8. A fusion protein that comprises said polypeptide of claim 4 and: a) a detection or purification tag selected from the group consisting of a FLAG, His6, and immunoglobulin peptide; b) a carrier protein selected from the group consisting of limpet hemocyanin, bovine serum albumin, and tetanus toxoid; or c) another peptide selected from the group consisting of luciferase, bacterial β-galactosidase, trpE, protein A, β-lactamase, alpha amylase, alcohol dehydrogenase, and alpha match factor of the yeast.
9. 9. A fusion protein comprising said polypeptide of claim 5 and: a) a detection or purification marker selected from the group consisting of FLAG, His6, and an immunoglobulin peptide, b) a carrier protein selected from the group formed by limpet hemocyanin, bovine serum albumin, tetanus toxoid, or c) another peptide selected from the group consisting of luciferase, bacterial β-galactosidase, trpE, protein A, β-lactamase, alpha amylase, alcohol dehydrogenase, and coincidence factor yeast alpha 10. A composition comprising said polypeptide of claim 1, that is: a) in a pharmaceutically acceptable carrier; b) in a sterile composition; c) in a regulated solution; or d) in an aqueous suspension. 1. A composition comprising said polypeptide of claim 4, that is: a) in a pharmaceutically acceptable carrier; b) in a sterile composition; c) in a regulated solution; or d) in an aqueous suspension. 12. A polypeptide of claim 4, that is: a) denatured; b) immunopurified; c) attached to a solid substrate; c) detectable labeling; or e) chemically synthesized. 13. A polypeptide of claim 5, that is: a) denatured; b) immunopurified; c) attached to a solid substrate; c) detectable labeling; or e) chemically synthesized. 14. A kit comprising said polypeptide of claim 1, and: a) a compartment comprising said protein, or b) instructions for the use or discarding of the reagents in said kit. 15. - A kit comprising said polypeptide of claim 4, and: a) a compartment comprising said protein, or b) instructions for the use or discarding of the reagents in said kit. 16. A method for developing an antibody, which comprises immunizing an animal with a polypeptide of claim 5. 17. A method for producing an antibody: antigen complex, comprising contacting a polypeptide of claim 5 with an antibody that binds specifically to said polypeptide, thereby forming said complex. 18. A composition of the material selected from the group consisting of: a) a substantially pure or recombinant IL-1 RD8 polypeptide exhibiting identity at a length of at least about 12 amino acids with respect to the Nr ID of Sec: 4; b) a 1L-1 RD8 of natural sequence comprising the Nr ID of Sec: 4; c) a fusion polypeptide comprising the sequence of IL-1 RD8; d) a substantially pure or recombinant IL-1 RD10 polypeptide exhibiting identity at a length of at least about 12 amino acids with respect to the Nr ID of Sec: 20; e) an IL-1 RD10 of natural sequence comprising the Nr ID of Sec: 20; and f) a fusion protein comprising an IL-1 RD10 sequence. 19. A substantially pure or isolated polypeptide comprising a segment exhibiting sequence identity with respect to a corresponding portion of a: a) IL-1 RD8 of claim 18, wherein: i) said polypeptide further exhibits identity with respect to to a distinctive segment of 9 amino acids; ii) said identity length is at least 17 amino acids; iii) said identity length is at least about 25 amino acids; or b) IL-1 RD10 of claim 18, wherein: i) said polypeptide further exhibits identity with respect to a distinctive segment of 9 amino acids; ii) said identity length is at least 17 amino acids; iii) said identity length is at least about 25 amino acids. 20. The composition of the subject of claim 18, wherein said: a) IL-1 RD8 comprises a mature sequence of the Nr ID of Sec 2 or 4; b) IL-1 RD10 comprises a mature sequence of the Nr ID of Sec: 18 or 20; or c) polypeptide: i) is from a warm-blooded animal selected from a primate, such as, for example, a human; ii) comprises at least one polypeptide segment of the Sec ID Nr: 4 or 20; iii) exhibits a number of portions exhibiting said identity; iv) is a natural allelic variant of a primate or rodent IL-1 D8 or primate IL-1 RD10; v) it has a length of at least about 30 amino acids; vi) exhibits at least two non-overlapping epitopes that are specific for a primate or rodent IL-1 RD8 or primate IL-1 RD10; vii) exhibits a sequence identity of at least about 90% over a length of at least about 20 amino acids with respect to primate IL-1 RD8 or primate IL-1 RD10; viii) has a molecular weight of at least 100 kD with natural glycosylation; ix) is a synthetic polypeptide; x) is attached to a solid substrate; xi) is combined with another chemical portion; xii) is a substitution of five parts or less of the natural sequence; or xiü) is a variant of elimination or insertion of the natural sequence. 21. A composition comprising: a) a sterile IL-1 RD8 polypeptide of claim 18; b) said IL-1 RD8 protein or peptide of claim 18 and a carrier, wherein said carrier is: i) an aqueous compound, including water, saline, and / or pH buffer; and / or ii) is formulated for oral, rectal, nasal, topical or parenteral administration; c) a sterile IL-1 RD10 polypeptide of claim 18; or d) said IL-1 RD10 polypeptide of claim 18 and a carrier, wherein said carrier is: i) an aqueous compound, including water, saline, and / or pH buffer; and / or ii) is formulated for oral, rectal, nasal, topical or parenteral administration. 21. A fusion protein of claim 18, comprising: a) a mature protein sequence of the Nr ID of Sec: 2, 4, 18 or 20; b) a detection or purification marker, including FLAG, His6, or Ig sequence; or c) a sequence of another receptor protein. 