Single chain forms of the glycoprotein hormone quartet

Single-chain forms of the glycoprotein hormone quartet, at least some members of which are found in most vertebrates, are disclosed. The .alpha. and .beta. subunits of the wild-type heterodimers or their variants or their fragments are covalently linked, optionally through a linker moiety. Some of the single-chain forms are agonists and others antagonists of the glycoprotein hormone activity.

TECHNICAL FIELD
 The invention relates to the field of protein engineering and the
 glycoprotein hormones which occur normally as heterodimers. More
 specifically, the invention concerns single-chain forms of chorionic
 gonadotropin (CG), thyroid stimulating hormone (TSH), luteinizing hormone
 (LH), and follicle stimulating hormone (FSH).
 BACKGROUND ART
 In humans, four important glycoprotein hormone heterodimers (LH, FSH, TSH
 AND CG) have identical .alpha. subunits and differing .beta. subunits.
 Three of these hormones
 PCT application WO90/09800, published Sep. 7, 1990 and incorporated herein
 by reference, describes a number of modified forms of these hormones. One
 important modification is C-terminal extension of the .beta. subunit by
 the carboxy terminal peptide of human chorionic gonadotropin or a variant
 thereof. Other muteins of these hormones are also described. The relevant
 positions for the CTP are from any one of positions 112-118 to position
 145 of the .beta. subunit of human chorionic gonadotropin. The PCT
 application describes variants of the CTP extension obtained by
 conservative amino acid substitutions such that the capacity of the CTP to
 alter the clearance characteristics is not destroyed. In addition, U.S.
 Serial No. 08/049,869 filed Apr. 20, 1993, incorporated herein by
 reference, describes modifying these hormones by extension or insertion of
 the CTP at locations other than the C-terminus and CTP fragments shorter
 than the sequence extending from positions 112-118 to 145.
 The CTP-extended .beta. subunit of FSH is also described in two papers by
 applicants herein: LaPolt, P. S. et al.; Endocrinology (1992)
 131:2514-2520 and Fares, F. A. et al.; Proc Natl Acad Sci USA (1992)
 89:4304-4308. Both of these papers are incorporated herein by reference.
 The crystal structure of the heterodimeric form of human chorionic
 gonadotropin has now been published in more or less contemporaneous
 articles, one by Lapthorn, A. J. et al. Nature (1994) 369:455-461 and the
 other by Wu, H. et al. Structure (1994) 2:545-558. The results of these
 articles are summarized by Patel, D. J. Nature (1994) 369:438-439.
 At least one instance of preparing a successful single-chain form of a
 heterodimer is now known. The naturally occurring sweetener protein,
 monellin, is isolated from serendipity berries in a heterodimeric form.
 Studies on the crystal structure of the heterodimer were consistent with
 the proposition that the C-terminus of the B chain could be linked to the
 N-terminus of the A chain through a linker which preserved the spatial
 characteristics of the heterodimeric form. Such a linkage is advantageous
 because, for use as a sweetener protein, it would be advantageous to
 provide this molecule in a form stable at high temperatures. This was
 successfully achieved by preparing the single-chain form, thus impeding
 heat denaturation, as described in U.S. Pat. No. 5,264,558.
 PCT application WO91/16922 published Nov. 14, 1991 describes a multiplicity
 of chimeric and otherwise modified forms of the heterodimeric glycoprotein
 hormones. In general, the disclosure is focused on chimeras of .alpha.
 subunits or .beta. subunits involving portions of various .alpha. or
 .beta. chains respectively. One construct simply listed in this
 application, and not otherwise described, fuses substantially all of the
 .beta. chain of human chorionic gonadotropin to the .alpha. subunit
 preprotein, i.e., including the secretory signal sequence for this
 subunit. This construct falls outside the scope of the present invention
 since the presence of the signal sequence intervening between the .beta.
 and .alpha. chains fails to serve as a linker moiety as defined and
 described herein.
 It has now been found that the normally heterodimeric glycoprotein hormones
 retain their properties when in single-chain form, including single-chain
 forms that contain the various CTP extensions and insertions described
 above.
 DISCLOSURE OF THE INVENTION
 The invention provides single-chain forms of the glycoprotein hormones, at
 least some of which hormones are found in most vertebrate species. The
 single-chain forms of the invention may either be glycosylated, partially
 glycosylated, or nonglycosylated and the .alpha. and .beta. chains that
 occur in the native glycoprotein hormones or variants of them may
 optionally be linked through a linker moiety. Particularly preferred
 linker moieties include the carboxy terminal peptide (CTP) unit either as
 a complete unit or only as a portion thereof, as well as shorter linkers
 of 1-16 amino acids. The resulting single-chain hormones either retain the
 activity of the unmodified heterodimeric form or are antagonists of this
 activity.
 Thus, in one aspect, the invention is directed to a glycosylated or
 nonglycosylated protein which comprises the amino acid sequence of the
 .alpha. subunit common to the glycoprotein hormones linked covalently,
 optionally through a linker moiety, to the amino acid sequence of the
 .beta. subunit of one of said hormones, or variants of said amino acid
 sequences wherein said variants are defined herein.
 The availability of single-chain forms preserves conformation so that the
 entire portions of the subunits that make up the single-chain forms are
 unnecessary. Thus, the invention includes single-chain forms of fragments
 of the subunits wherein the single-chain forms retain the biological
 activity exhibited by the single-chain forms of the complete subunits.
 In other aspects, the invention is directed to recombinant materials and
 methods to produce the single-chain proteins of the invention, to
 pharmaceutical compositions containing them; to antibodies specific for
 them; and to methods for their use.

MODES OF CARRYING OUT THE INVENTION
 Four "glycoprotein" hormones in humans provide a family which includes
 human chorionic gonadotropin (hCG), follicle stimulating hormone (FSH),
 luteinizing hormone (LH), and thyroid stimulating hormone (TSH). As used
 herein, "glycoprotein hormones" refers to the members of this family. All
 of these hormones are heterodimers comprised of .alpha. subunits which,
 for a given species, are identical in amino acid sequence among the group,
 and .beta. subunits which differ according to the member of the family.
 Thus, normally these glycoprotein hormones occur as heterodimers composed
 of .alpha. and .beta. subunits associated with each other but not
 covalently linked. Most vertebrates produce FSH, TSH and LH; chorionic
 gonadotropin has been found only in primates, including humans, and
 horses.
 Thus, this hormone "quartet" is composed of heterodimers wherein the
 .alpha. and .beta. subunits of each are encoded in different genes and are
 separately synthesized by the host. The host then assembles the separately
 synthesized subunits into a non-covalently linked heterodimeric complex.
 In this manner, the heterodimers of this hormone quartet differ from
 heterodimers such as insulin which is synthesized from a single gene (in
 this case with an intervening "pro" sequence) and the subunits are
 covalently coupled using disulfide linkages. This hormone quartet is also
 distinct from the immunoglobulins which are assembled from different loci,
 but are covalently bound through disulfide linkages. On the other hand,
 monellin, which is, however, a plant protein, is held together through
 noncovalent interaction between its A and B chains. It is not known at
 present whether the two chains are encoded on separate genes.
 Thus, a variety of factors is influential in determining the behavior of
 biologically active compounds which are dimers formed from subunits that
 are identical or different. The subunits may be covalently or
 noncovalently linked; they may be synthesized by the same or different
 genes; and they may or may not contain, in their precursor forms, a "pro"
 sequence linking the two members of the dimer. Based on the results
 obtained with the single-chain forms of the glycoprotein hormone quartet
 herein, it is apparent that single-chain forms of the biologically active
 dimers interleukin-12, interleukin-3 (IL-12 and IL-3), inhibin, tumor
 necrosis factor (TNF), and transforming growth factor (TGF) will also be
 biologically active.
 The single-chain forms of the heterodimers or homodimers have a number of
 advantages over their dimeric forms. First, they are generally more
 stable. LH, in particular, is noted for its instability and short
 half-life. Second, problems of recombinant production are reduced since
 only a single gene need be transcribed, translated and processed. This is
 particularly important for expression in bacteria. Third, of course, they
 provide an alternate form thus permitting fine tuning of activity levels
 and of in vivo half lives. Finally, single chain forms are unique starting
 materials for identifying truncated forms with the activity of the dimer.
 The linkage between the subunits permits the protein to be engineered
 without disturbing the overall folding of the protein.
 With respect to this last point, it will be evident that because the
 conformation is stabilized in the single-chain forms, less than the
 complete single-chain conjugate of the subunits that compose it will
 generally be needed. Therefore, the invention covers fragments of the
 single-chain proteins that retain biological activity; these fragments may
 be visualized as single-chain forms obtained from fragments of the
 subunits per se.
 Features of the Members of the Quartet
 The .beta. subunit of hCG is substantially larger than the other .beta.
 subunits in that it contains approximately 34 additional amino acids at
 the C-terminus referred to herein as the carboxy terminal portion (CTP)
 which, when glycosylated at the O-linked sites, is considered responsible
 for the comparatively longer serum half-life of hCG as compared to other
 gonadotropins (Matzuk, M. et al., Endocrinol (1989) 126:376). In the
 native hormone, this CTP extension contains four mucin-like O-linked
 oligosaccharides.
 In one embodiment of the present invention, the .alpha. and .beta. chains
 of the glycoprotein hormones are coupled into a single-chain proteinaceous
 material where the .alpha. and .beta. chain are covalently linked,
 optionally through a linker moiety. The linker moiety may include further
 amino acid sequence, and in particular the CTP units described herein can
 be advantageously included in the linker. In addition, the linker may
 include peptide or nonpeptide drugs which can be targeted to the receptors
 for the hormones.
 In addition to the head-to-tail configuration that is achievable by simply
 coupling the two peptide chains through a peptide bond, the .alpha. and
 .beta. chains can be linked head-to-head or tail-to-tail. Head to head and
 tail to tail couplings involve synthetic chemistry using standard
 techniques to link two carboxyl or two amino groups through a linker
 moiety. For example, two amino groups may be linked through an anhydride
 or through any dicarboxylic acid derivative; two carboxyl groups can be
 linked through diamines or diols using standard activation techniques.
 However, the most preferred form is a head to tail configuration wherein
 standard peptide linkages suffice and the single-chain compound can be
 prepared as a fusion protein recombinantly or using synthetic peptide
 techniques either in a single chain or, preferably, ligating individual
 portions of the entire sequence. Of course, if desired, peptide or
 non-peptide linker moieties can be used in this case as well, but this is
 unnecessary and the convenience of recombinant production of the
 single-chain protein would suggest that embodiments that permit this
 method of production comprise by far the most preferred approach.
 When a head-to-tail configuration is employed, linkers may consist
 essentially of additional peptide sequence. As is the case with the
 heterodimers, the two .beta. chains may be linked through a CTP unit as
 further described below. Thus, possible embodiments of the invention
 include, with the N-terminus at the left, .alpha.-FSH.beta.,
 .beta.FSH-.alpha., .alpha.-.beta.LH, .alpha.-CTP-.beta.LH,
 .beta.LH-CTP-.alpha., CTP-.beta.LH-CTP-.alpha.; and the like.
 The following definitions may be helpful in describing the single-chain
 forms of the molecules.
 As used herein, .alpha. subunit, and FSH, LH, TSH, and CG .beta. subunits
 as well as the heterodimeric forms have in general their conventional
 definitions and refer to the proteins having the amino acid sequences
 known in the art per se, or allelic variants thereof, regardless of the
 clycosylation pattern exhibited.
 "Native" forms of these peptides are those which have the amino acid
 sequences isolated from the relevant vertebrate tissue, and have these
 known sequences per se, or their allelic variants.
 "Variant" forms of these proteins are those which have deliberate
 alterations in amino acid sequence of the native protein produced by, for
 example, site-specific mutagenesis or by other recombinant manipulations,
 or which are prepared synthetically.
 These alterations consist of 1-10, preferably 1-8, and more preferably 1-5
 amino acid changes, including deletions, insertions, and substitutions,
 most preferably conservative amino acid substitutions as defined below.
 The resulting variants must retain activity which affects the
 corresponding activity of the native hormone--i.e., either they must
 retain the biological activity of the native hormone directly, or they
 must behave as antagonists, generally by virtue of being able to bind the
 receptors for the native hormones but lacking the ability to effect signal
 transduction. For example, it is known that if the glycosylation site at
 position 52 of the .alpha. subunit is removed by an amino acid
 substitution, therefore preventing all glycosylation at that site, the
 hormones which are heterodimers with this altered .alpha. subunit are
 generally agonists and are able to bind receptors preventing the native
 hormone from doing so in competition. (On the other hand, the
 glycosylation site of the .alpha. subunit at position 78 appears not
 greatly to affect the activity of the hormones.) Other alterations in the
 amino acid sequence may also result in antagonist rather than agonist
 activity for the variant.
 One set of preferred variants are those wherein the glycosylation sites of
 either the .alpha. or .beta. subunits or both have been altered. The
 .alpha. subunit contains two glycosylation sites, one at position 52 and
 the other at position 78, and the effect of alterations of these sites on
 activity has just been described. Similarly, the .beta. subunits generally
 contain two N-linked glycosylation sites (at positions that vary somewhat
 with the nature of the .beta. chain) and similar alterations can be made
 at these sites. The CTP extension of hCG contains four O-linked
 glycosylation sites, and conservative mutations at the serine residues
 (e.g., conversion of the serine to alanine) destroys these sites.
 Destruction of the O-linked glycosylation sites may effect conversion of
 against activity to antagonist activity.
 Finally, alterations in amino acid sequence that are proximal to the
 N-linked or O-linked glycosylation sites influence the nature of the
 glycosylation that is present on the resulting molecule and also alter
 activity.
 Alterations in amino acid sequence also include both insertions and
 deletions. Thus, truncated forms of the hormones are included among
 variants, e.g., mutants of the .alpha. subunit which ale lacking some or
 all of the amino acids at positions 85-92 at the C-terminus. In addition,
 .alpha. subunits with 1-10 amino acids deleted from the N-terminus are
 included. Some useful variants of the hormone quartet described herein are
 set forth in U.S. Pat. No. 5,177,193 issued Jan. 5, 1993 and incorporated
 herein by reference. As shown therein, the glycosylation patterns can be
 altered by destroying the relevant sites or, in the alternative, by choice
 of host cell in which the protein is produced.
 As explained above, the single chain forms are convenient starting
 materials for various engineered muteins. Such muteins include those with
 non-critical regions altered or removed. Such deletions and alterations
 may comprise entire loops, so that sequences of considerably more than 10
 amino acids may be deleted or changed. The single chain molecules must,
 however, retain at least the receptor binding domains and/or the regions
 involved in signal transduction.
 There is considerable literature on variants of the hormone quartet
 described herein and it is clear from this literature that a large number
 of possible variants which result both in agonist and antagonist activity
 can be prepared. Such variants are disclosed, for example, in Chen, F. et
 al. Molec Endocrinol (1992) 6:914-919; Yoo, J. et al. J Biol Chem (1993)
 268:13034-13042; Yoo, J. et al. J Biol Chem (1991) 266:17741-17743; Puett,
 D. et al. Glycoprotein Hormones, Lusbader, J. W. et al. EDS, Springer
 Verlag New York (1994) 122-134; Kuetmann, H. T. et al. (ibid) pages
 103-117; Erickson, L. D. et al. Endocrinology (1990) 126:2555-2560; and
 Bielinska, M. et al. J Cell Biol (1990) 111:330a (Abstract 1844).
 As described hereinabove, one method of constructing effective antagonists
 is to prepare a single-chain molecule containing two .beta. subunits of
 the same or different member of the glycoprotein quartet. Particularly
 preferred variants of these single-chain forms include those wherein one
 or more cystine-link is deleted, typically by substituting a neutral amino
 acid for one or both cysteines which participate in the link. Particularly
 preferred cystine links which may be deleted are those between positions
 26 and 110 and between positions 23 and 72.
 In addition, it has been demonstrated that the .beta. subunits of the
 hormone quartet can be constructed in chimeric forms so as to provide
 biological functions of both components of the chimera, or, in general,
 hormones of altered biological function. Thus, chimeric molecules which
 exhibit both FSH and LH/CG activities can be constructed as described by
 Moyle, Proc Natl Acad Sci (1991) 88:760-764; Moyle, Nature (1994)
 368:251-255. As disclosed in these papers, substituting amino acids
 101-109 of FSH-.beta. for the corresponding residues in the CG-.beta.
 subunit yields an analog with both hCG and FSH activity.
 Although it is recognized that glycosylation pattern has a profound
 influence on activity both qualitatively and quantitatively, for
 convenience the terms FSH, LH, TSH, and CG .beta. subunits refers to the
 amino acid sequence characteristic of the peptides, as does ".alpha.
 subunit." When only the .beta. chain is referred to, the terms will be,
 for example, FSH.beta.; when the heterodimer is referred to, the simple
 term "FSH" will be used. It will be clear from the context in what manner
 the glycosylation pattern is affected by, for example, recombinant
 expression host or alteration in the glycosylation sites. Forms of the
 glycoprotein with specified glycosylation patterns will be so noted.
 As used herein "peptide" and "protein" are used interchangeably, since the
 length distinction between them is arbitrary.
 As stated above, the subunits employed in forming the single-chain
 conjugates with or without linking moieties may represent the complete
 amino acid sequences of the subunits or only portions thereof Single-chain
 conjugates of .alpha. and .beta. subunits are composed of these subunits
 per se or of those fragments of the subunits which result in a
 single-chain form with biological activity comparable to that exhibited by
 the single chain composed of the corresponding complete subunits.
 In the single-chain forms of the present invention, the .alpha. and/or
 .beta. chain may contain a CTP extension inserted into a noncritical
 region.
 "Noncritical" regions of the .alpha. and .beta. subunits are those regions
 of the molecules not required for biological activity (including agonist
 and antagonist activity). In general, these regions are removed from
 binding sites, precursor cleavage sites, and catalytic regions. Regions
 critical for inducing proper folding, binding to receptors, catalytic
 activity and the like should be avoided; similarly, regions which are
 critical to assure the three-dimensional conformation of the protein
 should be avoided. It should be noted that some of the regions which are
 critical in the case of the dimer become non-critical in the single chain
 forms since the conformational restriction imposed by the single chain may
 obviate the necessity for these regions. The ascertainment of noncritical
 regions is readily accomplished by deleting or modifying candidate regions
 and conducting an appropriate assay for the desired activity. Regions
 where modifications result in loss of activity are critical; regions
 wherein the alteration results in the same or similar activity (including
 antagonist activity) are considered noncritical.
 It should be emphasized, that by "biological activity" is meant activity
 which is either agonistic or antagonistic to that of the native hormones.
 Thus, certain regions are critical for behavior of a variant as an
 antagonist, even though the antagonist is unable to directly provide the
 physiological effect of the hormone.
 For example, for the .alpha. subunit, positions 33-59 are thought to be
 necessary for signal transduction and the 20 amino acid stretch at the
 carboxy terminus is needed for signal transduction/receptor binding.
 Residues critical for assembly with the .beta. subunit include at least
 residues 33-58, particularly 37-40.
 Where the noncritical region is "proximal" to the N- or C-terminus, the
 insertion is at any location within 10 amino acids of the terminus,
 preferably within 5 amino acids, and most preferably at the terminus per
 se.
 In general, "proximal" is used to indicate a position which is within 10
 amino acids, preferably within five amino acids, of a referent position,
 and most preferably at the referent position per se. Thus, certain
 variants may contain substitutions of amino acids "proximal" to a
 glycosylation site, the definition is relevant here. In addition, the
 .alpha. and .beta. subunits may be linked to each other at positions
 "proximal" to their N- or C-termini.
 As used herein, the "CTP unit" refers to an amino acid sequence found at
 the carboxy terminus of human chorionic gonadotropin .beta. subunit which
 extends from amino acid 112-118 to residue 145 at the C-terminus or to a
 portion thereof. Thus, each "complete" CTP unit contains 28-34 amino
 acids, depending on the N-terminus of the CTP. The native sequence of
 positions 112-145 is shown in FIG. 2.
 By a "partial" CTP unit is meant an amino acid sequence which occurs
 between positions 112-118 to 145 inclusive, but which has at least one
 amino acid deleted from the shortest possible "complete" CTP unit (i.e.
 from positions 118-145). The "partial" CTP units included in the invention
 preferably contain at least one O-glycosylation site if agonist activity
 is desired. Some nonglycosylated forms of the hormones are antagonists and
 are useful as such. The CTP unit contains four such sites at the serine
 residues at positions 121 (site 1); 127 (site 2); 132 (site 3); and 138
 (site 4). The partial forms of CTP useful in agonists of the invention
 will contain one or more of these sites arranged in the order in which
 they appear in the native CTP sequence. Thus, the "partial" CTP unit
 employed in agonists of the invention may include all four glycosylation
 sites; sites 1, 2 and 3; sites 1, 2 and 4; sites 1, 3 and 4; sites 2, 3
 and 4; or simply sites 1 and 2; 1 and 3; 1 and 4; 2 and 3; 2 and 4; or 3
 and 4; or may contain only one of sites 1, 2, 3 or 4.
 By "tandem" inserts or extensions is meant that the insert or extension
 contains at least two "CTP units". Each CTP unit may be complete or a
 fragment, and native or a variant. All of the CTP units in the tandem
 extension or insert may be identical, or they may be different from each
 other. Thus, for example, the tandem extension or insert may generically
 be partial-complete; partial-partial; partial-complete-partial;
 complete-complete-partial, and the like wherein each of the noted partial
 or complete CTP units may independently be either a variant or the native
 sequence.
 The "linker moiety" is a moiety that joins the .alpha. and .beta. sequences
 without interfering with the activity that would otherwise be exhibited by
 the same .alpha. and .beta. chains as members of a heterodimer, or which
 alters that activity to convert it from agonist to antagonist activity.
 The level of activity may change within a reasonable range, but the
 presence of the linker cannot be such so as to deprive the single-chain
 form of both substantial agonist and substantial antagonist activity. The
 single-chain form must remain as a single-chain form when it is recovered
 from its production medium and must exhibit activity pertinent to the
 hormonal activity of the heterodimer, the elements of which form its
 components. A typical linker would be a peptide containing 1-100 amino
 acids.
 Variants
 The hormone subunits and the CTP units may correspond exactly to the native
 hormone or CTP sequence, or may be variants. The nature of the variants
 has been defined hereinabove. In such variants, 1-10, preferably 1-8, and
 most preferably 1-5 of the amino acids contained in the native sequence
 are substituted by a different amino acid compared to the native amino
 acid at that position, or 1-10, more preferably 1-8 and most preferably
 1-5 amino acids are simply deleted or combination of these. As pointed out
 above, when non-critical regions of the single chain forms are identified,
 in particular, through detecting the presence of non-critical "loops", the
 number of amino acids altered by deletion or substitution may be increased
 to 20 or 30 or any arbitrary number depending on the length of amino acid
 sequence in the relevant non-critical region. Of course, deletion or
 substitutions in more than one non-critical region results in still
 greater numbers of amino acids in the single chain forms being affected
 and substitution and deletions strategies may be used in combination. The
 substitutions or deletions taken cumulatively do not result in substantial
 elimination of agonist or antagonist activity associated with the hormone.
 Substitutions by conservative analogs of the native amino acid are
 preferred.
 "Conservative analog" means, in the conventional sense, an analog wherein
 the residue substituted is of the same general amino acid category as that
 for which substitution is made. Amino acids have been classified into such
 groups, as is understood in the art, by, for example, Dayhoff, M. et al.,
 Atlas of Protein Sequences and Structure (1972) 5:89-99. in general,
 acidic amino acids fall into one group; basic amino acids into another;
 neutral hydrophilic amino acids into another; and so forth.
 More specifically, amino acid residues can be generally subclassified into
 four major subclasses as follows:
 Acidic: The residue has a negative charge due to loss of H ion at
 physiological pH and the residue is attracted by aqueous solution so as to
 seek the surface positions in the conformation of a peptide in which it is
 contained when the peptide is in aqueous medium at physiological pH.
 Basic: The residue has a positive charge due to association with H ion at
 physiological pH and the residue is attracted by aqueous solution so as to
 seek the surface positions in the conformation of a peptide in which it is
 contained when the peptide is in aqueous medium at physiological pH.
 Neutral/nonpolar: The residues are not charged at physiological pH and the
 residue is repelled by aqueous solution so as to seek the inner positions
 in the conformation of a peptide in which it is contained when the peptide
 is in aqueous medium. These residues are also designated "hydrophobic"
 herein.
 Neutral/polar: The residues are not charged at physiological pH, but the
 residue is attracted by aqueous solution so as to seek the outer positions
 in the conformation of a peptide in which it is contained when the peptide
 is in aqueous medium.
 It is understood, of course, that in a statistical collection of individual
 residue molecules some molecules will be charged, and some not, and there
 will be an attraction for or repulsion from an aqueous medium to a greater
 or lesser extent. To fit the definition of "charged," a significant
 percentage (at least approximately 25%) of the individual molecules are
 charged at physiological pH. The degree of attraction or repulsion
 required for classification as polar or nonpolar is arbitrary and,
 therefore, amino acids specifically contemplated by the invention have
 been classified as one or the other. Most amino acids not specifically
 named can be classified on the basis of known behavior.
 Amino acid residues can be further subclassified as cyclic or noncyclic,
 and aromatic or nonaromatic, self-explanatory classifications with respect
 to the side chain substituent groups of the residues, and as small or
 large. The residue is considered small if it contains a total of 4 carbon
 atoms or less, inclusive of the carboxyl carbon. Small residues are, of
 course, always nonaromatic.
 For the naturally occurring protein amino acids, subclassification
 according to the foregoing scheme is as follows.
 Acidic: Aspartic acid and Glutamic acid;
 Basic/noncyclic: Arginine, Lysine;
 Basic/cyclic: Histidine;
 Neutral/polar/small: Glycine, serine, cysteine;
 Neutral/nonpolar/small: Alanine;
 Neutral/polar/large/nonaromatic: Threonine, Asparagine, Glutamine;
 Neutral/polar/large aromatic: Tyrosine;
 Neutral/nonpolar/large/nonaromatic: Valine, Isoleucine, Leucine,
 Methionine;
 Neutral/nonpolar/large/aromatic: Phenylalanine, and Tryptophan.
 The gene-encoded secondary amino acid proline, although technically within
 the group neutral/nonpolar/large/cyclic and nonaromatic, is a special case
 due to its known effects on the secondary conformation of peptide chains,
 and is not, therefore, included in this defined group.
 If the single-chain proteins of the invention are constructed by
 recombinant methods, they will contain only gene encoded amino acid
 substitutions; however, if any portion is synthesized by standard, for
 example, solid phase, peptide synthesis methods and ligated, for example,
 enzymatically, into the remaining protein, non-gene encoded amino acids,
 such as aminoisobutyric acid (Aib), phenylglycine (Phg), and the like can
 also be substituted for their analogous counterparts.
 These non-encoded amino acids also include, for example, .beta.-alanine
 (.beta.-Ala), or other omega-amino acids, such as 3-amino propionic,
 4-amino butyric and so forth, sarcosine (Sar), ornithine (Orn), citrulline
 (Cit), t-butylalanine (t-BuA), t-butylglycine (t-BuG), N-methylisoleucine
 (N-Melle), and cyclohexylalanine (Cha), norleucine (Nle), cysteic acid
 (Cya) 2-naphthylalanine (2-Nal);
 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic); mercaptovaleric
 acid (Mvl); .beta.-2-thienylalanine (Thi); and methionine sulfoxide (MSO).
 These also fall conveniently into particular categories.
 Based on the above definitions,
 Sar and .beta.-Ala and Aib are neutral/nonpolar/small;
 t-BuA, t-BuG, N-MeIle, Nle, Mvl and Cha are
 neutral/nonpolar/large/nonaromatic;
 Orn is basic/noncyclic;
 Cya is acidic;
 Cit, Acetyl Lys, and MSO are neutral/polar/ large/nonaromatic; and
 Phg, Nal, Thi and Tic are neutral/nonpolar/large/aromatic.
 The various omega-amino acids are classified according to size as
 neutral/nonpolar/small (.beta.-Ala, i.e., 3-aminopropionic,
 4-aminobutyric) or large (all others).
 Thus, amino acid substitutions other than those encoded in the gene can
 also be included in peptide compounds within the scope of the invention
 and can be classified within this general scheme according to their
 structure.
 Preferred Embodiments of the Single-Chain Hormones
 The single-chain hormones of the invention are most efficiently and
 economically produced using recombinant techniques. Therefore, those forms
 of .alpha. and .beta. chains, CTP units and other linker moieties which
 include only gene-encoded amino acids are preferred. It is possible,
 however, as set forth above, to construct at least portions of the
 single-chain hormones using synthetic peptide techniques or other organic
 synthesis techniques and therefore variants which contain nongene-encoded
 amino acids are also within the scope of the invention.
 In the most preferred embodiments of the single-chain hormones of the
 invention, the C-terminus of the .beta. subunit is covalently linked,
 optionally through a linker, to the N-terminus of the mature .alpha.
 subunit, forms wherein the C-terminus of the .alpha. subunit is linked to
 the N-terminus of the .beta. subunit are also useful, but may have less
 activity either as antagonists or agonists of the relevant receptor. The
 linkage can be a direct peptide linkage wherein the C-terminal amino acid
 of one subunit is directly linked through the peptide bond to the
 N-terminus of the other, however, in many instances it is preferable to
 include a linker moiety between the two termini. In many instances, the
 linker moiety will provide at least one .beta. turn between the two
 chains. The presence of proline residues in the linker may therefore be
 advantageous.
 As described above, the N-terminus of the .alpha. chain may also be coupled
 to the N-terminus of the .beta. chain or the C-terminus of the .alpha. to
 the C-terminus of the .beta. chain in any case through a linker unit.
 It should be understood that in discussing linkages between the termini of
 the subunits comprising the single chain forms, one or more termini may be
 altered by substitution and/or deletion as described above.
 While the head-to-head, tail-to-tail and head-to-tail configurations of the
 single-chain heterodimer have been described, the linkage between the two
 subunits may also occur at positions not precisely at the N- or C-terminus
 of each member but at positions proximal thereto.
 In one particularly preferred set of embodiments, the linkage is
 head-to-tail and the linker moiety will include one or more CTP units
 and/or variants or truncated forms thereof. Preferred forms of the CTP
 units used in such linker moieties are described hereinbelow.
 Further, the linker moiety may include a drug covalently, preferably
 releasably, bound to the linker moiety. Means for coupling the drug to the
 linker moiety and for providing for its release are conventional.
 In addition to their occurrence in the linker moiety, CTP and its variants
 and truncations may also be included in any noncritical region of the
 subunits making up the single-chain hormone. The nature of these
 inclusions, and their positions, is set forth in detail in the parent
 application herein.
 While CTP units are preferred inclusions in the linker moiety, it is
 understood that the linker may be any suitable covalently bound material
 which provides the appropriate spatial relationship between the .alpha.
 and .beta. subunits. Thus, for head-to-tail configurations the linker may
 generally be a peptide comprising an arbitrary number, but typically less
 than 100, more preferably less than 50 amino acids which has the proper
 hydrophilicity/hydrophobicity ratio to provide the appropriate spacing and
 confirmation in solution. In general, the linker should be on balance
 hydrophilic so as to reside in the surrounding solution and out of the way
 of the interaction between the .alpha. and .beta. subunits. It is
 preferable that the linker include .beta. turns typically provided by
 proline residues. Any suitable polymer, including peptide linkers, with
 the above-described correct characteristics may be used.
 One particular linker moiety that is not included within the scope of the
 invention is that which includes a signal peptide immediately upstream of
 the downstream subunit.
 Particularly preferred embodiments of the single-chain hormones of the
 invention include:
 .beta.FSH-.alpha.;
 .beta.LH-.alpha.;
 .beta.TSH-.alpha.;
 .beta.CG-.alpha.;
 .beta.FSH-CTP-.alpha.;
 .beta.LH-CTP-.alpha.;
 .beta.CG-CTP-.alpha.;
 .beta.FSH-CTP-CTP-.alpha.;
 .beta.LH-CTP-CTP-.alpha.;
 .beta.CG-CTP-CTP-.alpha.;
 and the like. Also particularly preferred are the human forms of the
 subunits. In the above constructions, "CTP" refers to CTP or its variants
 or truncations as further explained in the paragraph below.
 Preferred Embodiments of CTP Units
 The notation used for the CTP units of the invention is as follows: for
 portions of the complete CTP unit, the positions included in the portion
 are designated by their number as they appear in FIG. 2 herein. Where
 substitutions occur, the substituted amino acid is provided along with a
 superscript indicating its position. Thus, for example, CTP (120-143)
 represents that portion of CTP extending from positions 120 to 143; CTP
 (120-130; 136-143) represents a fused amino acid sequence lacking
 positions 118-119, 131-135, and 144-145 of the native sequence. CTP
 (Arg.sup.122) refers to a variant wherein the lysine at position 122 is
 substituted by an arginine; CTP (Ile.sup.134) refers to a variant wherein
 the leucine at position 134 is substituted by isoleucine. CTP (Val.sup.28
 Val.sup.143) represents a variant wherein two substitutions have been
 made, one for the leucine at position 128 and the other for the isoleucine
 at position 142. CTP (120-143; Ile.sup.128 Ala.sup.130) represents the
 relevant portion of the CTP unit where the two indicated substitutions
 have been made.
 Also preferred among variants of CTP are those wherein one or more of the
 O-linked glycosylation sites have been altered or deleted. One
 particularly preferred means of altering the site to prevent glycosylation
 is substitution of an alanine residue for the serine residue in these
 sites.
 Particularly preferred are those CTP units of the following formulas:
 #1 CTP (116-132)
 #2 CTP (118-128; 130-135)
 #3 CTP (117-142)
 #4 CTP (116-130)
 #5 CTP (116-123; 137-145)
 #6 CTP (115-133; 141-145)
 #7 CTP (117-140, Ser.sup.123 Gln.sup.140)
 #8 CTP (125-143, Ala.sup.130)
 #9 CTP (135-145, Glu.sup.139)
 #10 CTP (131-143, Val.sup.142 Val.sup.143)
 #11 CTP (118-132)
 #12 CTP (118-127)
 #13 CTP (118-145)
 #14 CTP (115-132)
 #15 CTP (115-127)
 #16 CTP (115-145)
 #17 CTP (112-145)
 #18 CTP (112-132)
 #19 CTP (112-127)
 Preferred Embodiments of the .alpha. and .beta. Subunits
 Of course, the native forms of the .alpha. and .beta. subunits in the
 single-chain form are among the preferred embodiments. However, certain
 variants are also preferred.
 In particular, variants of the .alpha. subunit in which the N-linked
 glycosylation site at position 52 is eliminated or altered by amino acid
 substitutions at or proximal to this site are preferred for antagonist
 activity. Similar modifications at the glycosylation site at position 78
 are -also preferred. Deletion of one or more amino acids at positions
 85-92 also affects the nature of the activity of hormones containing the
 .alpha. subunit and substitution or deletion of amino acids at these
 positions is also among the preferred embodiments.
 Similarly, the N-linked glycosylation sites in the .beta. chain can
 conveniently be modified to eliminate glycosylation and thus affect the
 agonist or antagonist activity of the .beta. chains. If CTP is present,
 either natively as in CG or by virtue of being present as a linker, the
 O-linked glycosylation sites in this moiety may also be altered.
 Particular variants containing modified or deleted glycosylation sites are
 set forth in Yoo, J. et al. J Biol Chem (1993) 268:13034-13042; Yoo, J. et
 al. J Biol Chem (1991) 266:17741-17743; and Bielinska, M. et al. J Cell
 Biol (1990) 111:330a (all cited above) and in Matzuk, M. M. et al. J Biol
 Chem (1989) 264:2409-2414, Keene, J. L. et al. J Biol Chem (1989)
 264:4769-4775; and Keene, J. L. et al. Mol Endocrinol (1989) 3:2011-2017.
 Not only may the glycosylation sites per se be modified directly, but
 positions proximal to these sites are preferentially modified so that the
 glycosylation status of the mutant will be affected. For the .alpha.
 subunit, for example, variants in which amino acids between positions
 50-60 are substituted, including both conservative and nonconservative
 substitutions, are favored, especially substitutions at positions 51, 53
 and 55 because of their proximity to the glycosylation site at Asn.sub.52.
 Also preferred are mutants of the .alpha. subunit wherein lysine at
 position 91 is converted to methionine or glutamic acid.
 Although the variants have been discussed in terms of variations in the
 individual subunits hereinabove, it will be recalled that the single chain
 forms of the dimer offer additional opportunities for modification.
 Specifically, regions that are critical to folding of the dimer may not be
 critical to the correct conformation of the single chain molecule and
 these regions are available for variation in the single chain form,
 although not described above in terms of individual members of the dimeric
 forms. Further, the single chain forms may be modified dramatically in the
 context of non-critical regions whose alteration and/or deletion do not
 affect the biological activity as described above.
 While for human use, the human forms of the glycoprotein quartet are
 desirable, it should be noted that the corresponding forms in other
 vertebrates are useful in veterinary contexts. Thus, the FSH, TSH and LH
 subunits characteristic of bovine, ovine, equine, porcine, feline, canine,
 and other species are appropriate to indications affecting these species
 per se.
 Suitable Drugs
 Suitable drugs that may be included in the linker moiety include peptides
 or proteins such as insulin-like growth factors; epidermal growth factors;
 acidic and basic fibroblast growth factors; platelet-derived growth
 factors; the various colony stimulating factors, such as granulocyte CSF,
 macrophage-CSF, and the like; as well as the various cytokines such as
 IL-2, IL-3 and the plethora of additional interleukin proteins; the
 various interferons; tumor necrosis factor; and the like. Peptide- or
 protein-based drugs have the advantage that they can be included in the
 single-chain and the entire construct can readily be produced by
 recombinant expression of a single gene. Also, small molecule drugs such
 as antibiotics, antiinflammatories, toxins, and the like can be used.
 In general, the drugs included within the linker moiety will be those
 desired to act in the proximity of the receptors to which the hormones
 ordinarily bind. Suitable provision for release of the drug from inclusion
 within the linker will be provided, for example, by also including sites
 for enzyme-catalyzed lysis as further described under the section headed
 Preparation Methods hereinbelow.
 Other Modifications
 The single-chain proteins of the invention may be further conjugated or
 derivatized in ways generally understood to derivatize amino acid
 sequences, such as phosphorylation, glycosylation, deglycosylation of
 ordinarily glycosylated forms, modification of the amino acid side chains
 (e.g., conversion of proline to hydroxyproline) and similar modifications
 analogous to those post-translational events which have been found to
 occur generally.
 The glycosylation status of the hormones of the invention is particularly
 important. The hormones may be prepared in nonglycosylated form either by
 producing them in procaryotic hosts or by mutating the glycosylation sites
 normally present in the subunits and/or any CTP units that may be present.
 Both nonglycosylated versions and partially glycosylated versions of the
 hormones can be prepared by manipulating the glycosylation sites.
 Normally, glycosylated versions are, of course, also included within the
 scope of the invention.
 As is generally known in the art, the single-chain proteins of the
 invention may also be coupled to labels, carriers, solid supports, and the
 like, depending on the desired application. The labeled forms may be used
 to track their metabolic fate; suitable labels for this purpose include,
 especially, radioisotope labels such as iodine 131, technetium 99, indium
 111, and the like. The labels may also be used to mediate detection of the
 single-chain proteins in assay systems; in this instance, radioisotopes
 may also be used as well as enzyme labels, fluorescent labels, chromogenic
 labels, and the like. The use of such labels is particularly helpful for
 these proteins since they are targeting agents receptor ligand.
 The proteins of the invention may also be coupled to carriers to enhance
 their immunogenicity in the preparation of antibodies specifically
 immunoreactive with these new modified forms. Suitable carriers for this
 purpose include keyhole limpet hemocyanin (KLH), bovine serum albumin
 (BSA) and diphtheria toxoid, and the like. Standard coupling techniques
 for linking the modified peptides of the invention to carriers, including
 the use of bifunctional linkers can be employed.
 Similar linking techniques, along with others, may be employed to couple
 the proteins of the invention to solid supports. When coupled, these
 proteins can then be used as affinity reagents for the separation of
 desired components with which specific reaction is exhibited.
 Preparation Methods
 Methods to construct the proteins of the invention are well known in the
 art. As set forth above, if only gene encoded amino acids are included,
 and the single-chain is in a head-to-tail configuration, the most
 practical approach at present is to synthesize these materials
 recombinantly by expression of the DNA encoding the desired protein. DNA
 containing the nucleotide sequence encoding the single-chain forms,
 including variants, can be prepared from native sequences. Techniques for
 site-directed mutagenesis, ligation of additional sequences, PCR, and
 construction of suitable expression systems are all, by now, well known in
 the art. Portions or all of the DNA encoding the desired protein can be
 constructed synthetically using standard solid phase techniques,
 preferably to include restriction sites for ease of ligation. Suitable
 control elements for transcription and translation of the included coding
 sequence can be provided to the DNA coding sequences. As is well known,
 expression systems are now available compatible with a wide variety of
 hosts, including procaryotic hosts such as bacteria and eucaryotic hosts
 such as yeast, plant cells, insect cells, mammalian cells, avian cells,
 and the like.
 The choice of host is particularly to posttranslational events, most
 particularly including glycosylation. The location of glycosylation is
 mostly controlled by the nature of the glycosylation sites within the
 molecule; however, the nature of the sugars occupying this site is largely
 controlled by the nature of the host. Accordingly, a fine-tuning of the
 properties of the hormones of the invention can be achieved by proper
 choice of host.
 A particularly preferred form of gene for the .alpha. subunit portion,
 whether the .alpha. subunit is modified or unmodified, is the "minigene"
 construction.
 As used herein, the .alpha. subunit "minigene" refers to the gene
 construction disclosed in Matzuk, M. M. et al, Mol Endocrinol (1988)
 2:95-100, in the description of the construction of pM.sup.2 /CG .alpha.
 or pM.sup.2 /.alpha.. This "minigene" is characterized by retention only
 of the intron sequence between exon 3 and exon 4, all upstream introns
 having been deleted. In the particular construction described, the
 N-terminal coding sequences which are derived from exon 2 and a portion of
 exon 3 are supplied from cDNA and are ligated directly through an XbaI
 restriction site into the coding sequence of exon 3 so that the introns
 between exons I and II and between exons II and III are absent. However,
 the intron between exons III and IV as well as the signals 3' of the
 coding sequence are retained. The resulting minigene can conveniently be
 inserted as a BamHI/BglII segment. Other means for construction of a
 comparable minigene are, of course, possible and the definition is not
 restricted to the particular construction wherein the coding sequences are
 ligated through an XbaI site. However, this is a convenient means for the
 construction of the gene, and there is no particular advantage to other
 approaches, such as synthetic or partially synthetic preparation of the
 gene. The definition includes those coding sequences for the .alpha.
 subunit which retain the intron between exons III and IV, or any other
 intron and preferably no other introns.
 For recombinant production, modified host cells using expression systems
 are used and cultured to produce the desired protein. These terms are used
 herein as follows:
 A "modified" recombinant host cell, i.e., a cell "modified to contain" with
 the recombinant expression systems of the invention, refers to a host cell
 which has been altered to contain this expression system by any convenient
 manner of introducing it, including transfection, viral infection, and so
 forth. "Modified" refers to cells containing this expression system
 whether the system is integrated into the chromosome or is
 extrachromosomal. The "modified" cells may either be stable with respect
 to inclusion of the expression system or not. In short, "modified"
 recombinant host cells with the expression system of the invention refers
 to cells which include this expression system as a result of their
 manipulation to include it, when they natively do not, regardless of the
 manner of effecting this incorporation.
 "Expression system" refers to a DNA molecule which includes a coding
 nucleotide sequence to be expressed and those accompanying control
 sequences necessary to effect the expression of the coding sequence.
 Typically, these controls include a promoter. termination regulating
 sequences, and, in some cases, an operator or other mechanism to regulate
 expression. The control sequences are those which are designed to be
 functional in a particular target recombinant host cell and therefore the
 host cell must be chosen so as to be compatible with the control sequences
 in the constructed expression system.
 If secretion of the protein produced is desired, additional nucleotide
 sequences encoding a signal peptide are also included so as to produce the
 signal peptide operably linked to the desired single-chain hormone to
 produce the preprotein. Upon secretion, the signal peptide is cleaved to
 release the mature single-chain hormone.
 As used herein "cells," "cell cultures," and "cell lines" are used
 interchangeably without particular attention to nuances of meaning. Where
 the distinction between them is important, it will be clear from the
 context. Where any can be meant, all are intended to be included.
 The protein produced may be recovered from the lysate of the cells if
 produced intracellularly, or from the medium if secreted. Techniques for
 recovering recombinant proteins from cell cultures are well understood in
 the art, and these proteins can be purified using known techniques such as
 chromatography, gel electrophoresis, selective precipitation, and the
 like.
 All or a portion of the hormones of the invention may be synthesized
 directly using peptide synthesis techniques known in the art. Synthesized
 portions may be ligated, and release sites for any drug contained in the
 linker moiety introduced by standard chemical means. For those embodiments
 which contain amino acids which are not encoded by the gene and those
 embodiments wherein the head-to-head or tail-to-tail configuration is
 employed, of course, the synthesis must be at least partly at the protein
 level. Head-to-head junctions at the natural N-termini or at positions
 proximal to the natural N-termini may be effected through linkers which
 contain functional groups reactive with amino groups, such as dicarboxylic
 acid derivatives. Tail-to-tail configurations at the C-termini or
 positions proximal to the C-termini may be effected through linkers which
 are diamines, diols, or combinations thereof.
 Antibodies
 The proteins of the invention may be used to generate antibodies
 specifically immunoreactive with these new compounds. These antibodies are
 useful in a variety of diagnostic and therapeutic applications.
 The antibodies are generally prepared using standard immunization protocols
 in mammals such as rabbits, mice, sheep or rats, and the antibodies are
 tittered as polyclonal antisera to assure adequate immunization. The
 polyclonal antisera can then be harvested as such for use in for example,
 immunoassays. Antibody-secreting cells from the host, such as spleen
 cells, or peripheral blood leukocytes, may be immortalized using known
 techniques and screened for production of monoclonal antibodies
 immunospecific with the proteins of the invention.
 By "immunospecific for the proteins" is meant antibodies which are
 immunoreactive with the single-chain proteins, but not with the
 heterodimers per se within the general parameters considered to determine
 affinity or nonaffinity. It is understood that specificity is a relative
 term, and an arbitrary limit could be chosen, such as a difference in
 immunoreactivity of 100-fold or greater. Thus, an immunospecific antibody
 included within the invention is at least 100 times more reactive with the
 single-chain protein than with the corresponding heterodimers.