22. A kit comprising a polypeptide of the claim 18, and a) a compartment comprising said polypeptide; and / or b) instructions for the use or disposal of the reagents in said kit. 23. A binding compound comprising an antigen binding site of an antibody, which specifically binds to a natural: A) protein IL-1 RD8 of claim 18, wherein: a) said protein is a protein of primate or rodent b) said binding compound is an Fv, Fab or Fab2 fragment; c) said binding compound is combined with another chemical moiety, or d) said antibody: i) is developed against a peptide sequence of a mature polypeptide of the Nr ID of Sec: 2 or 4; I) it develops against an IL-1 RD8 of primate or mature rodent; i¡¡) is developed for a purified human IL-1 RD8; iv) is developed for a purified mouse IL-1 RD8; v) is immunoselected; vi) is a polyclonal antibody; vii) is linked to a denatured IL-1 RD8; viii) exhibits a Kd with respect to the antigen of at least 30 μM, ix) is bound to a solid substrate, including pearls or plastic membrane; x) is a sterile composition, or xi) is detectably labeled, including a radioactive or fluorescent label; or B) the IL-1 RD10 polypeptide of claim 18, wherein a) said polypeptide is a primate polypeptide; b) said linking compound is a Fv, Fab or Fab2 fragment; c) said linking compound is combined with another chemical portion; or d) said antibody: i) was developed against a peptide sequence of a mature polypeptide of the Nr ID of Sec: 18 or 20; ii) was developed against a mature primate IL-1 RD10; iii) was developed for a purified human IL-1 RD10; V) is immunoselected; v) is a polyclonal antibody; vi) bind to a denatured IL-1 RD10; vii) exhibits a Kd with respect to the antigen of at least 30 μM; viii) is attached to a solid substrate, including pearls or plastic membrane; ix) is in a sterile composition; or x) is detectably labeled, including a radioactive or fluorescent label. 24. A kit comprises said binding compound of claim 25, and: a) a compartment comprising said binding compound, and / or b) instructions for the use or discarding of the reagents in said kit. 26. A method for: A) preparing an antibody of claim 23, which comprises immunizing an immune system with an immunogenic amount of: a) a primate IL-1 RD8 polypeptide; b) an IL-1 RD10 primate polypeptide; or thereby causing said compound to occur; or B) producing an antigen: antibody complex, comprising contacting: a) a primate IL-1 RD8 polypeptide with an antibody of claim 23A; or b) an IL-1 RD10 primate polypeptide with an antibody of claim 23B, thus allowing said complex to be formed. 27. A composition comprising: a) a sterile binding compound of claim 23, or b) said linking compound of claim 23 and a vehicle, wherein said vehicle is: i) an aqueous compound, including water, solution saline, and / or a pH regulator; and / or i) is formulated for oral, rectal, nasal, topical or parenteral administration. 28. An isolated or recombinant nucleic acid encoding a protein or peptide or fusion protein of claim 18, wherein: a) said IL-1 RD8 or IL-1 RD10 is from a mammal; or b) said nucleic acid: i) encodes an antigenic polypeptide sequence of the Nr ID of Sec: 2, 4, 18 or 20; ii) encodes a number of polypeptide sequences of the Nr ID of Sec: 2, 4, 18 or 20; ni) exhibits identity with respect to a natural cDNA that encodes said segment; V) is an expression vector; v) also includes an origin of replication; vi) it is from a natural source; vii) comprises a detectable label; viii) comprises a synthetic nucleotide sequence; ix) is less than 6 kb, preferably less than 3 kb; x) is from a mammal, including a primate, such as a human; xi) comprises a natural sequence that encodes full length; xii) is a hybridization probe for a gene encoding said IL-1 RD8 or IL-1 RD10; xiii) comprises a number of segments that do not overlap of at least 15 nucleotides of the NR ID of Sec: 1, 3 17 or 19 or xiv) is a PCR primer, PCR product or mutagenesis primer. 29. A cell transfected or transformed with a recombinant nucleic acid of claim 28. 30.- The cell of claim 29, wherein said cell is: a) a prokaryotic cell; b) a eukaryotic cell; c) a bacterial cell; d) a yeast cell; e) an insect cell; f) a mammalian cell; g) a mouse cell; h) a primate cell; or i) a human cell. 31. A kit comprising said nucleic acid of claim 28 and: a) a compartment comprising said nucleic acid; b) a compartment further comprising a primate or rodent IL-1 RD8 polypeptide or primate IL-1 RD10 and / or c) instructions for using or discarding reagents from said kit. 32. A method for: A) preparing a polypeptide, comprising expressing said nucleic acid of claim 28, thereby producing said polypeptide; or B) preparing a duplex nucleic acid, comprising contacting said nucleic acid of claim 28 with a hybridizing nucleic acid, thereby allowing said duplex to be formed. 33. - A nucleic acid that: a) hybridizes under washing conditions of 40 ° C and less than 2 M of salt in the Nr ID of Sec: 3 or 19; or b) exhibits identity over a stretch of at least about 30 nucleotides in an IL-1 RD8 or primate IL-1 RD10. 34. A nucleic acid of claim 33, wherein: a) said washing conditions are 55 ° C and / or 500 mM salt; or b) said stretch is at least 55 nucleotides. 35. The nucleic acid of claim 23, wherein: a) said washing conditions are at 65 ° C and / or 150 mM salt; or b) said stretch is at least 75 nucleotides. 36.- A method for modulating the physiology or development of a cell or tissue culture cells comprising contacting said cell with an agonist or antagonist of an IL-1 RD8 or primate IL-1 RD10. 37.- The method of claim 36, wherein said cell was transformed with a nucleic acid encoding either an IL-1 RD8 or IL-1 RD10, and another IL-1 R.