 By "specifically immunoreactive" is meant that the antibodies react with
 the single chain forms of compounds of the invention and not with other
 molecules, even closely related ones, in measurable degree. Thus, although
 the antibodies of the invention will specifically bind the single chain
 forms, they would bind the corresponding dimer or the individual subunits
 to a significantly lesser degree.
 Formulation
 The proteins of the invention are formulated and administered using methods
 comparable to those known for the heterodimers corresponding to the
 single-chain form. Thus, formulation and administration methods will vary
 according to the particular hormone used. However, the dosage level and
 frequency of administration may be altered as compared to the heterodimer,
 especially if CTP units are present in view of the extended biological
 half life due to its presence.
 Formulations for proteins of the invention are those typical of protein or
 peptide drugs such as found in Remington's Pharmaceutical Sciences, latest
 edition, Mack Publishing Company, Easton, Pa. Generally, proteins are
 administered by injection, typically intravenous, intramuscular,
 subcutaneous, or intraperitoneal injection, or using formulations for
 transmucosal or transdermal delivery. These formulations generally include
 a detergent or penetrant such as bile salts, fusidic acids, and the like.
 These formulations can be administered as aerosols or suppositories or, in
 the case of transdermal administration, in the form of skin patches.
 Oral administration is also possible provided the formulation protects the
 peptides of the invention from degradation in the digestive system.
 Optimization of dosage regimen and formulation is conducted as a routine
 matter and as generally performed in the art.
 These formulations can also be modified to include those suitable for
 veterinary use as is generally known in the art.
 Methods of Use
 The single-chain peptides of the invention may be used in many ways, most
 evidently as substitutes for the heterodimeric forms of the hormones.
 Thus, like the heterodimers, the agonist forms of the single-chain
 hormones of the invention can be used in treatment of infertility, as aids
 in vitro fertilization techniques, and other therapeutic methods
 associated with the native hormones. These techniques are applicable to
 humans as well as to other animals. The choice of the single-chain protein
 in terms of its species derivation will, of course, depend on the subject
 to which the method is applied.
 The single-chain hormones are also useful as reagents in a manner similar
 to the heterodimers.
 In addition, the single-chain hormones of the invention may be used as
 diagnostic tools to detect the presence or absence of antibodies with
 respect to the native proteins in biological samples. They are also useful
 as control reagents in assay kits for assessing the levels of these
 hormones in various samples. Protocols for assessing levels of the
 hormones themselves or of antibodies raised against them are standard
 immunoassay protocols commonly known in the art. Various competitive and
 direct assay methods can be used involving a variety of labeling
 techniques including radio-isotope labeling, fluorescence labeling, enzyme
 labeling and the like.
 The single-chain hormones of the invention are also useful in detecting and
 purifying receptors to which the native hormones bind. Thus, the
 single-chain hormones of the invention may be coupled to solid supports
 and used in affinity chromatographic preparation of receptors or
 antihormone antibodies. The resulting receptors are themselves useful in
 assessing hormone activity for candidate drugs in screening tests for
 therapeutic and reagent candidates.
 Finally, the antibodies uniquely reactive with the single-chain hormones of
 the invention can be used as purification tools for isolation of
 subsequent preparations of these materials. They can also be used to
 monitor levels of the single-chain hormones administered as drugs.
 The following examples are intended to illustrate but not to limit the
 invention.
 Example 1
 Preparation of DNA Encoding CG.beta.-.alpha.
 FIG. 1 shows the construction of an insert for an expression vector wherein
 the C-terminus of the .beta.-chain of human CG is linked to the N-terminus
 of the mature human .alpha. subunit.
 As shown in FIG. 1, the polymerase chain reaction (PCR) is utilized to fuse
 the two subunits between exon 3 of CG.beta. and exon 2 of the .alpha.
 subunit so that the codon for the carboxy terminal amino acid of CG.beta.
 is fused directly in reading frame to that of the N-terminal amino acid of
 the .alpha. subunit. This is accomplished by using a hybrid primer to
 amplify a fragment containing exon 3 of CG.beta. wherein the hybrid primer
 contains a "tail" encoding the N-terminal sequence of the .alpha. subunit.
 The resulting amplified fragment thus contains a portion of exon 2
 encoding human CG.alpha..
 Independently, a hybrid primer encoding the N-terminal sequence of the
 .alpha. subunit fused to the codons corresponding to the C-terminus of
 CG.beta. is used as one of the primers to amplify the .alpha. minigene.
 The two amplified fragments, each now containing overlapping portions
 encoding the other subunit are together amplified with two additional
 primers covering the entire span to obtain the SalI insert.
 In more detail, reaction 1 shows the production of a fragment containing
 exon 3 of CG.beta. and the first four amino acids of the mature .alpha.
 subunit as well as a SalI site 5'-ward of the coding sequences. It is
 obtained by amplifying a portion of the CG.beta. genomic sequence which is
 described by Matzuk, M. M. et al. Proc Natl Acad Sci USA (1987)
 84:6354-6358; Policastro, P. et al. J Biol Chem (1983) 258:11492-11499.
 Primer 1 (SEQ ID NO:41) provides the SalI site and has the sequence:
 5'-GGA GGA AGG GTG GTC GAC CTC TCT GGT-3'.
 SalI
 The other primer, primer 2 (SEQ ID NO:42), is complementary to four codons
 of the a N-terminal sequence and five codons of the CG.beta. C-terminal
 sequence and has the sequence:
 5'-CAC ATC AGG AGC.vertline.TTG TGG GAG GAT CGG-3'.
 .rarw._.alpha..vertline..beta._.fwdarw.
 The resultant amplified segment which is the product of reaction .alpha.
 thus has a SalI site 5'-ward of the fused coding region.
 In reaction II, an analogous fused coding region is obtained from the
 .alpha. minigene described hereinabove. Primer 3 (SEQ ID NO:43) is a
 hybrid primer containing four codons of the .beta. subunit and five codons
 of .alpha. and has the sequence:
 5'-ATC CTC CCA CAA.vertline.GCT CCT GAT GTG CAG-3'.
 .rarw._.beta..vertline..alpha._.fwdarw.
 Primer 4 (SEQ ID NO:44) contains a SalI site and is complementary to the
 extension of .alpha. exon 4. Primer 4 has the sequence:
 5'-TGA GTC GAC ATG ATA ATT CAG TGA TTG AAT-3'.
 SalI
 Thus, the products of reactions I and II overlap, and when subjected to PCR
 in the presence of primers 1 and 4 yield the desired SalI product as shown
 in reaction III.
 The amplified fragment containing CG.beta. exon 3 and the .alpha. minigene
 is inserted into the SalI site of pM.sup.2 HA-CG.beta.exon 1,2 an
 expression vector which is derived from pM.sup.2 containing CG.beta. exons
 1 and 2 in the manner described by Sachais, B., Snider, R. M., Lowe, J.,
 Krause, J. J Biol Chem (1993) 268:2319. pM.sup.2 containing CG.beta. exons
 1 and 2 is described in Matzuk, M. M. et al. Proc Nati Acad USA (1987)
 84:6354-6358 and Matzuk, M. M. et al. J Cell Biol (1988) 106:1049-1059.
 This expression vector then will produce the single-chain form human CG
 wherein the C-terminus of the .beta. subunit is directly linked to the
 N-terminus of the .alpha. subunit.
 Example 2
 Production and Activity of the Single-Chain Human CG
 The expression vector constructed in Example 1 was transfected into Chinese
 hamster ovary (CHO) cells and production of the protein was assessed by
 immunoprecipitation of radiolabeled protein on SDS gels. The culture
 medium was collected and the bioactivity of the single-chain protein was
 compared to the heterodimer in a competitive binding assay with respect to
 the human LH receptor. In this assay, the cDNA encoding the entire human
 LH receptor was inserted into the expression vector pCMX (Oikawa. J. X-C
 et al. Mol Endocrinol (1991) 5:759-768). Exponentially growing 293 cells
 were transfected with this vector using the method of Chen, C. et al. Mol
 Cell Biol (1987) 7:2745-2752.
 In the assay, the cells expressing human LH receptor (2.times.10.sup.5
 /tube) were incubated with 1 ng of labeled hCG in competition with the
 sample to be tested at 220.degree. C. for 18 hours. The samples were then
 diluted 5-fold with cold Dulbecco's PBS (2 ml) supplemented with 0.1% BSA
 and centrifuged at 800.times.g for 15 minutes. The pellets were washed
 twice with D's PBS and radioactivity was determined with a gamma counter.
 Specific binding was 10-12% of the total labeled (iodinated) hCG added in
 the absence of sample. The decrease in label in the presence of sample
 measures the binding ability in the sample. In this assay, with respect to
 the human LH receptor in 293 cells, the wild-type hCG had an ED.sub.50 of
 0.47 ng and the single-chain protein had an ED.sub.50 of 1.1 ng.
 In an additional assay for agonist activity, stimulation of cAMP production
 was assessed. In this case, 293 cells expressing human LH receptors
 (2.times.10.sup.5 /tube) were incubated with varying concentrations of the
 heterodimeric hCG or single-chain hCG and cultured for 18 hours. The
 extracellular cAMP levels were determined by specific radioimmunoassay as
 described by Davoren, J. B. et al. Biol Reprod (1985) 33:37-52. In this
 assay, the wild-type had an ED.sub.50 of 0.6 ng/ml and the single-chain
 form had an ED.sub.50 of 1.7 ng/ml. (ED.sub.50 is 50% of the effective
 dose.)
 Thus, in all cases, the behavior of both the wild-type and single-chain
 forms is similar.
 Example 3
 Additional Activity Assays
 The medium from CHO cells transfected with an expression vector for the
 .beta.FSH-CTP-.alpha. single-chain construct was recovered and assayed as
 described in Example 2. The results of the competition assay for binding
 to FSH receptor are shown in FIG. 3. The results indicate that the
 single-chain form is more effective than either wild-type FSH or FSH
 containing a CTP extension at the .beta. chain in inhibiting binding of
 FSH itself to the receptor. The ED.sub.50 for the single-chain form is
 approximately 50 mIU/ml while the ED.sub.50 for the extended heterodimer
 is somewhat over 100 mIU/ml. That for wild-type FSH is about 120 mIU/ml.
 The results of the signal transduction assay are shown in FIG. 4. The
 effectiveness of all three types of FSH is comparable.
 Example 4
 Construction of Additional Expression Vectors
 In a manner similar to that set forth in Example 1, expression vectors for
 the production of single-stranded FSH, TSH and LH (.beta.FSH-.alpha.,
 .beta.FSH-CTP-.alpha., .beta.TSH-.alpha., .beta.TSH-CTP-.alpha.,
 .beta.LH-.alpha., .beta.LH-CTP-.alpha.) are prepared and transfected into
 CHO cells. The resulting hormones show activities similar to those of the
 wild-type form, when assayed as set forth in Example 2.
 The following documents are cited in the examples set forth below:
 37. Moyle, W. R. et al. J Biol Chem (1975) 250:9163-9169.
 54. Campbell, R. K. et al. Mol Cell Endocrinol (1992) 83:195-200.
 64. Campbell, R. K. et al. Proc Nati Acad Sci USA (1991) 88:760-764.
 65. Skaf, R. et al. Endocrinology (1985) 117:106-113.
 Single chain gonadotropins with lutropin and/or folliotropin activity. The
 single-chain gonadotropins prepared in the following examples and
 additional illustrative gonadotropins are set forth in Table 1. The
 biological activity of these gonadotropins is set fort in Table 2. These
 appear at the end of the specification herein.
 Example 5
 Preparation and Use of Analog #1 (c.f, Table 1) a Single Chain Gonadotropin
 With Lutropin Activity
 See FIG. 5
 The coding sequences for analog #1 listed in Table 1 can be synthesized
 using the block ligation approach described (54) or they can be prepared
 starting with the coding sequences for the hCG .beta.-subunit and the
 human .alpha.-subunit. These can be cloned from a human placental cDNA
 library. The sequences encoding the signal peptide from the human
 .alpha.-subunit are deleted and the coding sequences for the proteins are
 spliced together using the SOEing technique (63) as follows: Primer #1
 (SEQ ID NO:45) (100 ng) having the sequence
 5'-ATGAAATCGACGGAATCAGACTCGAGCCAAGGATGGAGATGTTCCAGGGGCT GCT-3' and primer
 #2 (SEQ ID NO:46) (100 ng) having the sequence
 3'-GGGAGCCTGTGGGGCTAGGAGGGGGTTCCTAGGCCATCGCCTAGACCATCG-5' are mixed with
 the hCG .beta.-subunit cDNA (1 .mu.g) which serves as a template and PCR
 is performed for 25 temperature cycles of 94.degree. C. (30 seconds),
 50.degree. C. (60 seconds), 72.degree. C. (60 seconds) using Pfu DNA
 polymerase purchased from Strategene, LaJolla, Calif. and dioxynucleotide
 triphosphates and PCR buffer as described (63). Primer #3 (SEQ ID NO:47)
 (100 ng) having the sequence
 5'-GGATCCGGTAGCGGATCTGGTAGCGCTCCTGATGTGCAGGATTGCCCA-3' and primer #4 (SEQ
 ID NO:48) (100 ng) having the sequence
 3'-ACGTCATGAACAATAATAGTGTTTAGAATTCCATGGCCTAGGTAGAGTTCGAT TAGGCCT-5' are
 mixed with human .alpha.-subunit cDNA (1 .mu.g) which serves as a template
 and PCR is performed for 25 temperature cycles of 94.degree. C. (30
 seconds), 50.degree. C. (60 seconds), 72.degree. C. (60 seconds) using Pfu
 DNA polymerase and dioxynucleotide triphosphates and PCR buffer as
 described (63). These two PCR reactions give products that serve as
 intermediate templates in a third (final) PCR reaction that gives the
 desired constructs in a form suitable for cloning. The final PCR reaction
 is performed by mixing 1 .mu.l of the products from the first two PCR
 reactions alone with primer #5 (SEQ ID NO:49) having the sequence
 5'-ATGAAATCGACGGAATCAGACTCGAGCCAAGG-3' and primer #6 (SEQ ID NO:50) having
 the sequence 3'-ATTCCATGGCCTAGGTAGAGTTCGATTAGGCCT-5' for 25 temperature
 cycles of 94.degree. C. (30 seconds), 50.degree. C. (60 seconds),
 72.degree. C. (60 seconds) using Pfu DNA polymerase additional
 dioxynucleotide triphosphates, and PCR buffer. The final PCR product is
 digested with restriction enzymes XhoI and BglII and ligated into pSVL (an
 expression vector obtained from Pharmacia, Piscataway, N.J.) that has been
 digested with XhoI and bamHI to create a vector that will direct the
 synthesis of Analog 1. The XhoI site of the PCR product will ligate to the
 XhoI site of pSVL and the BglII site of the PCR product will ligate to the
 BamHI site of pSVL. The XhoI site will be regenerated and the BglII and
 BamHI sites will be eliminated. The sequences of the coding regions (i.e.,
 between the XbaI and KpnI sites, c.f, FIG. 6) of several constructs are
 determined until one is found that encodes a protein having the desired
 amino acid sequence illustrated in FIG. 6. This is done to eliminate the
 possible errors that arise as the result of PCR and other DNA manipulation
 and is a standard precaution to be certain that the desired sequence is
 obtained. The expressed protein is expected to lack amino acid residues
 MEMFQGLLLLLLLSMGGTWA (SEQ ID NO:51) that are the part of the signal
 sequence found in hCG .beta.-subunit and which are removed by the cell
 during protein synthesis. This vector is expressed in COS-7 cells as
 described (64) and the protein released into the medium is tested for its
 ability to inhibit the binding of radiolodinated hCG to monoclonal
 antibodies or to antisera prepared against hCG. The protein made by the
 COS-7 cells will compete with radioiodinated hCG for binding to one or
 more of the following antibodies: B101 (obtained from Columbia
 University), B105 (obtained from Columbia University), B107 (obtained from
 Columbia University), B109 (obtained from Columbia University), A201
 (obtained from Columbia University), HCU061 (obtained from Hybritech),
 HCZ107 (obtained from Hybritech), or HCO514 (obtained from Hybritech),
 ZMCG18 (obtained from Pierce), ZMCGI 3 (obtained from Pierce), or ZMCG7
 (obtained from Pierce) or 518B7 (obtained from Dr. Janet Roser, University
 of California at Davis). The protein released into the medium will compete
 with radiolabeled hCG for binding to receptors on corpora lutea as
 described by Campbell, Dean-Emig, and Moyle (64). It would be expected to
 stimulate testosterone formation in a Leydig cell assay performed similar
 to that described by Moyle et al. (37) and to stimulate ovulation in
 female animals and to stimulate testosterone formation in male mammals.
 This analog would also be expected to be a good starting point for use in
 a contraceptive vaccine using the template approach outlined in Example
 11. This analog is shown in Table 1 as Analog #1 and contains a linker
 sequence of GSGSGSGS (SEQ ID NO:52) . This linker can be modified by
 digesting the expression vector with ApaI and Eco47III endonuclease
 restriction enzymes, discarding the short piece, ligating a cassette of
 synthetic double stranded DNA with the desired amino acid codons
 containing any number of glycine or serine codons or other amino acid
 codons into the ApaI/Eco47III site by standard methods, sequencing the
 region between the ApaI/Eco47III to confirm the desired mutations have
 been made, and expressing the protein in COS-7 cells. This can be done to
 optimize the activity of the single chain gonadotropin. The protein is
 expected to function as a monomer or to combine to form active homodimers.
 In addition, several copies of the protein would be expected to combine to
 form multimers.
 Example 6
 Preparation and Use of Analog #2, a Single Chain Gonadotropin with Lutropin
 Activity
 See FIG. 6
 The coding sequences for Analog #2 listed in Table 1 can be synthesized
 using the block ligation approach described (54) or they can be prepared
 by PCR using primers #1 and #7 and the expression construct described in
 Example 5 and in FIG. 5 as a template. The sequence of primer #7 (SEQ ID
 NO:53) is 3'-TGGTGGGGAACTGGACACTACTGGGCGCCCCTAGGCCATCG-5'. The final PCR
 product is digested with restriction enzymes XhoI and BamHI and ligated
 with the large fragment of DNA obtained by digesting the expression
 construct described in Example 12 with XhoI and BamHI. The sequences of
 the coding regions between the XhoI and BamHI sites of several constructs
 are determined until one is found that encodes a protein having the amino
 acid sequence described in FIG. 7 is obtained. This will insure that
 cloning artifacts are not present in the region that has been altered. The
 expressed protein is expected to lack amino acid residues
 MEMFQGLLLLLLLSMGGTWA (SEQ ID NO:51) that are the part of the signal
 sequence found in hCG .beta.-subunit and which are removed by the cell
 during protein synthesis. This vector is expressed in COS-7 cells and the
 protein released into the medium is tested for its ability to inhibit the
 binding of radioiodinated hCG to monoclonal antibodies or to antisera
 prepared against hCG. The protein made by the COS-7 cells will compete
 with radioiodinated hCG for binding to one or more of the following
 antibodies: B101 (obtained from Columbia University), B105 (obtained from
 Columbia University), B107 (obtained from Columbia University), B109
 (obtained from Columbia University), A201 (obtained from Columbia
 University), HCU061 (obtained from Hybritech), or HCO514 (obtained from
 Hybritech), ZMCG18 (obtained from Pierce), ZMCG13 (obtained from Pierce),
 or ZMCG7 (obtained from Pierce) or 518B7 (obtained from Dr. Janet Roser,
 University of California at Davis). The protein released into the medium
 will compete with radiolabeled hCG for binding to receptors on corpora
 lutea as described by Campbell, Dean-Emig, and Moyle (64). It would be
 expected to stimulate testosterone formation in a Leydig cell assay
 performed similar to that described by Moyle et al. (37) and to stimulate
 ovulation in female animals and to stimulate testosterone formation in
 male mammals. This analog would also be expected to be a good starting
 point for use in a contraceptive vaccine using the template approach
 outlined in Example 11. This analog is shown in Table 1 as Analog #2 and
 contains a linker sequence of GSGSGSGS (SEQ ID NO:52). This linker can be
 modified by digesting the expression vector with SstII and Eco47III
 endonuclease restriction enzymes, discarding the short piece, ligating a
 cassette of synthetic double stranded DNA with the desired amino acid
 codons containing any number of glycine or serine codons or other amino
 acid codons into the SstII/Eco47III site by standard methods sequencing
 the region between the SstII/Eco47III to confirm the desired mutations
 have been made, and expressing the protein in COS-7 cells. This can be
 done to optimize the activity of the single chain gonadotropin. The
 protein is expected to function as a monomer or to combine to form active
 homodimers. In addition, several copies of the protein would be expected
 to combine to form multimers.
 Example 7
 Preparation and Use of Analog #3, a Single Chain Gonadotropin with Lutropin
 Activity
 See FIG. 7
 The coding sequences for analog #3 listed in Table 1 can be synthesized
 using the block ligation approach described (54) or they can be prepared
 in the fashion as described for Analog #2 in Example 6 except that primers
 #1 and #7 are replaced with primers #8 and #9 and that the hLH
 .beta.-subunit cDNA is used as a template in place of the hCG
 .beta.-subunit cDNA. The hLH .beta.-subunit cDNA can be obtained by
 screening a human pituitary library. The sequence of primer #8 (SEQ ID
 NO:54)is 5'-ATGAAATCGACGGAATCAGACTCGAGCCAAGGAATGGAGATGCTCCAGGGGC TGCT-3'
 and the sequence of primer #9 (SEQ ID NO:55) is
 3'-GTGGGGAACTGGACACTGGTGGGGGTTCCTAGGCCATCGCCTAGACCATCG-5'. The final PCR
 product is digested with restriction enzymes XhoI and BamHI and subcloned
 into the XhoI/BamHI sites of the expression vector created as described in
 Example 12. The sequences of the coding regions between the XhoI and BamHI
 sites of several constructs are determined until one is found that encodes
 a protein having the amino acid sequence shown in FIG. 8. The expressed
 protein is expected to lack amino acid residues MEMLQGLLLLLLLSMGGAWA (SEQ
 ID NO:56) that are the part of the signal sequence found in hLH
 .beta.-subunit and which are removed by the cell during protein synthesis.
 This vector is expressed in COS-7 cells and the protein released into the
 medium is tested for its ability to inhibit the binding of radioiodinated
 hCG to monoclonal antibodies or to antisera prepared against hCG. The
 protein made by the COS-7 cells will compete with radioiodinated hCG for
 binding to one or more of the following antibodies: B101 (obtained from
 Columbia University), B105 (obtained from Columbia University), A201
 (obtained from Columbia University), HCU061 (obtained from Hybritech),
 ZMCG7 (obtained from Pierce) or 518B7 (obtained from Dr. Janet Roser,
 University of California at Davis). The protein released into the medium
 will compete with radiolabeled hCG for binding to receptors on corpora
 lutea as described by Campbell, Dean-Emig, and Moyle (64). It would be
 expected to stimulate testosterone formation in a Leydig cell assay
 performed similar to that described by Moyle et al. (37) and to stimulate
 ovulation in female animals and to stimulate testosterone formation in
 male mammals. This analog would also be expected to be a good starting
 point for use in designing vaccines to enhance or inhibit fertility using
 the template procedure outlined earlier. This analog is shown in Table 1
 as Analog #3 and contains a linker sequence of GSGSGSGS (SEQ ID NO:52).
 This linker can be modified by digesting the expression vector with BamHI
 and Eco47III endonuclease restriction enzymes, discarding the short piece,
 ligating a cassette of synthetic double stranded DNA with the desired
 amino acid codons containing any number of glycine or serine codons or
 other amino acid codons into the BamHI/Eco47III site by standard methods,
 sequencing the region between the BamHI/Eco47III to confirm the desired
 mutations have been made, and expressing the protein in COS-7 cells. This
 can be done to optimize the activity of the single chain gonadotropin. The
 protein is expected to function as a monomer or to combine to form active
 homodimers. In addition, several copies of the protein would be expected
 to combine to form multimers.
 Example 8
 Preparation and Use of Analog #4, a Single Chain Gonadotropin with
 Follitropin Activity
 See FIG. 8
 The coding sequences for analog #4 listed in Table 1 can be synthesized
 using the block ligation approach described (54) or they can be prepared
 in the fashion as described for Analog #2 in Example 13 except that
 primers #1 and #7 are replaced with primers #10 and #11 and that the hFSH
 .beta.-subunit cDNA is used as a template in place of the hCG
 .beta.-subunit cDNA. The hFSH .beta.-subunit cDNA can be obtained from a
 human pituitary gland library. The sequence of primer #10 (SEQ ID NO:57)
 is 5'-ATGAAATCGACGGAATCAGACTCGAGCCAAGGATGAAGACACTCCAGTTTTTC TTCC-3' and
 the sequence of primer #11 (SEQ ID NO:58) is
 3'-GACGAGGAAACCACTTTACTTTCTTCCTAGGCCATCGCCTAGACCA-5'. The final PCR
 product is digested with restriction enzymes XhoI and BamHI and subcloned
 into the XhoI/BamHI sites of the expression vector created as described in
 Example 12. The sequences of the coding regions between the XbaI and BamHI
 sites of several constructs are determined until one is found that encodes
 a protein having the amino acid sequence illustrated in FIG. 9. The
 expressed protein is expected to lack amino acid residues
 MKTLQFFFLFCCWKAICC that are the part of the signal sequence found in hFSH
 .beta.-subunit and which are removed by the cell during protein synthesis.
 The vector is expressed in COS-7 cells and the protein made by the cells
 will compete with radioiodinated hFSH for binding to one or more of the
 following antibodies: ZMFS 1 (obtained from Pierce), A201 (obtained from
 Columbia University), HCU061 (obtained from Hybritech), FSG761 (obtained
 from Hybritech), FSR093.3 (obtained from Hybritech), FSH107 (obtained from
 Hybritech), FSB061 (obtained from Hybritech), FSM210 (obtained from
 Hybritech), and FSM268 (obtained from Hybritech). The protein released
 into the medium will compete with hFSH for binding to receptors on bovine
 testes as described by Campbell, Dean-Emig, and Moyle (64). It would be
 expected to stimulate estradiol formation in a granulosa cell assay
 performed similar to that described by Skaf et al (65) and to stimulate
 follicle development and spermatogenesis in female and male mammals. This
 analog is also a useful starting compound to select for an immunogen that
 elicits antibodies to FSH and is part of a contraceptive vaccine. This
 analog is shown in Table 1 as Analog #4 and contains a linker sequence of
 GSGSGSGS (SEQ ID NO:52). This linker can be modified by digesting the
 expression vector with ApaI and Eco47III endonuclease restriction enzymes,
 discarding the short piece, ligating a cassette of synthetic double
 stranded DNA with the desired amino acid codons containing any number of
 glycine or serine codons or other amino acid codons into the
 BamHI/Eco47III site by standard methods, sequencing the region between the
 ApaI/Eco47III to confirm the desired mutations have been made, and
 expressing the protein in COS-7 cells. This can be done to optimize the
 activity of the single chain gonadotropin. The protein is expected to
 function as a monomer or to combine to form active homodimers. In
 addition, several copies of the protein would be expected to combine to
 form multimers.
 Example 9
 Preparation and Use of Analog #5, a Single Chain Gonadotropin with FSH
 Activity That is Structurally More Similar to hCG Than hFSH
 See FIG. 9
 The coding sequences for analog #5 listed in Table 1 can be synthesized
 using the block ligation approach described (54) or they can be prepared
 in the fashion as described for Analog #2 in Example 6 except that primer
 #7 is replaced with primer #12. The sequence of primer #12 (SEQ ID NO:60)
 is 3'-CGACAGTCGACAGTTACACGTGAGACGCTGTCGCTGTCGTGACTAACATGACA
 CGCTCCGGACCCCGGGTCGATGACGAGGAAACCACTTTACTTTCTTCCTAGGC CATCG-5'. The final
 PCR product is digested with restriction enzymes XhoI and BamHI and
 subcloned into the XhoI/BamHI sites of the expression vector created as
 described in Example 12. The sequences of the coding regions between the
 XbaI and BamHI sites of several constructs are determined until one is
 found that encodes a protein having the amino acid sequence illustrated in
 FIG. 10. The expressed protein is expected to lack amino acid residues
 MEMLQGLLLLLLLSMGGAWA (SEQ ID NO:56) that are the part of the signal
 sequence found in hCG .beta.-subunit and which are removed by the cell
 during protein synthesis. This vector is expressed in COS-7 cells and the
 protein released into the medium is tested for its ability to inhibit the
 binding of radioiodinated hCG to monoclonal antibodies or to antisera
 prepared against hCG. The protein made by the COS-7 cells will compete
 with radioiodinated hCG for binding to one or more of the following
 antibodies: B101 (obtained from Columbia University), B105 (obtained from
 Columbia University), B107 (obtained from Columbia University), B109
 (obtained from Columbia University), A201 (obtained from Columbia
 University), HCU061 (obtained from Hybritech), or HCO514 (obtained from
 Hybritech), ZMCG18 (obtained from Pierce), ZMCG13 (obtained from Pierce),
 or ZMCG7 (obtained from Pierce) or 518B7 (obtained from Dr. Janet Roser,
 University of California at Davis). The protein released into the medium
 will compete with hFSH for binding to receptors on bovine testes as
 described by Campbell, Dean-Emig, and Moyle (64). It would be expected to
 stimulate estradiol formation in a granulosa cell assay performed similar
 to that described by Skaf et al (65) and to stimulate follicle development
 and spermatogenesis in female and male mammals. This analog is shown in
 Table 1 as Analog #5 and contains a linker sequence of GSGSGSGS (SEQ ID
 NO:52). This linker can be modified by digesting the expression vector
 with ApaI and Eco47III endonuclease restriction enzymes, discarding the
 short piece, ligating a cassette of synthetic double stranded DNA with the
 desired amino acid codons containing any number of glycine or serine
 codons or other amino acid codons into the BamHI/Eco47III site by standard
 methods, sequencing the region between the ApaI/Eco47III to confirm the
 desired mutations have been made, and expressing the protein in COS-7
 cells. This can be done to optimize the activity of the single chain
 gonadotropin. The protein is expected to function as a monomer or to
 combine to form active homodimers. In addition, several copies of the
 protein would be expected to combine to form multimers.
 Example 10
 Preparation and Use of Analog #6, a Single Chain Gonadotropin with FSH and
 LH Activities That is Structurally More Similar to hCG Than hFSH
 See FIG. 10
 The coding sequences for analog #6 listed in Table 1 can be synthesized
 using the block ligation approach described (54) or they can be prepared
 in the fashion as described for Analog #2 in Example 6 except that primer
 #7 is replaced with primer #l3. The sequence of primer #13 (SEQ ID NO:61)
 is 3'-ACGGCGGCGTCGTGGTGACTGACGTGACACGCTCCGGACCCCGGGTCGATGA
 CGAGGAAACCACTTTACTTTCTTCCTAGGCCATCG-5'. The final PCR product is digested
 with restriction enzymes XhoI and BamHI and subcloned into the XhoI/BamHI
 sites of the expression vector created as described in Example 12. The
 sequences of the coding regions between the XbaI and BamHI sites of
 several constructs are determined until one is found that encodes a
 protein having the amino acid sequence illustrated in FIG. 11. The
 expressed protein is expected to lack amino acid residues
 MEMLQGLLLLLLLSMGGAWA (SEQ ID NO:56) that are the part of the signal
 sequence found in hCG-subunit and which are removed by the cell during
 protein synthesis. This vector is expressed in COS-7 cells and the protein
 released into the medium is tested for its ability to inhibit the binding
 of radioiodinated hCG to monoclonal antibodies or to antisera prepared
 against hCG. The protein made by the COS-7 cells will compete with
 radioiodinated hCG for binding to one or more of the following antibodies:
 B107 (obtained from Columbia University), B105 (obtained from Columbia
 University), B107 (obtained from Columbia University), B109 (obtained from
 Columbia University), A201 (obtained from Columbia University), HCU061
 (obtained from Hybritech), or HCO514 (obtained from Hybritech), ZMCG18
 (obtained from Pierce), ZMCG13 (obtained from Pierce), or ZMCG7 (obtained
 from Pierce) or 518B7 (obtained from Dr. Janet Roser, University of
 California at Davis). The protein released into the medium will compete
 with hFSH for binding to receptors on bovine testes as described by
 Campbell, Dean-Emig, and Moyle (64). It would be expected to stimulate
 estradiol formation in a granulosa cell assay performed similar to that
 described by Skaf et al (65) and to stimulate follicle development and
 spermatogenesis in female and male mammals. The protein released into the
 medium will compete with radiolabeled hCG for binding to receptors on
 corpora lutea as described by Campbell, Dean-Emig, and Moyle (64). It
 would be expected to stimulate testosterone formation in a Leydig cell
 assay performed similar to that described by Moyle et al. (37) and to
 stimulate ovulation in female animals and to stimulate testosterone
 formation in male mammals. This analog is shown in Table 1 as Analog #6
 and contains a linker sequence of GSGSGSGS (SEQ ID NO:52). This linker can
 be modified by digesting the expression vector with ApaI and Eco47III
 endonuclease restriction enzymes, discarding the short piece, ligating a
 cassette of synthetic double stranded DNA with the desired amino acid
 codons containing any number of glycine or serine codons or other amino
 acid codons into the BamHI/Eco47III site by standard methods, sequencing
 the region between the ApaI/Eco47III to confirm the desired mutations have
 been made, and expressing the protein in COS-7 cells. This can be done to
 optimize the activity of the single chain gonadotropin. The protein is
 expected to function as a monomer or to combine to form active homodimers.
 In addition, several copies of the protein would be expected to combine to
 form multimers.
 Example 11
 Preparation and Use of Analog #7, a Single Chain Gonadotropin with FSH and
 LH Activities That is Structurally More Similar to hCG Than hFSH
 The coding sequences for analog 47 listed in Table 1 can be synthesized
 using the block ligation approach described (54) or they can be prepared
 in the fashion as described for Analog #2 in Example 6 except that primer
 #7 is replaced with primer #14. The sequence of primer #14 (SEQ ID NO: 62)
 is 3'-ACGGCGGCGTCGTGGTGACTGACGTGACACGCTCCGGACCCCGGGTCGATGA
 CGAGGAAACCACTTCCTAGGCCATCG-5'. The final PCR product is digested with
 restriction enzymes XhoI and BamHI and subcloned into the XhoI/BamHI sites
 of the expression vector created as described in Example 12. The sequences
 of the coding regions between the XbaI and BamHI sites of several
 constructs are determined until one is found that encodes a protein having
 the amino acid sequence illustrated in FIG. 12. The expressed protein is
 expected to lack amino acid residues MEMLQGLLLLLLLSMGGAWA (SEQ ID NO:56)
 that are the part of the signal sequence found in hCG .beta.-subunit and
 which are removed by the cell during protein synthesis. This vector is
 expressed in COS-7 cells and the protein released into the medium is
 tested for its ability to inhibit the binding of radioiodinated hCG to
 monoclonal antibodies or to antisera prepared against hCG. The protein
 made by the COS-7 cells will compete with radioiodinated hCG for binding
 to one or more of the following antibodies. B101 (obtained from Columbia
 University), B105 (obtained from Columbia University), B107 (obtained from
 Columbia University), B109 (obtained from Columbia University), A201
 (obtained from Columbia University), HCU061 (obtained from Hybritech), or
 HCO514 (obtained from Hybritech), ZMCG18 (obtained from Pierce), ZMCG-13
 (obtained from Pierce), or ZMCG7 (obtained from Pierce) or 518B7 (obtained
 from Dr. Janet Roser, University of California at Davis). The protein
 released into the medium will compete with hFSH for binding to receptors
 on bovine testes as described by Campbell, Dean-Emig, and Moyle (64). It
 would be expected to stimulate estradiol formation in a granulosa cell
 assay performed similar to that described by Skaf et al (65) and to
 stimulate follicle development and spermatogenesis in female and male
 mammals. The protein released into the medium will compete with
 radiolabeled hCG for binding to receptors on corpora lutea as described by
 Campbell, Dean-Emig, and Moyle (64). It would be expected to stimulate
 testosterone formation in a Leydig cell assay performed similar to that
 described by Moyle et al. (37) and to stimulate ovulation in female
 animals and to stimulate testosterone formation in male mammals. This
 analog is shown in Table 1 as Analog #17 and contains a linker sequence of
 GSGSGSGS (SEQ ID NO:52). This linker can be modified by digesting the
 expression vector with ApaI and Eco47III endonuclease restriction enzymes,
 discarding the short piece, ligating a cassette of synthetic double
 stranded DNA with the desired amino acid codons containing any number of
 glycine or serine codons or other amino acid codons into the
 BamHI/Eco47III site by standard methods, sequencing the region between the
 ApaI/Eco47III to confirm the desired mutations have been made, and
 expressing the protein in COS-7 cells. This can be done to optimize the
 activity of the single chain gonadotropin. The protein is expected to
 function as a monomer or to combine to form active homodimers. In
 addition, several copies of the protein would be expected to combine to
 form multimers.
 Example 12
 Preparation and Use of Analog #8, a Single Chain Gonadotropin with FSH and
 LH Activities That is Structurally More Similar to hCG Than hFSH
 See FIG. 12
 The coding sequences for analog #8 listed in Table 1 can be synthesized
 using the block ligation approach described (54) or they can be prepared
 in the fashion as described for Analog #2 in Example 6 except that primer
 #7 is replaced with primer #15. The sequence of primer #15 (SEQ ID NO:63)
 is 3'-ACGGCGGCGTCGTGGTGACTGACGTGACACGCTCCGGACCCCGGGTCGATGA
 CGCTACTGGGCGCCCCTAGGCCATCG-5'. The final PCR product is digested with
 restriction enzymes XhoI and BamHI and subcloned into the XhoI/BamHI sites
 of the expression vector created as described in Example 5. The sequences
 of the coding regions between the XbaI and BamHI sites of several
 constructs are determined until one is found that encodes a protein having
 the amino acid sequence illustrated in FIG. 6. The expressed protein is
 expected to lack amino acid residues MEMLQGLLLLLLLSMGGAWA (SEQ ID NO:56)
 that are the part of the signal sequence found in hCG .beta.-subunit and
 which are removed by the cell during protein synthesis. This vector is
 expressed in COS-7 cells and the protein released into the medium is
 tested for its ability to inhibit the binding of radioiodinated hCG to
 monoclonal antibodies or to antisera prepared against hCG. The protein
 made by the COS-7 cells will compete with radioiodinated hCG for binding
 to one or more of the following antibodies. B1010 (obtained from Columbia
 University), B105 (obtained from Columbia University), B107 (obtained from
 Columbia University), B109 (obtained from Columbia University), A201
 (obtained from Columbia University), HCU061 (obtained from Hybritech), or
 HCO514 (obtained from Hybritech), ZMCG18 (obtained from Pierce), ZMCG13
 (obtained from Pierce), or ZMCG7 (obtained from Pierce) or 518B7 (obtained
 from Dr. Janet Roser, University of California at Davis). The protein
 released into the medium will compete with hFSH for binding to receptors
 on bovine testes as described by Campbell, Dean-Emig, and Moyle (64). It
 would be expected to stimulate estradiol formation in a granulosa cell
 assay performed similar to that described by Skaf et al (65) and to
 stimulate follicle development and spermatogenesis in female and male
 mammals. The protein released into the medium will compete with
 radiolabeled hCG for binding to receptors on corpora lutea as described by
 Campbell, Dean-Emig, and Moyle (64). It would be expected to stimulate
 testosterone formation in a Leydig cell assay performed similar to that
 described by Moyle et al. (37) and to stimulate ovulation in female
 animals and to stimulate testosterone formation in male mammals. This
 analog is shown in Table 1 as Analog #8 and contains a linker sequence of
 GSGSGSGS (SEQ ID NO:52). This linker can be modified by digesting the
 expression vector with ApaI and Eco47III endonuclease restriction enzymes,
 discarding the short piece, ligating a cassette of synthetic double
 stranded DNA with the desired amino acid codons containing any number of
 glycine or serine codons or other amino acid codons into the
 BamHI/Eco47III site by standard methods, sequencing the region between the
 ApaI/Eco47III to confirm the desired mutations have been made, and
 expressing the protein in COS-7 cells. This can be done to optimize the
 activity of the single chain gonadotropin. The protein is expected to
 function as a monomer or to combine to form active homodimers. In
 addition, several copies of the protein would be expected to combine to
 form multimers.
 Example 13
 Preparation and Use of Analog #9, a Single Chain Gonadotropin with
 Follitropin Activity
 See FIG. 13
 The coding sequences for analog #9 listed in Table 1 can be synthesized
 using the block ligation approach described (54) or they can be prepared
 by digesting the construct described in Example 8 used to express Analog 4
 with the restriction enzymes ApaI and BamHI. The small piece is replaced
 with a cassette of synthetic DNA to give the sequence illustrated in FIG.
 13. The coding sequence between the ApaI and BamHI sites of several
 constructs is determined until one is found that encodes a protein having
 the amino acid sequence illustrated in FIG. 13. The expressed protein is
 expected to lack amino acid residues MKTLQFFFLFCCWKAICC (SEQ ID NO:59)
 that are the part of the signal sequence found in hFSH .beta.-subunit and
 which are removed by the cell during protein synthesis. The vector is
 expressed in COS-7 cells and the protein made by the cells will compete
 with radioiodinated hFSH for binding to one or more of the following
 antibodies ZMFS1 (obtained from Pierce), A201 (obtained from Columbia
 University). HCU061 (obtained from Hybritech), FSG761 (obtained from
 Hybritech), FSR093.3 (obtained from Hybritech), FSH107 (obtained from
 Hybritech), FSB061 (obtained from Hybritech), FSM210 (obtained from
 Hybritech), and FSM268 (obtained from Hybritech). The protein released
 into the medium will compete with hFSH for binding to receptors on bovine
 testes as described by Campbell, Dean-Emig, and Moyle (64). It would be
 expected to stimulate estradiol formation in a granulosa cell assay
 performed similar to that described by Skaf et al (65) and to stimulate
 follicle development and spermatogenesis in female and male mammals. This
 analog is also a useful starting compound to select for an immunogen that
 elicits antibodies to FSH and is part of a contraceptive vaccine. This
 analog is shown in Table 1 as Analog #9 and contains a linker sequence of
 GSGSGSGS (SEQ ID NO:52). This linker can be modified by digesting the
 expression vector with ApaI and Eco47III endonuclease restriction enzymes,
 discarding the short piece, ligating a cassette of synthetic double
 stranded DNA with the desired amino acid codons containing any number of
 glycine or serine codons or other amino acid codons into the
 BamHI/Eco47III site by standard methods, sequencing the region between the
 ApaI/Eco47III to confirm the desired mutations have been made, and
 expressing the protein in COS-7 cells. This can be done to optimize the
 activity of the single chain gonadotropin. The protein is expected to
 function as a monomer or to combine to form active homodimers. In
 addition, several copies of the protein would be expected to combine to
 form multimers.
 Example 14
 Preparation and Use of Analog #10, a Single Chain Gonadotropin with
 Follitropin Activity
 See FIG. 14
 The coding sequences for Analog #10 listed in Table 1 can be synthesized
 using the block ligation approach described (54) or they can be prepared
 by digesting the construct described in Example 8 used to express Analog 4
 with the restriction enzymes ApaI and BamHI. The small piece is replaced
 with a cassette of synthetic DNA to give the sequence illustrated in FIG.
 14. The coding sequence between the ApaI and BamHI sites of several
 constructs is determined until one is found that encodes a protein having
 the amino acid sequence illustrated in FIG. 14. The expressed protein is
 expected to lack amino acid residues MKTLQFFFLFCCWKAICC (SEQ ID NO:59)
 that are the part of the signal sequence found in hFSH .beta.-subunit and
 which are removed by the cell during protein synthesis. The vector is
 expressed in COS-7 cells and the protein made by the cells will compete
 with radioiodinated hFSH for binding to one or more of the following
 antibodies: ZMFS1 (obtained from Pierce), A201 (obtained from Columbia
 University), HCU061 (obtained from Hybritech), FSG761 (obtained from
 Hybritech), FSR093.3 (obtained from Hybritech), FSH 107 (obtained from
 Hybritech), FSB061 (obtained from Hybritech), FSM210 (obtained from
 Hybritech), and FSM268 (obtained from Hybritech). The protein released
 into the medium will compete with hFSH for binding to receptors on bovine
 testes as described by Campbell, Dean-Emig, and Moyle (64). It would be
 expected to stimulate estradiol formation in a granulosa cell assay
 performed similar to that described by Skaf et al (65) and to stimulate
 follicle development and spermatogenesis in female and male mammals. This
 analog is also a useful starting compound to select for an immunogen that
 elicits antibodies to FSH and is part of a contraceptive vaccine. This
 analog is shown in Table 1 as Analog #10 and contains a linker sequence of
 GSGSGSGS (SEQ ID NO:52). This linker can be modified by digesting the
 expression vector with ApaI and Eco47III endonuclease restriction enzymes,
 discarding the short piece, ligating a cassette of synthetic double
 stranded DNA with the desired amino acid codons containing any number of
 glycine or serine codons or other amino acid codons into the
 BamHI/Eco47III site by standard methods, sequencing the region between the
 ApaI/Eco47III to confirm the desired mutations have been made, and
 expressing the protein in COS-7 cells. This can be done to optimize the
 activity of the single chain gonadotropin. The protein is expected to
 function as a monomer or to combine to form active homodimers. In
 addition, several copies of the protein would be expected to combine to
 form multimers.
 Example 15
 Preparation of an .alpha.-subunit Analog Lacking Glycosylation Sites
 See FIG. 15
 Analogs1-10 are expected to contain 4 asparagine-linked oligosaccharides
 since they contain 4 sets of codons for the sequence
 Asparagine-X-Threonine/Serine where X is any amino acid except proline.
 Removal of the asparagine-linked oligosaccharides, particularly those of
 the .alpha.-subunit, has been shown to reduce hormone efficacy. The
 asparagine-linked glycosylation signals can be removed from the
 .alpha.-subunit portion of the single chain gonadotropins using PCR as
 described here. PCR primer 16 (SEQ ID NO:64) having the sequence:
 5'-TGCTTCTCTAGAGCATATCCCACTCCACTAAGGTCCAAGAAGACGATGTTGGT
 CCAAAAGCAAGTCACCT-3' and PCR primer 17 (SEQ ID NO:65) having the
 sequence:3'-CAAAGTTTCACCTCGTTGTGTGCCGCACGGTGACGTCATGAACAATAATAGTG
 TTTAGAATTCCATGGCCATG-5' are used in a PCR reaction with a the vector that
 is capable of directing the expression of Analog1 and that was described
 in Example 5 and FIG. 5. After 25 cycles in the conditions described in
 Example 5, the PCR product and the expression vector are digested with
 XbaI and KpnI. The small fragment produced by digestion of the vector is
 discarded and the digested PCR product is ligated into the vector in its
 place. This produces an expression vector that encodes Analog 11, an
 analog that contains only 2 Asn-linked glycosylation signals but that is
 expected to retain its affinity for antibodies and antisera that bind to
 hCG. It is also expected to retain its affinity for LH receptors as shown
 by its ability to compete with hCG for binding to membranes from rat
 corpora lutea. However, it is expected to have a reduced ability to induce
 signal transduction, especially when its ability to elicit cyclic AMP
 accumulation is tested (37). It is possible to create similar derivatives
 of Analogs 2-10 in which the oligosaccharides are removed from the portion
 of the protein derived from the .alpha.-subunit by digesting each of the
 expression vectors with BamHI and KpnI, discarding the smaller piece, and
 ligating the small BamHI/KpnI fragment obtained by digestion of Analog 1I.
 Thus, Analog 2 would become Analog 12, Analog 3 would become Analog 13,
 Analog 4 would become Analog 14, Analog 5 would become Analog 15, Analog 6
 would become Analog 16, Analog 7 would become Analog 17, Analog 8 would
 become Analog 18, Analog 9 would become Analog 19, and Analog 10 would
 become Analog 20. Note that it would also be possible to remove only one
 of the two glycosylation signals on the portion of the single chain
 gonadotropins derived from the .alpha.-subunit simply by changing the
 sequences of primers 16 and, 17 during their synthesis and following the
 protocol outlined here. Each of these analogs would exhibit the same
 antibody and receptor binding as their precursors. They would have reduced
 efficacy and as a consequence, they would inhibit signal transduction.
 Analogs 11, 12, and 13 would reduce the activity of LH and would stimulate
 fertility when given in the early part of the follicular phase of the
 menstrual cycle. They would reduce the activity of hCG and would prevent
 fertility when administered near the time of expected menses.
 Example 16
 Preparation of Analog1a Lacking Asparagine-linked Oligosaccharides
 See FIGS. 16 and 17
 The efficacy of gonadotropins is proportional to their content of
 carbohydrates and while Analogs 11, 12, 13 14, 15, 16, 17, 18, 19, and 20
 have lower efficacy, it is possible to reduce their efficacy further by
 eliminating all oligosaccharide chains. The asparagine-linked
 oligosaccharide chains can be eliminated from Analog 11 by PCR SOEing (63)
 using primers 1 and 18 in one reaction and primers 2 and 19 in a second
 reaction. The expression vector for Analog 11 serves as a template in both
 reactions. The sequence of primer #18 (SEQ ID NO:66) is
 5'-CGGGGTAGGTTCGGTGGGACCGACACCTCTTCCTCCCGACGGGG-3' and the sequence of
 primer #19 (SEQ ID NO:67) is
 3'-GTGGAGAAGGAGGGCTGCCCCGTGTGCATCACCGTCAACACCACCATC-5'. After 25
 temperature cycles at 94.degree. C. (30 sec), 55.degree. C. (60 sec), and
 72.degree. C. (60 sec), each PCR reaction is mixed with primer #5 and
 additional primer #2, new buffer, enzyme, and deoxynucleotide
 triphosphates. The reaction product after 25 additional cycles is cut with
 XhoI and BamHI and substituted for the original DNA found between the
 XhoI/BamHI sites of the vector encoding Analog 11. This is accomplished by
 digesting the vector with XhoI and BamHI, discarding the small fragment
 and then ligating the large fragment with the XhoI/BamHI digested PCR
 product. Several clones are subjected to DNA sequencing until the one
 encoding the analog outlined in FIG. 18 termed Analog 1a is obtained. When
 this is expressed in COS-7 cells, the protein that is made will be
 recognized by the same antibodies and antisera as Analog 1. Analog 1a will
 also bind to lutropin receptors but will have reduced efficacy relative to
 hCG. Thus, it will be useful for reducing the function of LH or hCG. When
 administered early in the follicular phase of the menstrual cycle, Analog
 1a will reduce androgen synthesis. As a consequence. estradiol synthesis
 will decline, FSH levels will rise and fertility will be stimulated.
 Analog, 1a will also be useful for inhibiting premature luteinization of
 the follicle. When administered in the luteal phase at about the time of
 expected menses, the analog will block the actions of hCG and serve as a
 menses inducer and an inhibitor of fertility.
 Analog 1a will also serve as a good starting compound to design vaccines
 using the template strategy described earlier.
 Example 17
 Preparation of Other Gonadotropins Lacking Asparagine-linked
 Oligosaccharides
 The coding vectors for Analogs 2a, 5a, 6a, 7a, and 8a are readily prepared
 from Analog 1a and Analogs 12, 15, 16, 17, and 18. Analog 1a is digested
 with KpnI and MstII and the small fragment discarded. The large fragment
 is ligated separately to the small fragment prepared by KpnI-MstII
 digestion of the coding vectors for Analogs 12, 15, 16, 17, and 18.
 Analogs 2a, 5a, 6a, 7a, and 8a will bind the same antibodies and receptors
 as Analogs 2, 5, 6, 7, and 8, respectively. However, their abilities to
 elicit signal transduction will be reduced. Consequently, they will serve
 as inhibitors. Analog 2a will be effective primarily in blocking binding
 of hormones to LH receptors. Depending on the time that it is
 administered, Analog 2a will elicit fertility (i.e., when given early in
 the menstrual cycle) or will inhibit fertility (i.e., when given near the
 time of implantation or expected menses). In this regard Analogs 1a and 2a
 will have similar activities. Analog 5a will be effective primarily in
 blocking binding of hormones to FSH receptors. Analog 5a will be useful
 for suppressing hyperovarian stimulation. Analogs 6a, 7a, and 8a will be
 inhibitors of binding to LH and FSH receptors. These will be useful for
 suppressing hyperovarian stimulation and for blocking premature
 luteinization.
 The coding vectors for Analogs 3a and 4a can be made by SOEing PCR (63) in
 which Analogs 13 and 14 serve as templates. The strategy for design of the
 primers is similar as that described for the preparation of primers used
 to modify the expression vector for Analog 1a. When Analogs 3a and 4a are
 expressed in COS-7 cells, the proteins that are made will be recognized by
 the same antibodies and antisera as Analogs 3 and 4, respectively. Analog
 3a will be useful for inhibiting the activity of hormones that bind to LH
 receptors. As such it will stimulate fertility when given early in the
 follicular phase. Analog 4a will be useful for inhibiting the activity of
 FSH. Analog 3a will be useful as a starting molecule for designing the
 vaccine to be used to increase fertility using the template strategy and
 antibodies that are able to partially neutralize the activity of LH.
 Analog 3a will also be useful as a starting molecule for designing the
 vaccine to prevent fertility using the template strategy and antibodies
 that are able to neutralize LH activity. Antibody 4a will also be useful
 as a starting molecule for designing the anti-FSH vaccine described
 earlier using the template strategy.
 The coding vectors for Analogs 9a and 10a can be prepared from the coding
 vector for Analog 4a. The coding vector for Analog 4a is digested with
 BalI and KpnI and the small fragment discarded. The small BalI-KpnI
 fragments from the coding vectors for analogs 19 and 20 are ligated
 separately with the large Analog 4a fragment to produce coding vectors for
 Analogs 9a and 10a. When produced in COS-7 cells, Analogs 9a and 10a will
 have similar antibody and FSH receptor binding specificities as Analogs 9
 and 10. Analogs 9a and 10a will have lower efficacy and will inhibit the
 activity of FSH. Thus, they will be useful for reducing ovarian
 hyperstimulation. They will also be useful starting vectors for the design
 of anti-FSH vaccines using the template strategy.
 Example 18
 Typical Procedure for Introducing a Glycosylation Site in a Gonadotropin
 Due to the positive influence of oligosaccharide residues on the stability
 of hormones in circulation, it is often useful to add extra
 oligosaccharide chains to the proteins. Addition of oligosaccharides can
 also be used to prevent unwanted antibody or receptor interactions.
 Surfaces of the protein that do not interact with receptors are useful
 places to add oligosaccharide chains that are to be used to stimulate
 hormone function. This can have a valuable effect in modulating the
 activities of single chain glycoprotein hormones or of modulating the
 activities of the A,.beta.-heterodimeric glycoprotein hormones. For
 example, addition of a glycosylation signal to FSH .beta.-subunit at
 residues 71-73 to cause the creation of an asparagine-linked
 oligosaccharide at residue 71 will lead to a hormone that has higher
 activity. Conversely, addition of a glycosylation residue in this region
 of the protein after the other glycosylations have been removed will
 enhance its inhibitory activity. Methods for performing the mutagenesis
 are standard in the art and range from total synthesis of the coding
 sequences by block ligation of synthetic oligonucleotides (54) to SOEing
 PCR (63). Several examples of mutagenesis by SOEing PCR have already been
 given.
 Example 19
 Use of Sequences Other Than Those Derived From Human Subunits
 Analogs 1-20, Analogs1b-10b and, in particular, Analogs 1A-10a will serve
 as useful starting compounds for template directed vaccine design. For
 development of hormone-specific vaccines for use in humans, it is useful
 to make analogs similar to those listed in Table 1 with a nonhuman
 .alpha.-subunit in place of the human .alpha.-subunit. This is because the
 bovine .alpha.-subunit renders the proteins more dissimilar to the human
 hormones than the analogs listed in Table 1. The approach to designing
 single chain glycoprotein hormones is similar to that listed in Examples
 12-21 except that the coding sequences for the nonhuman .alpha.-subunits
 are substituted for the human .alpha.-subunit sequences illustrated.
 Similarly, the glycosylation signals can be removed by altering the codons
 for asparagine or serine or threonine or inserting a proline between
 asparagine and the serine or threonine.
 In addition, when using the template strategy to design immunogens it is
 often desirable to start with a nonhuman molecule that has little, if any
 affinity for the templates used in positive selection and to introduce
 residues that will result in selection. These analogs can be prepared by
 substituting the FSH, LH, or TSH .beta.-subunit sequences from nonhuman
 sources in place of the human FSH, LH, and hCG sequences illustrated in
 Examples 5-18 and Table 1.
 TABLE 1
 Structures of Single Chain Gonadotropins
 Analog Composition
 1 n-hCG.beta.(1-145)-Linker-human.alpha.(1-92)-c
 2 n-hCG.beta.(1-114)-Linker-human.alpha.(1-92)-c
 3 n-hLH.beta.(1-114)-Linker-human.alpha.(1-92)-c
 4 n-hFSH.beta.(1-111)-Linker-human.alpha.(1-92)-c
 5 n-hCG.beta.(1-93 )-hFSH.beta.(88-111)-Linker-human.alpha.(1-92)-c
 6 n-hCG.beta.(1-100)-hFSH.beta.(95-111)-Linker-human.alpha.(1-92)-c
 7 n-hCG.beta.(1-100)-hFSH.beta.(95-108)-Linker-human.alpha.(1-92)-c
 8
 n-hCG.beta.(1-100)-hFSH.beta.(95-103)-DDPR-Linker-human.alpha.(1-92)-c
 9 n-hFSH.beta.(1-108)-Linker-human.alpha.(1-92)-c
 10 n-hFSH.beta.(1-104)-Linker-human.alpha.(1-92)-c
 1a
 n-hCG.beta.(1-145)[N13X,N30X]-Linker-human.alpha.(1-92)[N52X,N78X]-c
 2a
 n-hCG.beta.(1-114)[N13X,N30X]-Linker-human.alpha.(1-92)[N52X,N78X]-c
 3a n-hLH.beta.(1-114)[N30X]-Linker-human.alpha.(1-92)[N52X,N78X]-c
 4a
 n-hFSH.beta.(1-111)[N7X,N24X]-Linker-human.alpha.(1-92)[N52X,N78X]-c
 5a
 n-hCG.beta.(1-93)[N13X,N30X]-hFSH.beta.(88-111)-Linker-human.alpha.(1-92)[
 N52X,N78X]-c
 6a
 n-hCG.beta.(1-100)[N13X,N30X]-hFSH.beta.(95-111)-Linker-human.alpha.(1-92)
 [N52X,N78X]-c
 7a
 n-hCG.beta.(1-100)[N13X,N30X]-hFSH.beta.(95-108)-Linker-human.alpha.(1-92)
 [N52X,N78X]-c
 8a
 n-hCG.beta.(1-100)[N13X,N30X]-hFSH.beta.(95-103)-DDPR-Linker-human.alpha.(
 1-92)[N52X,N78X]-c
 9a n-hFSH.beta.(1-108)-Linker-human.alpha.(1-92)-[N52X,N78X]-c
 10a n-hFSH.beta.(1-104)[N7X,N24X]-Linker-human.alpha.(1-92)-c
 1b
 n-hCG.beta.(1-145)[N13X,N30X,P78X,V79T]-Linker-human.alpha.(1-92)[N52X,N78
 X]-c
 2b
 n-hCG.beta.(1-114)[N13X,N30X,P78X,V79T]-Linker-human.alpha.(1-92)[N52X,N78
 X]-c
 3b
 n-hLH.beta.(1-114)[N30X,P78X,V79T]-Linker-human.alpha.(1-92)[N52X,N78X]-c
 4b
 n-hFSH.beta.(1-111)[N7X,N24X,D71N,L73T]-Linker-human.alpha.(1-92)[N52X,N78
 X]-c
 5b
 n-hCG.beta.(1-93)[N13X,N30X,P78X,V79T]-hFSH.beta.(88-111)-Linker-human.alp
 ha.(1-92)[N52X,N78X]-c
 6b
 n-hCG.beta.(1-100)[N13X,N30X,P78X,V79T]-hFSH.beta.(95-111)-Linker-human.al
 pha.(1-92)[N52X,N78X]-c
 7b
 n-hCG.beta.(1-100)[N13X,N30X,P78X,V79T]-hFSH.beta.(95-108)-Linker-human.al
 pha.(1-92)[N52X,N78X]-c
 8b
 n-hCG.beta.(1-100)[N13X,N30X,P78X,V79T]-hFSH.beta.(95-103)-DDPR-Linker-hum
 an.alpha.(1-
 92)[N52X,N78X]-c
 9b
 n-hFSH.beta.(1-108)[N7X,N24X,D71N,L73T]-Linker-human.alpha.(1-92)-[N52X,N7
 8X]-c
 10b
 n-hFSH.beta.(1-104)[N7X,N24X,D71N,L73T]-Linker-human.alpha.(1-92)-[N52X,N7
 8X]-c
 Definitions of the Letters and Sequences in Table 1
 "n-" refers to the N-terminus of the protein.
 "-c" refers to the C-terminus of the protein.
 "hCG.beta.(1-145)" refers to the hCG .beta.-subunit amino acid sequence
 residues 1-145:
 SKEPLRPRCRPfNATLAVEKEGCPVCITVNTTICAGYCPTMTRVLQGVLPA
 LPQVVCNYRDVRFESIRLPGCPRGVNPVVSYAVALSCQCALCRRSTTDCGGPKD
 HPLTCDDPRFQDSSSSKAPPPSLPSPSRLPGPSDTPILPO (SEQ ID NO:68)
 "hCG.beta.(1-114)" refers to the hCG .beta.-subunit amino acid sequence
 residues 1-114:
 SKEPLRPRCRPINATLAVEKEGCPVCITVNTTICAGYCPTMTRVLQGVLPA
 LPQVVCNYRDVRFESIRLPGCPRGVNPVVSYAVALSCQCALCRRSTTDCGGPKD HPLTCDDPR (SEQ ID
 NO:69)
 "hCG.beta.(1-93)" refers to the hCG .beta.-subunit amino acid sequence
 residues 1-93:
 SKEPLRPRCRPINATLAVEKEGCPVCITVNTTICAGYCPTMTRVLQGVLPA
 LPQVVCNYRDVRFESIRLPGCPRGVNPVVSYAVALSCQCALC (SEQ ID NO:70)
 "hLH.beta.(1-114)" refers to the hLH .beta.-subunit amino acid sequence
 residues 1-114:
 SREPLRPWCHPINAILAVEKEGCPVCITVNTTICAGYCPTMMRVLQAVLPP
 LPQVVCTYRDVRFESIRLPGCPRGVDPVVSFPVALSCRCGPCRRSTSDCGGPKDH PLTCDRPQ (SEQ ID
 NO:71)
 "hFSH.beta.(1-111)" refers to the hFSH .beta.-subunit amino acid sequence
 residues 1-111:
 NSCELTNITIAVEKEGCGFCITINTTWCAGYCYTRDLVYKDPKIQKTC
 TFKELVYETVRVPGCAHHADSLYTYPVATQCHCGKCDSDSTDCTVRGLGPSYCS FGEMKE (SEQ ID
 NO:72)
 "hFSH.beta.(1-108)" refers to the hFSH .beta.-subunit amino acid sequence
 residues 1-108:
 NSCELTNITIAVEKEGCGFCITINTTWCAGYCYTRDLVYKDPKIQKTC
 TFKELVYETVRVPGCAHHADSLYTYPVATQCHCGKCDSDSTDCTVRGLGPSYCS FGE (SEQ ID NO:73)
 "hFSH.beta.(1-104)" refers to the hFSH .beta.-subunit amino acid sequence
 residues 1-104:
 NSCELTNITIAVEKEGCGFCITfNTTWCAGYCYTRDLVYKDPKIQKTC
 TFKELVYETVRVPGCAHHADSLYTYPVATQCHCGKCDSDSTDCTVRGLGPSYC (SEQ ID NO:7)
 "hFSH.beta.(88-111)" refers to the hFSH .beta.-subunit amino acid sequence
 residues 88-111:
 DSDSTDCTVRGLGPSYCSFGEMKE (SEQ ID NO:75)
 "hFSH.beta.(95-111)" refers to the hFSH .beta.-subunit amino acid sequence
 residues 95-111:
 TVRGLGPSYCSFGEMKE (SEQ ID NO:76)
 "hFSH.beta.(95-108)" refers to the hFSH .beta.subunit amino acid sequence
 residues 95-108:
 TVRGLGPSYCSFGE (SEQ ID NO:77)
 "hFSH.beta.(95-103)" refers to the hFSH .beta.-subunit amino acid sequence
 residues 95-103:
 TVRGLGPSY (SEQ ID NO:78)
 "N13X" refers to the substitution of glutamine or other amino acid for hCG
 .beta.-subunit residue asparagine 13 and analogs
 "N30X" refers to the substitution of glutamine or other amino acid for hCG
 or hLH .beta.-subunit residue asparagine 30 and analogs
 "N52X" refers to the substitution of glutamine or other amino acid for
 human .alpha.-subunit residue asparagine 52 and analogs
 "N78X" refers to the substitution of glutamine or other amino acid for
 human .alpha.-subunit residue asparagine 78 and analogs
 "P78X" refers to the substitution of any amino acid except proline for
 proline 78 in the .beta.-subunits of hCG or hLH and analogs
 "V79T" refers to the substitution of threonine or serine for valine 79 in
 hCG or hLH .beta.-subunit and analogs
 "D71 IN" refers to the substitution of asparagine for aspartic acid 71 in
 hFSH .beta.-subunits and analogs
 "L73T" refers to the substitution of threonine or serine for leucine 73 in
 hFSH .beta.-subunits and analogs
 "human.alpha.(1-92)" refers to the human .alpha.-subunit sequence residues
 1-92
 APDVQDCPECTLQENPFFSQPGAPILQCMGCCFSRAYPTPLRSKKTMLVQK
 NVTSESTCCVAKSYNRVTVMGGFKVENHTACHCSTCYYHKS (SEQ ID NO:79)
 "Linker" refers to a sequence containing repeating glycine and serine amino
 acids such as GS, GSGS (SEQ ID NO:80), GSGSGS (SEQ ID NO:81), GSGSGSGS
 (SEQ ID NO:52), GSGSGSGSGS (SEQ ID NO:82) or any other sequence of amino
 acids that permits the .beta.- and .alpha.-subunit sequences of the single
 chain gonadotropin to form a complex in which the .alpha.- and
 .beta.-subunit portions combine with the .beta.- and .alpha.-subunit
 portions of the same or other molecule.
 "DDPR (SEQ ID NO:83) " refers to the amino acid sequence
 Asparagine-Asparagine-Proline-Arginine.
 Notes for Table 1
 1. The order of the components from left to right in the table is the order
 in which the components occur in the protein from the amino-terminus to
 the carboxy-terminus.
 2. Due to the high conservation of sequence in all vertebrate gonadotropins
 that can be seen from the alignment of their cysteine residues, single
 chain gonadotropins can be prepared by substitution of any homologous
 residues for the corresponding portions of the hCG, hLH, and hFSH
 .beta.-subunits.
 3. The sequence of the other vertebrate gonadotropin .alpha.-subunits can
 be substituted for humanA(1-92). This includes but is not limited to
 bovine .alpha.-subunit residues 1-96.
 4. As shown, the order of the components has the sequences derived from the
 .beta.-subunit amino-terminal of the sequences derived from the
 .alpha.-subunit. The order of the components in the table can be reversed
 such that the .alpha.-subunit sequences are amino-terminal of the
 .beta.-subunit sequences.
 5. The amino acid sequences are shown in the standard single letter code
 except as noted.
 6. Coding sequences for all these analogs can be made by standard
 recombinant DNA methods that are well known in the art. One procedure for
 making these is that provided by Campbell et al. (54). They can be
 expressed in eukaryotic cells by methods well known in the art using
 vectors that have been designed for eukaryotic expression and that are
 available from InVitrogen, San Diego, Calif. Those that do not contain
 oligosaccharide chains can also be made in E. coli by methods well known
 in the art using vectors such as the pET vectors that can be obtained from
 Novagen.
 7. The glycosylation sites at hCG .beta.-subunit asparagines 13 and/or 30
 can be destroyed by substitution of the asparagine as illustrated and/or
 by substitution of residues 14 and/or 31 with a proline and/or by
 substitution of residues 15 and/or 32 with any other amino acid other than
 serine or threonine.
 8. The glycosylation site at hLH .beta.-subunit asparagine 30 can be
 destroyed by substitution of the asparagine as illustrated and/or by
 substitution of residue 31 with a proline and/or by substitution of
 residue 32 with any other amino acid other than serine or threonine.
 9. The glycosylation sites at human .alpha.-subunit asparagines 52 and/or
 78 can be destroyed by substitution of the asparagine as illustrated
 and/or by substitution of residues 53 and/or 79 with a proline and/or by
 substitution of residues 54 and/or 80 with any other amino acid other than
 serine or threonine.
 10. The glycosylation sites at nonhuman .alpha.-subunit asparagines 56
 and/or 82 can be destroyed by substitution of the asparagine with any
 other amino acid and/or by substitution of residues 57 and/or 83 with a
 proline and/or by substitution of residues 58 and/or 84 with any other
 amino acid other than serine or threonine.
 TABLE 2
 Properties and uses of the analogs illustrated in Table 1
 Analog Activity Use
 1 LH Induce ovulation; Increase male fertility
 2 LH Induce ovulation; Increase male fertility
 3 LH Induce ovulation; Increase male fertility
 4 FSH Induce follicle development; Increase male
 fertility
 5 FSH Induce follicle development; Increase male
 fertility
 6 FSH and LH Induce follicle development; Increase male
 fertility
 7 FSH and LH Induce follicle development; Increase male
 fertility
 8 FSH and LH Induce follicle development; Increase male
 fertility
 9 FSH Induce follicle development; Increase male
 fertility
 10 FSH Induce follicle development; Increase male
 fertility
 1a Anti-LH *Facilitate ovulation; Terminate pregnancy;
 Reduce androgen secretion
 2a Anti-LR *Facilitate ovulation; Terminate pregnancy;
 Reduce androgen secretion
 3a Anti-LH *Facilitate ovulation; Terminate pregnancy;
 Reduce androgen secretion
 4a Anti-FSH Treat ovarian hyperstimulation; Reduce
 spermatogenesis
 5a Anti-FSH Treat ovarian hyperstimulation; Reduce
 spermatogenesis
 6a Anti-FSH and Anti-LH Treat ovarian hyperstimulation; Reduce
 spermatogenesis
 7a Anti-FSH and Anti-LH Treat ovarian hyperstimulation; Reduce
 spermatogenesis
 8a Anti-FSH and Anti-LH Treat ovarian hyperstimulation; Reduce
 spermatogenesis
 9a Anti-FSH Treat ovarian hyperstimulation; Reduce
 spermatogenesis
 10a Anti-FSH Treat ovarian hyperstimulation; Reduce
 spermatogenesis
 1b Anti-LH *Facilitate ovulation; Terminate pregnancy;
 Reduce androgen secretion
 2b Anti-LH *Facilitate ovulation; Terminate pregnancy;
 Reduce androgen secretion
 3b Anti-LH *Facilitate ovulation; Terminate pregnancy;
 Reduce androgen secretion
 4b Anti-FSH Treat ovarian hyperstimulation; Reduce
 spermatogenesis
 5b Anti-FSH Treat ovarian hyperstimulation; Reduce
 spermatogenesis
 6b Anti-FSH and Anti-LH Treat ovarian hyperstimulation; Reduce
 spermatogenesis
 7b Anti-FSH and Anti-LH Treat ovarian hyperstimulation; Reduce
 spermatogenesis
 8b Anti-FSH and Anti-LH Treat ovarian hyperstimulation; Reduce
 spermatogenesis
 9b Anti-FSH Treat ovarian hyperstimulation; Reduce
 spermatogenesis
 10b Anti-FSH Treat ovarian hyperstimulation; Reduce
 spermatogenesis.
 The compounds of the present invention can be administered to mammals,
 e.g., animals or humans, in amounts effective to provide the desired
 therapeutic effect. Since the activity of the compounds and the degree of
 the desired therapeutic effect vary, the dosage level of the compound
 employed will also vary. The actual dosage administered will also be
 determined by such generally recognized factors as the body weight of the
 patient and the individual hypersensitiveness of the particular patient.
 Throughout this application, various publications have been referenced, The
 disclosures in these publications are incorporated herein by reference in
 order to more fully describe the state of the art.
 SEQUENCE LISTING
 (1) GENERAL INFORMATION:
 (iii) NUMBER OF SEQUENCES: 83
 (2) INFORMATION FOR SEQ ID NO: 1:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 28 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1
 Ser Ser Ser Ser Lys Ala Pro Pro Pro Ser Leu Pro Ser Pro Ser Arg
 1 5 10 15
 Leu Pro Gly Pro Ser Asp Thr Pro Ile Leu Pro Gln
 20 25
 (2) INFORMATION FOR SEQ ID NO: 2:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 836 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (ix) FEATURE:
 (A) NAME/KEY: Coding Sequence
 (B) LOCATION: 33...827
 (D) OTHER INFORMATION:
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2
 ATGAAATCGA CGGAATCAGA CTCGAGCCAA GG ATG GAG ATG TTC CAG GGG CTG 53
 Met Glu Met Phe Gln Gly Leu
 1 5
 CTG CTG TTG CTG CTG CTG AGC ATG GGC GGG ACA TGG GCA TCC AAG GAG 101
 Leu Leu Leu Leu Leu Leu Ser Met Gly Gly Thr Trp Ala Ser Lys Glu
 10 15 20
 CCG CTT CGG CCA CGG TGC CGC CCC ATC AAT GCC ACC CTG GCT GTG GAG 149
 Pro Leu Arg Pro Arg Cys Arg Pro Ile Asn Ala Thr Leu Ala Val Glu
 25 30 35
 AAG GAG GGC TGC CCC GTG TGC ATC ACC GTC AAC ACC ACC ATC TGT GCC 197
 Lys Glu Gly Cys Pro Val Cys Ile Thr Val Asn Thr Thr Ile Cys Ala
 40 45 50 55
 GGC TAC TGC CCC ACC ATG ACC CGC GTG CTG CAG GGG GTC CTG CCG GCC 245
 Gly Tyr Cys Pro Thr Met Thr Arg Val Leu Gln Gly Val Leu Pro Ala
 60 65 70
 CTG CCT CAG GTG GTG TGC AAC TAC CGC GAT GTG CGC TTC GAG TCC ATC 293
 Leu Pro Gln Val Val Cys Asn Tyr Arg Asp Val Arg Phe Glu Ser Ile
 75 80 85
 CGG CTC CCT GGC TGC CCG CGC GGC GTG AAC CCC GTG GTC TCC TAC GCC 341
 Arg Leu Pro Gly Cys Pro Arg Gly Val Asn Pro Val Val Ser Tyr Ala
 90 95 100
 GTG GCT CTC AGC TGT CAA TGT GCA CTC TGC CGC CGC AGC ACC ACT GAC 389
 Val Ala Leu Ser Cys Gln Cys Ala Leu Cys Arg Arg Ser Thr Thr Asp
 105 110 115
 TGC GGG GGT CCC AAG GAC CAC CCC TTG ACC TGT GAT GAC CCC CGC TTC 437
 Cys Gly Gly Pro Lys Asp His Pro Leu Thr Cys Asp Asp Pro Arg Phe
 120 125 130 135
 CAG GAC TCC TCT TCC TCA AAG GCC CCT CCC CCC AGC CTT CCA AGC CCA 485
 Gln Asp Ser Ser Ser Ser Lys Ala Pro Pro Pro Ser Leu Pro Ser Pro
 140 145 150
 TCC CGA CTC CCG GGG CCC TCG GAC ACC CCG ATC CTC CCC CAA GGA TCC 533
 Ser Arg Leu Pro Gly Pro Ser Asp Thr Pro Ile Leu Pro Gln Gly Ser
 155 160 165
 GGT AGC GGA TCT GGT AGC GCT CCT GAT GTG CAG GAT TGC CCA GAA TGC 581
 Gly Ser Gly Ser Gly Ser Ala Pro Asp Val Gln Asp Cys Pro Glu Cys
 170 175 180
 ACG CTA CAG GAA AAC CCA TTC TTC TCC CAG CCG GGT GCC CCA ATA CTT 629
 Thr Leu Gln Glu Asn Pro Phe Phe Ser Gln Pro Gly Ala Pro Ile Leu
 185 190 195
 CAG TGC ATG GGC TGC TGC TTC TCT AGA GCA TAT CCC ACT CCA CTA AGG 677
 Gln Cys Met Gly Cys Cys Phe Ser Arg Ala Tyr Pro Thr Pro Leu Arg
 200 205 210 215
 TCC AAG AAG ACG ATG TTG GTC CAA AAG AAC GTC ACC TCA GAG TCC ACT 725
 Ser Lys Lys Thr Met Leu Val Gln Lys Asn Val Thr Ser Glu Ser Thr
 220 225 230
 TGC TGT GTA GCT AAA TCA TAT AAC AGG GTC ACA GTA ATG GGG GGT TTC 773
 Cys Cys Val Ala Lys Ser Tyr Asn Arg Val Thr Val Met Gly Gly Phe
 235 240 245
 AAA GTG GAG AAC CAC ACG GCG TGC CAC TGC AGT ACT TGT TAT TAT CAC 821
 Lys Val Glu Asn His Thr Ala Cys His Cys Ser Thr Cys Tyr Tyr His
 250 255 260
 AAA TCT TAAGGTACC 836
 Lys Ser
 265
 (2) INFORMATION FOR SEQ ID NO: 3:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 265 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (v) FRAGMENT TYPE: internal
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3
 Met Glu Met Phe Gln Gly Leu Leu Leu Leu Leu Leu Leu Ser Met Gly
 1 5 10 15
 Gly Thr Trp Ala Ser Lys Glu Pro Leu Arg Pro Arg Cys Arg Pro Ile
 20 25 30
 Asn Ala Thr Leu Ala Val Glu Lys Glu Gly Cys Pro Val Cys Ile Thr
 35 40 45
 Val Asn Thr Thr Ile Cys Ala Gly Tyr Cys Pro Thr Met Thr Arg Val
 50 55 60
 Leu Gln Gly Val Leu Pro Ala Leu Pro Gln Val Val Cys Asn Tyr Arg
 65 70 75 80
 Asp Val Arg Phe Glu Ser Ile Arg Leu Pro Gly Cys Pro Arg Gly Val
 85 90 95
 Asn Pro Val Val Ser Tyr Ala Val Ala Leu Ser Cys Gln Cys Ala Leu
 100 105 110
 Cys Arg Arg Ser Thr Thr Asp Cys Gly Gly Pro Lys Asp His Pro Leu
 115 120 125
 Thr Cys Asp Asp Pro Arg Phe Gln Asp Ser Ser Ser Ser Lys Ala Pro
 130 135 140
 Pro Pro Ser Leu Pro Ser Pro Ser Arg Leu Pro Gly Pro Ser Asp Thr
 145 150 155 160
 Pro Ile Leu Pro Gln Gly Ser Gly Ser Gly Ser Gly Ser Ala Pro Asp
 165 170 175
 Val Gln Asp Cys Pro Glu Cys Thr Leu Gln Glu Asn Pro Phe Phe Ser
 180 185 190
 Gln Pro Gly Ala Pro Ile Leu Gln Cys Met Gly Cys Cys Phe Ser Arg
 195 200 205
 Ala Tyr Pro Thr Pro Leu Arg Ser Lys Lys Thr Met Leu Val Gln Lys
 210 215 220
 Asn Val Thr Ser Glu Ser Thr Cys Cys Val Ala Lys Ser Tyr Asn Arg
 225 230 235 240
 Val Thr Val Met Gly Gly Phe Lys Val Glu Asn His Thr Ala Cys His
 245 250 255
 Cys Ser Thr Cys Tyr Tyr His Lys Ser
 260 265
 (2) INFORMATION FOR SEQ ID NO: 4:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 834 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4
 TCCGGATTAG CTTGAGATGG ATCCGGTACC TTAAGATTTG TGATAATAAC AAGTACTGCA 60
 GTGGCACGCC GTGTGGTTCT CCACTTTGAA ACCCCCCATT ACTGTGACCC TGTTATATGA 120
 TTTAGCTACA CAGCAAGTGG ACTCTGAGGT GACGTTCTTT TGGACCAACA TCGTCTTCTT 180
 GGACCTTAGT GGAGTGGGAT ATGCTCTAGA GAAGCAGCAG CCCATGCACT GAAGTATTGG 240
 GGCACCCGGC TGGGAGAAGA ATGGGTTTTC CTGTAGCGTG CATTCTGGGC AATCCTGCAC 300
 ATCAGGAGCG CTACCAGATC CGCTACCGGA TCCTTGGGGG AGGATCGGGG TGTCCGAGGG 360
 CCCCGGGAGT CGGGATGGGC TTGGAAGGCT GGGGGGAGGG GCCTTTGAGG AAGAGGAGTC 420
 CTGGAAGCGG GGGTCATCAC AGGTCAAGGG GTGGTCCTTG GGACCCCCGC AGTCAGTGGT 480
 GCTGCGGCGG CAGAGTGCAC ATTGACAGCT GAGAGCCACG GCGTAGGAGA CCACGGGGTT 540
 CACGCCGCGC GGGCAGCCAG GGAGCCGGAT GGACTCGAAG CGCACATCGC GGTAGTTGCA 600
 CACCACCTGA GGCAGGGCCG GCAGGACCCC CTGCAGCACG CGGGTCATGG TGGGGCAGTA 660
 GCCGGCACAG ATGGTGGTGT TGACGGTGAT GCACACGGGG CAGCCCTCCT TCTCCACAGC 720
 CAGGGTGGCA TTGATGGGGC GGCACCGTGG CCGAAGCGGC TCCTTGGATG CCCATGTCCC 780
 GCCCATGCTC AGCAGCAGCA ACAGCAGCAG CCCCTGGAAC ATCTCCATCC TTGG 834
 (2) INFORMATION FOR SEQ ID NO: 5:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 743 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (ix) FEATURE:
 (A) NAME/KEY: Coding Sequence
 (B) LOCATION: 33...734
 (D) OTHER INFORMATION:
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 5
 ATGAAATCGA CGGAATCAGA CTCGAGCCAA GG ATG GAG ATG TTC CAG GGG CTG 53
 Met Glu Met Phe Gln Gly Leu
 1 5
 CTG CTG TTG CTG CTG CTG AGC ATG GGC GGG ACA TGG GCA TCC AAG GAG 101
 Leu Leu Leu Leu Leu Leu Ser Met Gly Gly Thr Trp Ala Ser Lys Glu
 10 15 20
 CCG CTT CGG CCA CGG TGC CGC CCC ATC AAT GCC ACC CTG GCT GTG GAG 149
 Pro Leu Arg Pro Arg Cys Arg Pro Ile Asn Ala Thr Leu Ala Val Glu
 25 30 35
 AAG GAG GGC TGC CCC GTG TGC ATC ACC GTC AAC ACC ACC ATC TGT GCC 197
 Lys Glu Gly Cys Pro Val Cys Ile Thr Val Asn Thr Thr Ile Cys Ala
 40 45 50 55
 GGC TAC TGC CCC ACC ATG ACC CGC GTG CTG CAG GGG GTC CTG CCG GCC 245
 Gly Tyr Cys Pro Thr Met Thr Arg Val Leu Gln Gly Val Leu Pro Ala
 60 65 70
 CTG CCT CAG GTG GTG TGC AAC TAC CGC GAT GTG CGC TTC GAG TCC ATC 293
 Leu Pro Gln Val Val Cys Asn Tyr Arg Asp Val Arg Phe Glu Ser Ile
 75 80 85
 CGG CTC CCT GGC TGC CCG CGC GGC GTG AAC CCC GTG GTC TCC TAC GCC 341
 Arg Leu Pro Gly Cys Pro Arg Gly Val Asn Pro Val Val Ser Tyr Ala
 90 95 100
 GTG GCT CTC AGC TGT CAA TGT GCA CTC TGC CGC CGC AGC ACC ACT GAC 389
 Val Ala Leu Ser Cys Gln Cys Ala Leu Cys Arg Arg Ser Thr Thr Asp
 105 110 115
 TGC GGG GGT CCC AAG GAC CAC CCC TTG ACC TGT GAT GAC CCG CGG GGA 437
 Cys Gly Gly Pro Lys Asp His Pro Leu Thr Cys Asp Asp Pro Arg Gly
 120 125 130 135
 TCC GGT AGC GGA TCT GGT AGC GCT CCT GAT GTG CAG GAT TGC CCA GAA 485
 Ser Gly Ser Gly Ser Gly Ser Ala Pro Asp Val Gln Asp Cys Pro Glu
 140 145 150
 TGC ACG CTA CAG GAA AAC CCA TTC TTC TCC CAG CCG GGT GCC CCA ATA 533
 Cys Thr Leu Gln Glu Asn Pro Phe Phe Ser Gln Pro Gly Ala Pro Ile
 155 160 165
 CTT CAG TGC ATG GGC TGC TGC TTC TCT AGA GCA TAT CCC ACT CCA CTA 581
 Leu Gln Cys Met Gly Cys Cys Phe Ser Arg Ala Tyr Pro Thr Pro Leu
 170 175 180
 AGG TCC AAG AAG ACG ATG TTG GTC CAA AAG AAC GTC ACC TCA GAG TCC 629
 Arg Ser Lys Lys Thr Met Leu Val Gln Lys Asn Val Thr Ser Glu Ser
 185 190 195
 ACT TGC TGT GTA GCT AAA TCA TAT AAC AGG GTC ACA GTA ATG GGG GGT 677
 Thr Cys Cys Val Ala Lys Ser Tyr Asn Arg Val Thr Val Met Gly Gly
 200 205 210 215
 TTC AAA GTG GAG AAC CAC ACG GCG TGC CAC TGC AGT ACT TGT TAT TAT 725
 Phe Lys Val Glu Asn His Thr Ala Cys His Cys Ser Thr Cys Tyr Tyr
 220 225 230
 CAC AAA TCT TAAGGTACC 743
 His Lys Ser
 (2) INFORMATION FOR SEQ ID NO: 6:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 234 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (v) FRAGMENT TYPE: internal
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 6
 Met Glu Met Phe Gln Gly Leu Leu Leu Leu Leu Leu Leu Ser Met Gly
 1 5 10 15
 Gly Thr Trp Ala Ser Lys Glu Pro Leu Arg Pro Arg Cys Arg Pro Ile
 20 25 30
 Asn Ala Thr Leu Ala Val Glu Lys Glu Gly Cys Pro Val Cys Ile Thr
 35 40 45
 Val Asn Thr Thr Ile Cys Ala Gly Tyr Cys Pro Thr Met Thr Arg Val
 50 55 60
 Leu Gln Gly Val Leu Pro Ala Leu Pro Gln Val Val Cys Asn Tyr Arg
 65 70 75 80
 Asp Val Arg Phe Glu Ser Ile Arg Leu Pro Gly Cys Pro Arg Gly Val
 85 90 95
 Asn Pro Val Val Ser Tyr Ala Val Ala Leu Ser Cys Gln Cys Ala Leu
 100 105 110
 Cys Arg Arg Ser Thr Thr Asp Cys Gly Gly Pro Lys Asp His Pro Leu
 115 120 125
 Thr Cys Asp Asp Pro Arg Gly Ser Gly Ser Gly Ser Gly Ser Ala Pro
 130 135 140
 Asp Val Gln Asp Cys Pro Glu Cys Thr Leu Gln Glu Asn Pro Phe Phe
 145 150 155 160
 Ser Gln Pro Gly Ala Pro Ile Leu Gln Cys Met Gly Cys Cys Phe Ser
 165 170 175
 Arg Ala Tyr Pro Thr Pro Leu Arg Ser Lys Lys Thr Met Leu Val Gln
 180 185 190
 Lys Asn Val Thr Ser Glu Ser Thr Cys Cys Val Ala Lys Ser Tyr Asn
 195 200 205
 Arg Val Thr Val Met Gly Gly Phe Lys Val Glu Asn His Thr Ala Cys
 210 215 220
 His Cys Ser Thr Cys Tyr Tyr His Lys Ser
 225 230
 (2) INFORMATION FOR SEQ ID NO: 7:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 717 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 7
 GGTACCTTAA GATTTGTGAT AATAACAAGT ACTGCAGTGG CACGCCGTGT GGTTCTCCAC 60
 TTTGAAACCC CCCATTACTG TGACCCTGTT ATATGATTTA GCTACACAGC AAGTGGACTC 120
 TGAGGTGACG TTCTTTTGGA CCAACATCGT CTTCTTGGAC CTTAGTGGAG TGGGATATGC 180
 TCTAGAGAAG CAGCAGCCCA TGCACTGAAG TATTGGGGCA CCCGGCTGGG AGAAGAATGG 240
 GTTTTCCTGT AGCGTGCATT CTGGGCAATC CTGCACATCA GGAGCGCTAC CAGATCCGCT 300
 ACCGGATCCC CGCGGGTCAT CACAGGTCAA GGGGTGGTCC TTGGGACCCC CGCAGTCAGT 360
 GGTGCTGCGG CGGCAGAGTG CACATTGACA GCTGAGAGCC ACGGCGTAGG AGACCACGGG 420
 GTTCACGCCG CGCGGGCAGC CAGGGAGCCG GATGGACTCG AAGCGCACAT CGCGGTAGTT 480
 GCACACCACC TGAGGCAGGG CCGGCAGGAC CCCCTGCAGC ACGCGGGTCA TGGTGGGGCA 540
 GTAGCCGGCA CAGATGGTGG TGTTGACGGT GATGCACACG GGGCAGCCCT CCTTCTCCAC 600
 AGCCAGGGTG GCATTGATGG GGCGGCACCG TGGCCGAAGC GGCTCCTTGG ATGCCCATGT 660
 CCCGCCCATG CTCAGCAGCA GCAACAGCAG CAGCCCCTGG AACATCTCCA TCCTTGG 717
 (2) INFORMATION FOR SEQ ID NO: 8:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 744 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (ix) FEATURE:
 (A) NAME/KEY: Coding Sequence
 (B) LOCATION: 34...735
 (D) OTHER INFORMATION:
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 8
 ATGAAATCGA CGGAATCAGA CTCGAGCCAA GGA ATG GAG ATG CTC CAG GGG CTG 54
 Met Glu Met Leu Gln Gly Leu
 1 5
 CTG CTG TTG CTG CTG CTG AGC ATG GGC GGG GCA TGG GCA TCC AGG GAG 102
 Leu Leu Leu Leu Leu Leu Ser Met Gly Gly Ala Trp Ala Ser Arg Glu
 10 15 20
 CCG CTT CGG CCA TGG TGC CAC CCC ATC AAT GCC ATC CTG GCT GTG GAG 150
 Pro Leu Arg Pro Trp Cys His Pro Ile Asn Ala Ile Leu Ala Val Glu
 25 30 35
 AAG GAG GGC TGC CCC GTG TGC ATC ACC GTC AAC ACC ACC ATC TGT GCC 198
 Lys Glu Gly Cys Pro Val Cys Ile Thr Val Asn Thr Thr Ile Cys Ala
 40 45 50 55
 GGC TAC TGC CCC ACC ATG ATG CGC GTG CTG CAG GCG GTC CTG CCG CCC 246
 Gly Tyr Cys Pro Thr Met Met Arg Val Leu Gln Ala Val Leu Pro Pro
 60 65 70
 CTG CCT CAG GTG GTG TGC ACC TAC CGT GAT GTG CGC TTC GAG TCC ATC 294
 Leu Pro Gln Val Val Cys Thr Tyr Arg Asp Val Arg Phe Glu Ser Ile
 75 80 85
 CGG CTC CCT GGC TGC CCG CGT GGC GTG GAC CCC GTG GTC TCC TTC CCT 342
 Arg Leu Pro Gly Cys Pro Arg Gly Val Asp Pro Val Val Ser Phe Pro
 90 95 100
 GTG GCT CTC AGC TGT CGC TGT GGA CCC TGC CGC CGC AGC ACC TCT GAC 390
 Val Ala Leu Ser Cys Arg Cys Gly Pro Cys Arg Arg Ser Thr Ser Asp
 105 110 115
 TGT GGG GGT CCC AAA GAC CAC CCC TTG ACC TGT GAC CAC CCC CAA GGA 438
 Cys Gly Gly Pro Lys Asp His Pro Leu Thr Cys Asp His Pro Gln Gly
 120 125 130 135
 TCC GGT AGC GGA TCT GGT AGC GCT CCT GAT GTG CAG GAT TGC CCA GAA 486
 Ser Gly Ser Gly Ser Gly Ser Ala Pro Asp Val Gln Asp Cys Pro Glu
 140 145 150
 TGC ACG CTA CAG GAA AAC CCA TTC TTC TCC CAG CCG GGT GCC CCA ATA 534
 Cys Thr Leu Gln Glu Asn Pro Phe Phe Ser Gln Pro Gly Ala Pro Ile
 155 160 165
 CTT CAG TGC ATG GGC TGC TGC TTC TCT AGA GCA TAT CCC ACT CCA CTA 582
 Leu Gln Cys Met Gly Cys Cys Phe Ser Arg Ala Tyr Pro Thr Pro Leu
 170 175 180
 AGG TCC AAG AAG ACG ATG TTG GTC CAA AAG AAC GTC ACC TCA GAG TCC 630
 Arg Ser Lys Lys Thr Met Leu Val Gln Lys Asn Val Thr Ser Glu Ser
 185 190 195
 ACT TGC TGT GTA GCT AAA TCA TAT AAC AGG GTC ACA GTA ATG GGG GGT 678
 Thr Cys Cys Val Ala Lys Ser Tyr Asn Arg Val Thr Val Met Gly Gly
 200 205 210 215
 TTC AAA GTG GAG AAC CAC ACG GCG TGC CAC TGC AGT ACT TGT TAT TAT 726
 Phe Lys Val Glu Asn His Thr Ala Cys His Cys Ser Thr Cys Tyr Tyr
 220 225 230
 CAC AAA TCT TAAGGTACC 744
 His Lys Ser
 (2) INFORMATION FOR SEQ ID NO: 9:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 234 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (v) FRAGMENT TYPE: internal
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 9
 Met Glu Met Leu Gln Gly Leu Leu Leu Leu Leu Leu Leu Ser Met Gly
 1 5 10 15
 Gly Ala Trp Ala Ser Arg Glu Pro Leu Arg Pro Trp Cys His Pro Ile
 20 25 30
 Asn Ala Ile Leu Ala Val Glu Lys Glu Gly Cys Pro Val Cys Ile Thr
 35 40 45
 Val Asn Thr Thr Ile Cys Ala Gly Tyr Cys Pro Thr Met Met Arg Val
 50 55 60
 Leu Gln Ala Val Leu Pro Pro Leu Pro Gln Val Val Cys Thr Tyr Arg
 65 70 75 80
 Asp Val Arg Phe Glu Ser Ile Arg Leu Pro Gly Cys Pro Arg Gly Val
 85 90 95
 Asp Pro Val Val Ser Phe Pro Val Ala Leu Ser Cys Arg Cys Gly Pro
 100 105 110
 Cys Arg Arg Ser Thr Ser Asp Cys Gly Gly Pro Lys Asp His Pro Leu
 115 120 125
 Thr Cys Asp His Pro Gln Gly Ser Gly Ser Gly Ser Gly Ser Ala Pro
 130 135 140
 Asp Val Gln Asp Cys Pro Glu Cys Thr Leu Gln Glu Asn Pro Phe Phe
 145 150 155 160
 Ser Gln Pro Gly Ala Pro Ile Leu Gln Cys Met Gly Cys Cys Phe Ser
 165 170 175
 Arg Ala Tyr Pro Thr Pro Leu Arg Ser Lys Lys Thr Met Leu Val Gln
 180 185 190
 Lys Asn Val Thr Ser Glu Ser Thr Cys Cys Val Ala Lys Ser Tyr Asn
 195 200 205
 Arg Val Thr Val Met Gly Gly Phe Lys Val Glu Asn His Thr Ala Cys
 210 215 220
 His Cys Ser Thr Cys Tyr Tyr His Lys Ser
 225 230
 (2) INFORMATION FOR SEQ ID NO: 10:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 718 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 10
 GGTACCTTAA GATTTGTGAT AATAACAAGT ACTGCAGTGG CACGCCGTGT GGTTCTCCAC 60
 TTTGAAACCC CCCATTACTG TGACCCTGTT ATATGATTTA GCTACACAGC AAGTGGACTC 120
 TGAGGTGACG TTCTTTTGGA CCAACATCGT CTTCTTGGAC CTTAGTGGAG TGGGATATGC 180
 TCTAGAGAAG CAGCAGCCCA TGCACTGAAG TATTGGGGCA CCCGGCTGGG AGAAGAATGG 240
 GTTTTCCTGT AGCGTGCATT CTGGGCAATC CTGCACATCA GGAGCGCTAC CAGATCCGCT 300
 ACCGGATCCT TGGGGGTGGT CACAGGTCAA GGGGTGGTCT TTGGGACCCC CACAGTCAGA 360
 GGTGCTGCGG CGGCAGGGTC CACAGCGACA GCTGAGAGCC ACAGGGAAGG AGACCACGGG 420
 GTCCACGCCA CGCGGGCAGC CAGGGAGCCG GATGGACTCG AAGCGCACAT CACGGTAGGT 480
 GCACACCACC TGAGGCAGGG GCGGCAGGAC CGCCTGCAGC ACGCGCATCA TGGTGGGGCA 540
 GTAGCCGGCA CAGATGGTGG TGTTGACGGT GATGCACACG GGGCAGCCCT CCTTCTCCAC 600
 AGCCAGGATG GCATTGATGG GGTGGCACCA TGGCCGAAGC GGCTCCCTGG ATGCCCATGC 660
 CCCGCCCATG CTCAGCAGCA GCAACAGCAG CAGCCCCTGG AGCATCTCCA TTCCTTGG 718
 (2) INFORMATION FOR SEQ ID NO: 11:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 728 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (ix) FEATURE:
 (A) NAME/KEY: Coding Sequence
 (B) LOCATION: 33...719
 (D) OTHER INFORMATION:
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 11
 ATGAAATCGA CGGAATCAGA CTCGAGCCAA GG ATG AAG ACA CTC CAG TTT TTC 53
 Met Lys Thr Leu Gln Phe Phe
 1 5
 TTC CTT TTC TGT TGC TGG AAA GCA ATC TGC TGC AAT AGC TGT GAG CTG 101
 Phe Leu Phe Cys Cys Trp Lys Ala Ile Cys Cys Asn Ser Cys Glu Leu
 10 15 20
 ACC AAC ATC ACC ATT GCA ATA GAG AAA GAA GAA TGT CGT TTC TGC ATA 149
 Thr Asn Ile Thr Ile Ala Ile Glu Lys Glu Glu Cys Arg Phe Cys Ile
 25 30 35
 AGC ATC AAC ACC ACT TGG TGT GCT GGC TAC TGC TAC ACC AGG GAT CTG 197
 Ser Ile Asn Thr Thr Trp Cys Ala Gly Tyr Cys Tyr Thr Arg Asp Leu
 40 45 50 55
 GTG TAT AAG GAC CCA GCC AGG CCC AAA ATC CAG AAA ACA TGT ACC TTC 245
 Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe
 60 65 70
 AAG GAA CTG GTA TAT GAA ACA GTG AGA GTG CCC GGC TGT GCT CAC CAT 293
 Lys Glu Leu Val Tyr Glu Thr Val Arg Val Pro Gly Cys Ala His His
 75 80 85
 GCA GAT TCC TTG TAT ACA TAC CCA GTG GCC ACC CAG TGT CAC TGT GGC 341
 Ala Asp Ser Leu Tyr Thr Tyr Pro Val Ala Thr Gln Cys His Cys Gly
 90 95 100
 AAG TGT GAC AGC GAC AGC ACT GAT TGT ACT GTG CGA GGC CTG GGG CCC 389
 Lys Cys Asp Ser Asp Ser Thr Asp Cys Thr Val Arg Gly Leu Gly Pro
 105 110 115
 AGC TAC TGC TCC TTT GGT GAA ATG AAA GAA GGA TCC GGT AGC GGA TCT 437
 Ser Tyr Cys Ser Phe Gly Glu Met Lys Glu Gly Ser Gly Ser Gly Ser
 120 125 130 135
 GGT AGC GCT CCT GAT GTG CAG GAT TGC CCA GAA TGC ACG CTA CAG GAA 485
 Gly Ser Ala Pro Asp Val Gln Asp Cys Pro Glu Cys Thr Leu Gln Glu
 140 145 150
 AAC CCA TTC TTC TCC CAG CCG GGT GCC CCA ATA CTT CAG TGC ATG GGC 533
 Asn Pro Phe Phe Ser Gln Pro Gly Ala Pro Ile Leu Gln Cys Met Gly
 155 160 165
 TGC TGC TTC TCT AGA GCA TAT CCC ACT CCA CTA AGG TCC AAG AAG ACG 581
 Cys Cys Phe Ser Arg Ala Tyr Pro Thr Pro Leu Arg Ser Lys Lys Thr
 170 175 180
 ATG TTG GTC CAA AAG AAC GTC ACC TCA GAG TCC ACT TGC TGT GTA GCT 629
 Met Leu Val Gln Lys Asn Val Thr Ser Glu Ser Thr Cys Cys Val Ala
 185 190 195
 AAA TCA TAT AAC AGG GTC ACA GTA ATG GGG GGT TTC AAA GTG GAG AAC 677
 Lys Ser Tyr Asn Arg Val Thr Val Met Gly Gly Phe Lys Val Glu Asn
 200 205 210 215
 CAC ACG GCG TGC CAC TGC AGT ACT TGT TAT TAT CAC AAA TCT TAAGGTACC 728
 His Thr Ala Cys His Cys Ser Thr Cys Tyr Tyr His Lys Ser
 220 225
 728
 (2) INFORMATION FOR SEQ ID NO: 12:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 229 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (v) FRAGMENT TYPE: internal
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 12
 Met Lys Thr Leu Gln Phe Phe Phe Leu Phe Cys Cys Trp Lys Ala Ile
 1 5 10 15
 Cys Cys Asn Ser Cys Glu Leu Thr Asn Ile Thr Ile Ala Ile Glu Lys
 20 25 30
 Glu Glu Cys Arg Phe Cys Ile Ser Ile Asn Thr Thr Trp Cys Ala Gly
 35 40 45
 Tyr Cys Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys
 50 55 60
 Ile Gln Lys Thr Cys Thr Phe Lys Glu Leu Val Tyr Glu Thr Val Arg
 65 70 75 80
 Val Pro Gly Cys Ala His His Ala Asp Ser Leu Tyr Thr Tyr Pro Val
 85 90 95
 Ala Thr Gln Cys His Cys Gly Lys Cys Asp Ser Asp Ser Thr Asp Cys
 100 105 110
 Thr Val Arg Gly Leu Gly Pro Ser Tyr Cys Ser Phe Gly Glu Met Lys
 115 120 125
 Glu Gly Ser Gly Ser Gly Ser Gly Ser Ala Pro Asp Val Gln Asp Cys
 130 135 140
 Pro Glu Cys Thr Leu Gln Glu Asn Pro Phe Phe Ser Gln Pro Gly Ala
 145 150 155 160
 Pro Ile Leu Gln Cys Met Gly Cys Cys Phe Ser Arg Ala Tyr Pro Thr
 165 170 175
 Pro Leu Arg Ser Lys Lys Thr Met Leu Val Gln Lys Asn Val Thr Ser
 180 185 190
 Glu Ser Thr Cys Cys Val Ala Lys Ser Tyr Asn Arg Val Thr Val Met
 195 200 205
 Gly Gly Phe Lys Val Glu Asn His Thr Ala Cys His Cys Ser Thr Cys
 210 215 220
 Tyr Tyr His Lys Ser
 225
 (2) INFORMATION FOR SEQ ID NO: 13:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 702 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 13
 GGTACCTTAA GATTTGTGAT AATAACAAGT ACTGCAGTGG CACGCCGTGT GGTTCTCCAC 60
 TTTGAAACCC CCCATTACTG TGACCCTGTT ATATGATTTA GCTACACAGC AAGTGGACTC 120
 TGAGGTGACG TTCTTTTGGA CCAACATCGT CTTCTTGGAC CTTAGTGGAG TGGGATATGC 180
 TCTAGAGAAG CAGCAGCCCA TGCACTGAAG TATTGGGGCA CCCGGCTGGG AGAAGAATGG 240
 GTTTTCCTGT AGCGTGCATT CTGGGCAATC CTGCACATCA GGAGCGCTAC CAGATCCGCT 300
 ACCGGATCCT TCTTTCATTT CACCAAAGGA GCAGTAGCTG GGCCCCAGGC CTCGCACAGT 360
 ACAATCAGTG CTGTCGCTGT CACACTTGCC ACAGTGACAC TGGGTGGCCA CTGGGTATGT 420
 ATACAAGGAA TCTGCATGGT GAGCACAGCC GGGCACTCTC ACTGTTTCAT ATACCAGTTC 480
 CTTGAAGGTA CATGTTTTCT GGATTTTGGG CCTGGCTGGG TCCTTATACA CCAGATCCCT 540
 GGTGTAGCAG TAGCCAGCAC ACCAAGTGGT GTTGATGCTT ATGCAGAAAC GACATTCTTC 600
 TTTCTCTATT GCAATGGTGA TGTTGGTCAG CTCACAGCTA TTGCAGCAGA TTGCTTTCCA 660
 GCAACAGAAA AGGAAGAAAA ACTGGAGTGT CTTCATCCTT GG 702
 (2) INFORMATION FOR SEQ ID NO: 14:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 752 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (ix) FEATURE:
 (A) NAME/KEY: Coding Sequence
 (B) LOCATION: 33...743
 (D) OTHER INFORMATION:
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 14
 ATGAAATCGA CGGAATCAGA CTCGAGCCAA GG ATG GAG ATG TTC CAG GGG CTG 53
 Met Glu Met Phe Gln Gly Leu
 1 5
 CTG CTG TTG CTG CTG CTG AGC ATG GGC GGG ACA TGG GCA TCC AAG GAG 101
 Leu Leu Leu Leu Leu Leu Ser Met Gly Gly Thr Trp Ala Ser Lys Glu
 10 15 20
 CCG CTT CGG CCA CGG TGC CGC CCC ATC AAT GCC ACC CTG GCT GTG GAG 149
 Pro Leu Arg Pro Arg Cys Arg Pro Ile Asn Ala Thr Leu Ala Val Glu
 25 30 35
 AAG GAG GGC TGC CCC GTG TGC ATC ACC GTC AAC ACC ACC ATC TGT GCC 197
 Lys Glu Gly Cys Pro Val Cys Ile Thr Val Asn Thr Thr Ile Cys Ala
 40 45 50 55
 GGC TAC TGC CCC ACC ATG ACC CGC GTG CTG CAG GGG GTC CTG CCG GCC 245
 Gly Tyr Cys Pro Thr Met Thr Arg Val Leu Gln Gly Val Leu Pro Ala
 60 65 70
 CTG CCT CAG GTG GTG TGC AAC TAC CGC GAT GTG CGC TTC GAG TCC ATC 293
 Leu Pro Gln Val Val Cys Asn Tyr Arg Asp Val Arg Phe Glu Ser Ile
 75 80 85
 CGG CTC CCT GGC TGC CCG CGC GGC GTG AAC CCC GTG GTC TCC TAC GCC 341
 Arg Leu Pro Gly Cys Pro Arg Gly Val Asn Pro Val Val Ser Tyr Ala
 90 95 100
 GTG GCT CTC AGC TGT CAA TGT GCA CTC TGC GAC AGC GAC AGC ACT GAT 389
 Val Ala Leu Ser Cys Gln Cys Ala Leu Cys Asp Ser Asp Ser Thr Asp
 105 110 115
 TGT ACT GTG CGA GGC CTG GGG CCC AGC TAC TGC TCC TTT GGT GAA ATG 437
 Cys Thr Val Arg Gly Leu Gly Pro Ser Tyr Cys Ser Phe Gly Glu Met
 120 125 130 135
 AAA GAA GGA TCC GGT AGC GGA TCT GGT AGC GCT CCT GAT GTG CAG GAT 485
 Lys Glu Gly Ser Gly Ser Gly Ser Gly Ser Ala Pro Asp Val Gln Asp
 140 145 150
 TGC CCA GAA TGC ACG CTA CAG GAA AAC CCA TTC TTC TCC CAG CCG GGT 533
 Cys Pro Glu Cys Thr Leu Gln Glu Asn Pro Phe Phe Ser Gln Pro Gly
 155 160 165
 GCC CCA ATA CTT CAG TGC ATG GGC TGC TGC TTC TCT AGA GCA TAT CCC 581
 Ala Pro Ile Leu Gln Cys Met Gly Cys Cys Phe Ser Arg Ala Tyr Pro
 170 175 180
 ACT CCA CTA AGG TCC AAG AAG ACG ATG TTG GTC CAA AAG AAC GTC ACC 629
 Thr Pro Leu Arg Ser Lys Lys Thr Met Leu Val Gln Lys Asn Val Thr
 185 190 195
 TCA GAG TCC ACT TGC TGT GTA GCT AAA TCA TAT AAC AGG GTC ACA GTA 677
 Ser Glu Ser Thr Cys Cys Val Ala Lys Ser Tyr Asn Arg Val Thr Val
 200 205 210 215
 ATG GGG GGT TTC AAA GTG GAG AAC CAC ACG GCG TGC CAC TGC AGT ACT 725
 Met Gly Gly Phe Lys Val Glu Asn His Thr Ala Cys His Cys Ser Thr
 220 225 230
 TGT TAT TAT CAC AAA TCT TAAGGTACC 752
 Cys Tyr Tyr His Lys Ser
 235
 (2) INFORMATION FOR SEQ ID NO: 15:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 237 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (v) FRAGMENT TYPE: internal
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 15
 Met Glu Met Phe Gln Gly Leu Leu Leu Leu Leu Leu Leu Ser Met Gly
 1 5 10 15
 Gly Thr Trp Ala Ser Lys Glu Pro Leu Arg Pro Arg Cys Arg Pro Ile
 20 25 30
 Asn Ala Thr Leu Ala Val Glu Lys Glu Gly Cys Pro Val Cys Ile Thr
 35 40 45
 Val Asn Thr Thr Ile Cys Ala Gly Tyr Cys Pro Thr Met Thr Arg Val
 50 55 60
 Leu Gln Gly Val Leu Pro Ala Leu Pro Gln Val Val Cys Asn Tyr Arg
 65 70 75 80
 Asp Val Arg Phe Glu Ser Ile Arg Leu Pro Gly Cys Pro Arg Gly Val
 85 90 95
 Asn Pro Val Val Ser Tyr Ala Val Ala Leu Ser Cys Gln Cys Ala Leu
 100 105 110
 Cys Asp Ser Asp Ser Thr Asp Cys Thr Val Arg Gly Leu Gly Pro Ser
 115 120 125
 Tyr Cys Ser Phe Gly Glu Met Lys Glu Gly Ser Gly Ser Gly Ser Gly
 130 135 140
 Ser Ala Pro Asp Val Gln Asp Cys Pro Glu Cys Thr Leu Gln Glu Asn
 145 150 155 160
 Pro Phe Phe Ser Gln Pro Gly Ala Pro Ile Leu Gln Cys Met Gly Cys
 165 170 175
 Cys Phe Ser Arg Ala Tyr Pro Thr Pro Leu Arg Ser Lys Lys Thr Met
 180 185 190
 Leu Val Gln Lys Asn Val Thr Ser Glu Ser Thr Cys Cys Val Ala Lys
 195 200 205
 Ser Tyr Asn Arg Val Thr Val Met Gly Gly Phe Lys Val Glu Asn His
 210 215 220
 Thr Ala Cys His Cys Ser Thr Cys Tyr Tyr His Lys Ser
 225 230 235
 (2) INFORMATION FOR SEQ ID NO: 16:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 726 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 16
 GGTACCTTAA GATTTGTGAT AATAACAAGT ACTGCAGTGG CACGCCGTGT GGTTCTCCAC 60
 TTTGAAACCC CCCATTACTG TGACCCTGTT ATATGATTTA GCTACACAGC AAGTGGACTC 120
 TGAGGTGACG TTCTTTTGGA CCAACATCGT CTTCTTGGAC CTTAGTGGAG TGGGATATGC 180
 TCTAGAGAAG CAGCAGCCCA TGCACTGAAG TATTGGGGCA CCCGGCTGGG AGAAGAATGG 240
 GTTTTCCTGT AGCGTGCATT CTGGGCAATC CTGCACATCA GGAGCGCTAC CAGATCCGCT 300
 ACCGGATCCT TCTTTCATTT CACCAAAGGA GCAGTAGCTG GGCCCCAGGC CTCGCACAGT 360
 ACAATCAGTG CTGTCGCTGT CGCAGAGTGC ACATTGACAG CTGAGAGCCA CGGCGTAGGA 420
 GACCACGGGG TTCACGCCGC GCGGGCAGCC AGGGAGCCGG ATGGACTCGA AGCGCACATC 480
 GCGGTAGTTG CACACCACCT GAGGCAGGGC CGGCAGGACC CCCTGCAGCA CGCGGGTCAT 540
 GGTGGGGCAG TAGCCGGCAC AGATGGTGGT GTTGACGGTG ATGCACACGG GGCAGCCCTC 600
 CTTCTCCACA GCCAGGGTGG CATTGATGGG GCGGCACCGT GGCCGAAGCG GCTCCTTGGA 660
 TGCCCATGTC CCGCCCATGC TCAGCAGCAG CAACAGCAGC AGCCCCTGGA ACATCTCCAT 720
 CCTTGG 726
 (2) INFORMATION FOR SEQ ID NO: 17:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 752 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (ix) FEATURE:
 (A) NAME/KEY: Coding Sequence
 (B) LOCATION: 33...743
 (D) OTHER INFORMATION:
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 17
 ATGAAATCGA CGGAATCAGA CTCGAGCCAA GG ATG GAG ATG TTC CAG GGG CTG 53
 Met Glu Met Phe Gln Gly Leu
 1 5
 CTG CTG TTG CTG CTG CTG AGC ATG GGC GGG ACA TGG GCA TCC AAG GAG 101
 Leu Leu Leu Leu Leu Leu Ser Met Gly Gly Thr Trp Ala Ser Lys Glu
 10 15 20
 CCG CTT CGG CCA CGG TGC CGC CCC ATC AAT GCC ACC CTG GCT GTG GAG 149
 Pro Leu Arg Pro Arg Cys Arg Pro Ile Asn Ala Thr Leu Ala Val Glu
 25 30 35
 AAG GAG GGC TGC CCC GTG TGC ATC ACC GTC AAC ACC ACC ATC TGT GCC 197
 Lys Glu Gly Cys Pro Val Cys Ile Thr Val Asn Thr Thr Ile Cys Ala
 40 45 50 55
 GGC TAC TGC CCC ACC ATG ACC CGC GTG CTG CAG GGG GTC CTG CCG GCC 245
 Gly Tyr Cys Pro Thr Met Thr Arg Val Leu Gln Gly Val Leu Pro Ala
 60 65 70
 CTG CCT CAG GTG GTG TGC AAC TAC CGC GAT GTG CGC TTC GAG TCC ATC 293
 Leu Pro Gln Val Val Cys Asn Tyr Arg Asp Val Arg Phe Glu Ser Ile
 75 80 85
 CGG CTC CCT GGC TGC CCG CGC GGC GTG AAC CCC GTG GTC TCC TAC GCC 341
 Arg Leu Pro Gly Cys Pro Arg Gly Val Asn Pro Val Val Ser Tyr Ala
 90 95 100
 GTG GCT CTC AGC TGT CAA TGT GCA CTC TGC CGC CGC AGC ACC ACT GAC 389
 Val Ala Leu Ser Cys Gln Cys Ala Leu Cys Arg Arg Ser Thr Thr Asp
 105 110 115
 TGC ACT GTG CGA GGC CTG GGG CCC AGC TAC TGC TCC TTT GGT GAA ATG 437
 Cys Thr Val Arg Gly Leu Gly Pro Ser Tyr Cys Ser Phe Gly Glu Met
 120 125 130 135
 AAA GAA GGA TCC GGT AGC GGA TCT GGT AGC GCT CCT GAT GTG CAG GAT 485
 Lys Glu Gly Ser Gly Ser Gly Ser Gly Ser Ala Pro Asp Val Gln Asp
 140 145 150
 TGC CCA GAA TGC ACG CTA CAG GAA AAC CCA TTC TTC TCC CAG CCG GGT 533
 Cys Pro Glu Cys Thr Leu Gln Glu Asn Pro Phe Phe Ser Gln Pro Gly
 155 160 165
 GCC CCA ATA CTT CAG TGC ATG GGC TGC TGC TTC TCT AGA GCA TAT CCC 581
 Ala Pro Ile Leu Gln Cys Met Gly Cys Cys Phe Ser Arg Ala Tyr Pro
 170 175 180
 ACT CCA CTA AGG TCC AAG AAG ACG ATG TTG GTC CAA AAG AAC GTC ACC 629
 Thr Pro Leu Arg Ser Lys Lys Thr Met Leu Val Gln Lys Asn Val Thr
 185 190 195
 TCA GAG TCC ACT TGC TGT GTA GCT AAA TCA TAT AAC AGG GTC ACA GTA 677
 Ser Glu Ser Thr Cys Cys Val Ala Lys Ser Tyr Asn Arg Val Thr Val
 200 205 210 215
 ATG GGG GGT TTC AAA GTG GAG AAC CAC ACG GCG TGC CAC TGC AGT ACT 725
 Met Gly Gly Phe Lys Val Glu Asn His Thr Ala Cys His Cys Ser Thr
 220 225 230
 TGT TAT TAT CAC AAA TCT TAAGGTACC 752
 Cys Tyr Tyr His Lys Ser
 235
 (2) INFORMATION FOR SEQ ID NO: 18:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 237 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (v) FRAGMENT TYPE: internal
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 18
 Met Glu Met Phe Gln Gly Leu Leu Leu Leu Leu Leu Leu Ser Met Gly
 1 5 10 15
 Gly Thr Trp Ala Ser Lys Glu Pro Leu Arg Pro Arg Cys Arg Pro Ile
 20 25 30
 Asn Ala Thr Leu Ala Val Glu Lys Glu Gly Cys Pro Val Cys Ile Thr
 35 40 45
 Val Asn Thr Thr Ile Cys Ala Gly Tyr Cys Pro Thr Met Thr Arg Val
 50 55 60
 Leu Gln Gly Val Leu Pro Ala Leu Pro Gln Val Val Cys Asn Tyr Arg
 65 70 75 80
 Asp Val Arg Phe Glu Ser Ile Arg Leu Pro Gly Cys Pro Arg Gly Val
 85 90 95
 Asn Pro Val Val Ser Tyr Ala Val Ala Leu Ser Cys Gln Cys Ala Leu
 100 105 110
 Cys Arg Arg Ser Thr Thr Asp Cys Thr Val Arg Gly Leu Gly Pro Ser
 115 120 125
 Tyr Cys Ser Phe Gly Glu Met Lys Glu Gly Ser Gly Ser Gly Ser Gly
 130 135 140
 Ser Ala Pro Asp Val Gln Asp Cys Pro Glu Cys Thr Leu Gln Glu Asn
 145 150 155 160
 Pro Phe Phe Ser Gln Pro Gly Ala Pro Ile Leu Gln Cys Met Gly Cys
 165 170 175
 Cys Phe Ser Arg Ala Tyr Pro Thr Pro Leu Arg Ser Lys Lys Thr Met
 180 185 190
 Leu Val Gln Lys Asn Val Thr Ser Glu Ser Thr Cys Cys Val Ala Lys
 195 200 205
 Ser Tyr Asn Arg Val Thr Val Met Gly Gly Phe Lys Val Glu Asn His
 210 215 220
 Thr Ala Cys His Cys Ser Thr Cys Tyr Tyr His Lys Ser
 225 230 235
 (2) INFORMATION FOR SEQ ID NO: 19:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 726 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 19
 GGTACCTTAA GATTTGTGAT AATAACAAGT ACTGCAGTGG CACGCCGTGT GGTTCTCCAC 60
 TTTGAAACCC CCCATTACTG TGACCCTGTT ATATGATTTA GCTACACAGC AAGTGGACTC 120
 TGAGGTGACG TTCTTTTGGA CCAACATCGT CTTCTTGGAC CTTAGTGGAG TGGGATATGC 180
 TCTAGAGAAG CAGCAGCCCA TGCACTGAAG TATTGGGGCA CCCGGCTGGG AGAAGAATGG 240
 GTTTTCCTGT AGCGTGCATT CTGGGCAATC CTGCACATCA GGAGCGCTAC CAGATCCGCT 300
 ACCGGATCCT TCTTTCATTT CACCAAAGGA GCAGTAGCTG GGCCCCAGGC CTCGCACAGT 360
 GCAGTCAGTG GTGCTGCGGC GGCAGAGTGC ACATTGACAG CTGAGAGCCA CGGCGTAGGA 420
 GACCACGGGG TTCACGCCGC GCGGGCAGCC AGGGAGCCGG ATGGACTCGA AGCGCACATC 480
 GCGGTAGTTG CACACCACCT GAGGCAGGGC CGGCAGGACC CCCTGCAGCA CGCGGGTCAT 540
 GGTGGGGCAG TAGCCGGCAC AGATGGTGGT GTTGACGGTG ATGCACACGG GGCAGCCCTC 600
 CTTCTCCACA GCCAGGGTGG CATTGATGGG GCGGCACCGT GGCCGAAGCG GCTCCTTGGA 660
 TGCCCATGTC CCGCCCATGC TCAGCAGCAG CAACAGCAGC AGCCCCTGGA ACATCTCCAT 720
 CCTTGG 726
 (2) INFORMATION FOR SEQ ID NO: 20:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 743 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (ix) FEATURE:
 (A) NAME/KEY: Coding Sequence
 (B) LOCATION: 33...734
 (D) OTHER INFORMATION:
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 20
 ATGAAATCGA CGGAATCAGA CTCGAGCCAA GG ATG GAG ATG TTC CAG GGG CTG 53
 Met Glu Met Phe Gln Gly Leu
 1 5
 CTG CTG TTG CTG CTG CTG AGC ATG GGC GGG ACA TGG GCA TCC AAG GAG 101
 Leu Leu Leu Leu Leu Leu Ser Met Gly Gly Thr Trp Ala Ser Lys Glu
 10 15 20
 CCG CTT CGG CCA CGG TGC CGC CCC ATC AAT GCC ACC CTG GCT GTG GAG 149
 Pro Leu Arg Pro Arg Cys Arg Pro Ile Asn Ala Thr Leu Ala Val Glu
 25 30 35
 AAG GAG GGC TGC CCC GTG TGC ATC ACC GTC AAC ACC ACC ATC TGT GCC 197
 Lys Glu Gly Cys Pro Val Cys Ile Thr Val Asn Thr Thr Ile Cys Ala
 40 45 50 55
 GGC TAC TGC CCC ACC ATG ACC CGC GTG CTG CAG GGG GTC CTG CCG GCC 245
 Gly Tyr Cys Pro Thr Met Thr Arg Val Leu Gln Gly Val Leu Pro Ala
 60 65 70
 CTG CCT CAG GTG GTG TGC AAC TAC CGC GAT GTG CGC TTC GAG TCC ATC 293
 Leu Pro Gln Val Val Cys Asn Tyr Arg Asp Val Arg Phe Glu Ser Ile
 75 80 85
 CGG CTC CCT GGC TGC CCG CGC GGC GTG AAC CCC GTG GTC TCC TAC GCC 341
 Arg Leu Pro Gly Cys Pro Arg Gly Val Asn Pro Val Val Ser Tyr Ala
 90 95 100
 GTG GCT CTC AGC TGT CAA TGT GCA CTC TGC CGC CGC AGC ACC ACT GAC 389
 Val Ala Leu Ser Cys Gln Cys Ala Leu Cys Arg Arg Ser Thr Thr Asp
 105 110 115
 TGC ACT GTG CGA GGC CTG GGG CCC AGC TAC TGC TCC TTT GGT GAA GGA 437
 Cys Thr Val Arg Gly Leu Gly Pro Ser Tyr Cys Ser Phe Gly Glu Gly
 120 125 130 135
 TCC GGT AGC GGA TCT GGT AGC GCT CCT GAT GTG CAG GAT TGC CCA GAA 485
 Ser Gly Ser Gly Ser Gly Ser Ala Pro Asp Val Gln Asp Cys Pro Glu
 140 145 150
 TGC ACG CTA CAG GAA AAC CCA TTC TTC TCC CAG CCG GGT GCC CCA ATA 533
 Cys Thr Leu Gln Glu Asn Pro Phe Phe Ser Gln Pro Gly Ala Pro Ile
 155 160 165
 CTT CAG TGC ATG GGC TGC TGC TTC TCT AGA GCA TAT CCC ACT CCA CTA 581
 Leu Gln Cys Met Gly Cys Cys Phe Ser Arg Ala Tyr Pro Thr Pro Leu
 170 175 180
 AGG TCC AAG AAG ACG ATG TTG GTC CAA AAG AAC GTC ACC TCA GAG TCC 629
 Arg Ser Lys Lys Thr Met Leu Val Gln Lys Asn Val Thr Ser Glu Ser
 185 190 195
 ACT TGC TGT GTA GCT AAA TCA TAT AAC AGG GTC ACA GTA ATG GGG GGT 677
 Thr Cys Cys Val Ala Lys Ser Tyr Asn Arg Val Thr Val Met Gly Gly
 200 205 210 215
 TTC AAA GTG GAG AAC CAC ACG GCG TGC CAC TGC AGT ACT TGT TAT TAT 725
 Phe Lys Val Glu Asn His Thr Ala Cys His Cys Ser Thr Cys Tyr Tyr
 220 225 230
 CAC AAA TCT TAAGGTACC 743
 His Lys Ser
 (2) INFORMATION FOR SEQ ID NO: 21:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 234 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (v) FRAGMENT TYPE: internal
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 21
 Met Glu Met Phe Gln Gly Leu Leu Leu Leu Leu Leu Leu Ser Met Gly
 1 5 10 15
 Gly Thr Trp Ala Ser Lys Glu Pro Leu Arg Pro Arg Cys Arg Pro Ile
 20 25 30
 Asn Ala Thr Leu Ala Val Glu Lys Glu Gly Cys Pro Val Cys Ile Thr
 35 40 45
 Val Asn Thr Thr Ile Cys Ala Gly Tyr Cys Pro Thr Met Thr Arg Val
 50 55 60
 Leu Gln Gly Val Leu Pro Ala Leu Pro Gln Val Val Cys Asn Tyr Arg
 65 70 75 80
 Asp Val Arg Phe Glu Ser Ile Arg Leu Pro Gly Cys Pro Arg Gly Val
 85 90 95
 Asn Pro Val Val Ser Tyr Ala Val Ala Leu Ser Cys Gln Cys Ala Leu
 100 105 110
 Cys Arg Arg Ser Thr Thr Asp Cys Thr Val Arg Gly Leu Gly Pro Ser
 115 120 125
 Tyr Cys Ser Phe Gly Glu Gly Ser Gly Ser Gly Ser Gly Ser Ala Pro
 130 135 140
 Asp Val Gln Asp Cys Pro Glu Cys Thr Leu Gln Glu Asn Pro Phe Phe
 145 150 155 160
 Ser Gln Pro Gly Ala Pro Ile Leu Gln Cys Met Gly Cys Cys Phe Ser
 165 170 175
 Arg Ala Tyr Pro Thr Pro Leu Arg Ser Lys Lys Thr Met Leu Val Gln
 180 185 190
 Lys Asn Val Thr Ser Glu Ser Thr Cys Cys Val Ala Lys Ser Tyr Asn
 195 200 205
 Arg Val Thr Val Met Gly Gly Phe Lys Val Glu Asn His Thr Ala Cys
 210 215 220
 His Cys Ser Thr Cys Tyr Tyr His Lys Ser
 225 230
 (2) INFORMATION FOR SEQ ID NO: 22:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 717 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 22
 GGTACCTTAA GATTTGTGAT AATAACAAGT ACTGCAGTGG CACGCCGTGT GGTTCTCCAC 60
 TTTGAAACCC CCCATTACTG TGACCCTGTT ATATGATTTA GCTACACAGC AAGTGGACTC 120
 TGAGGTGACG TTCTTTTGGA CCAACATCGT CTTCTTGGAC CTTAGTGGAG TGGGATATGC 180
 TCTAGAGAAG CAGCAGCCCA TGCACTGAAG TATTGGGGCA CCCGGCTGGG AGAAGAATGG 240
 GTTTTCCTGT AGCGTGCATT CTGGGCAATC CTGCACATCA GGAGCGCTAC CAGATCCGCT 300
 ACCGGATCCT TCACCAAAGG AGCAGTAGCT GGGCCCCAGG CCTCGCACAG TGCAGTCAGT 360
 GGTGCTGCGG CGGCAGAGTG CACATTGACA GCTGAGAGCC ACGGCGTAGG AGACCACGGG 420
 GTTCACGCCG CGCGGGCAGC CAGGGAGCCG GATGGACTCG AAGCGCACAT CGCGGTAGTT 480
 GCACACCACC TGAGGCAGGG CCGGCAGGAC CCCCTGCAGC ACGCGGGTCA TGGTGGGGCA 540
 GTAGCCGGCA CAGATGGTGG TGTTGACGGT GATGCACACG GGGCAGCCCT CCTTCTCCAC 600
 AGCCAGGGTG GCATTGATGG GGCGGCACCG TGGCCGAAGC GGCTCCTTGG ATGCCCATGT 660
 CCCGCCCATG CTCAGCAGCA GCAACAGCAG CAGCCCCTGG AACATCTCCA TCCTTGG 717
 (2) INFORMATION FOR SEQ ID NO: 23:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 743 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (ix) FEATURE:
 (A) NAME/KEY: Coding Sequence
 (B) LOCATION: 33...734
 (D) OTHER INFORMATION:
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 23
 ATGAAATCGA CGGAATCAGA CTCGAGCCAA GG ATG GAG ATG TTC CAG GGG CTG 53
 Met Glu Met Phe Gln Gly Leu
 1 5
 CTG CTG TTG CTG CTG CTG AGC ATG GGC GGG ACA TGG GCA TCC AAG GAG 101
 Leu Leu Leu Leu Leu Leu Ser Met Gly Gly Thr Trp Ala Ser Lys Glu
 10 15 20
 CCG CTT CGG CCA CGG TGC CGC CCC ATC AAT GCC ACC CTG GCT GTG GAG 149
 Pro Leu Arg Pro Arg Cys Arg Pro Ile Asn Ala Thr Leu Ala Val Glu
 25 30 35
 AAG GAG GGC TGC CCC GTG TGC ATC ACC GTC AAC ACC ACC ATC TGT GCC 197
 Lys Glu Gly Cys Pro Val Cys Ile Thr Val Asn Thr Thr Ile Cys Ala
 40 45 50 55
 GGC TAC TGC CCC ACC ATG ACC CGC GTG CTG CAG GGG GTC CTG CCG GCC 245
 Gly Tyr Cys Pro Thr Met Thr Arg Val Leu Gln Gly Val Leu Pro Ala
 60 65 70
 CTG CCT CAG GTG GTG TGC AAC TAC CGC GAT GTG CGC TTC GAG TCC ATC 293
 Leu Pro Gln Val Val Cys Asn Tyr Arg Asp Val Arg Phe Glu Ser Ile
 75 80 85
 CGG CTC CCT GGC TGC CCG CGC GGC GTG AAC CCC GTG GTC TCC TAC GCC 341
 Arg Leu Pro Gly Cys Pro Arg Gly Val Asn Pro Val Val Ser Tyr Ala
 90 95 100
 GTG GCT CTC AGC TGT CAA TGT GCA CTC TGC CGC CGC AGC ACC ACT GAC 389
 Val Ala Leu Ser Cys Gln Cys Ala Leu Cys Arg Arg Ser Thr Thr Asp
 105 110 115
 TGC ACT GTG CGA GGC CTG GGG CCC AGC TAC TGC GAT GAC CCG CGG GGA 437
 Cys Thr Val Arg Gly Leu Gly Pro Ser Tyr Cys Asp Asp Pro Arg Gly
 120 125 130 135
 TCC GGT AGC GGA TCT GGT AGC GCT CCT GAT GTG CAG GAT TGC CCA GAA 485
 Ser Gly Ser Gly Ser Gly Ser Ala Pro Asp Val Gln Asp Cys Pro Glu
 140 145 150
 TGC ACG CTA CAG GAA AAC CCA TTC TTC TCC CAG CCG GGT GCC CCA ATA 533
 Cys Thr Leu Gln Glu Asn Pro Phe Phe Ser Gln Pro Gly Ala Pro Ile
 155 160 165
 CTT CAG TGC ATG GGC TGC TGC TTC TCT AGA GCA TAT CCC ACT CCA CTA 581
 Leu Gln Cys Met Gly Cys Cys Phe Ser Arg Ala Tyr Pro Thr Pro Leu
 170 175 180
 AGG TCC AAG AAG ACG ATG TTG GTC CAA AAG AAC GTC ACC TCA GAG TCC 629
 Arg Ser Lys Lys Thr Met Leu Val Gln Lys Asn Val Thr Ser Glu Ser
 185 190 195
 ACT TGC TGT GTA GCT AAA TCA TAT AAC AGG GTC ACA GTA ATG GGG GGT 677
 Thr Cys Cys Val Ala Lys Ser Tyr Asn Arg Val Thr Val Met Gly Gly
 200 205 210 215
 TTC AAA GTG GAG AAC CAC ACG GCG TGC CAC TGC AGT ACT TGT TAT TAT 725
 Phe Lys Val Glu Asn His Thr Ala Cys His Cys Ser Thr Cys Tyr Tyr
 220 225 230
 CAC AAA TCT TAAGGTACC 743
 His Lys Ser
 (2) INFORMATION FOR SEQ ID NO: 24:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 234 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (v) FRAGMENT TYPE: internal
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 24
 Met Glu Met Phe Gln Gly Leu Leu Leu Leu Leu Leu Leu Ser Met Gly
 1 5 10 15
 Gly Thr Trp Ala Ser Lys Glu Pro Leu Arg Pro Arg Cys Arg Pro Ile
 20 25 30
 Asn Ala Thr Leu Ala Val Glu Lys Glu Gly Cys Pro Val Cys Ile Thr
 35 40 45
 Val Asn Thr Thr Ile Cys Ala Gly Tyr Cys Pro Thr Met Thr Arg Val
 50 55 60
 Leu Gln Gly Val Leu Pro Ala Leu Pro Gln Val Val Cys Asn Tyr Arg
 65 70 75 80
 Asp Val Arg Phe Glu Ser Ile Arg Leu Pro Gly Cys Pro Arg Gly Val
 85 90 95
 Asn Pro Val Val Ser Tyr Ala Val Ala Leu Ser Cys Gln Cys Ala Leu
 100 105 110
 Cys Arg Arg Ser Thr Thr Asp Cys Thr Val Arg Gly Leu Gly Pro Ser
 115 120 125
 Tyr Cys Asp Asp Pro Arg Gly Ser Gly Ser Gly Ser Gly Ser Ala Pro
 130 135 140
 Asp Val Gln Asp Cys Pro Glu Cys Thr Leu Gln Glu Asn Pro Phe Phe
 145 150 155 160
 Ser Gln Pro Gly Ala Pro Ile Leu Gln Cys Met Gly Cys Cys Phe Ser
 165 170 175
 Arg Ala Tyr Pro Thr Pro Leu Arg Ser Lys Lys Thr Met Leu Val Gln
 180 185 190
 Lys Asn Val Thr Ser Glu Ser Thr Cys Cys Val Ala Lys Ser Tyr Asn
 195 200 205
 Arg Val Thr Val Met Gly Gly Phe Lys Val Glu Asn His Thr Ala Cys
 210 215 220
 His Cys Ser Thr Cys Tyr Tyr His Lys Ser
 225 230
 (2) INFORMATION FOR SEQ ID NO: 25:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 717 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 25
 GGTACCTTAA GATTTGTGAT AATAACAAGT ACTGCAGTGG CACGCCGTGT GGTTCTCCAC 60
 TTTGAAACCC CCCATTACTG TGACCCTGTT ATATGATTTA GCTACACAGC AAGTGGACTC 120
 TGAGGTGACG TTCTTTTGGA CCAACATCGT CTTCTTGGAC CTTAGTGGAG TGGGATATGC 180
 TCTAGAGAAG CAGCAGCCCA TGCACTGAAG TATTGGGGCA CCCGGCTGGG AGAAGAATGG 240
 GTTTTCCTGT AGCGTGCATT CTGGGCAATC CTGCACATCA GGAGCGCTAC CAGATCCGCT 300
 ACCGGATCCC CGCGGGTCAT CGCAGTAGCT GGGCCCCAGG CCTCGCACAG TGCAGTCAGT 360
 GGTGCTGCGG CGGCAGAGTG CACATTGACA GCTGAGAGCC ACGGCGTAGG AGACCACGGG 420
 GTTCACGCCG CGCGGGCAGC CAGGGAGCCG GATGGACTCG AAGCGCACAT CGCGGTAGTT 480
 GCACACCACC TGAGGCAGGG CCGGCAGGAC CCCCTGCAGC ACGCGGGTCA TGGTGGGGCA 540
 GTAGCCGGCA CAGATGGTGG TGTTGACGGT GATGCACACG GGGCAGCCCT CCTTCTCCAC 600
 AGCCAGGGTG GCATTGATGG GGCGGCACCG TGGCCGAAGC GGCTCCTTGG ATGCCCATGT 660
 CCCGCCCATG CTCAGCAGCA GCAACAGCAG CAGCCCCTGG AACATCTCCA TCCTTGG 717
 (2) INFORMATION FOR SEQ ID NO: 26:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 719 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (ix) FEATURE:
 (A) NAME/KEY: Coding Sequence
 (B) LOCATION: 33...700
 (D) OTHER INFORMATION:
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 26
 ATGAAATCGA CGGAATCAGA CTCGAGCCAA GG ATG AAG ACA CTC CAG TTT TTC 53
 Met Lys Thr Leu Gln Phe Phe
 1 5
 TTC CTT TTC TGT TGC TGG AAA GCA ATC TGC TGC AAT AGC TGT GAG CTG 101
 Phe Leu Phe Cys Cys Trp Lys Ala Ile Cys Cys Asn Ser Cys Glu Leu
 10 15 20
 ACC AAC ATC ACC ATT GCA ATA GAG AAA GAA GAA TGT CGT TTC TGC ATA 149
 Thr Asn Ile Thr Ile Ala Ile Glu Lys Glu Glu Cys Arg Phe Cys Ile
 25 30 35
 AGC ATC AAC ACC ACT TGG TGT GCT GGC TAC TGC TAC ACC AGG GAT CTG 197
 Ser Ile Asn Thr Thr Trp Cys Ala Gly Tyr Cys Tyr Thr Arg Asp Leu
 40 45 50 55
 GTG TAT AAG GAC CCA GCC AGG CCC AAA ATC CAG AAA ACA TGT ACC TTC 245
 Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe
 60 65 70
 AAG GAA CTG GTA TAT GAA ACA GTG AGA GTG CCC GGC TGT GCT CAC CAT 293
 Lys Glu Leu Val Tyr Glu Thr Val Arg Val Pro Gly Cys Ala His His
 75 80 85
 GCA GAT TCC TTG TAT ACA TAC CCA GTG GCC ACC CAG TGT CAC TGT GGC 341
 Ala Asp Ser Leu Tyr Thr Tyr Pro Val Ala Thr Gln Cys His Cys Gly
 90 95 100
 AAG TGT GAC AGC GAC AGC ACT GAT TGT ACT GTG CGA GGC CTG GGG CCC 389
 Lys Cys Asp Ser Asp Ser Thr Asp Cys Thr Val Arg Gly Leu Gly Pro
 105 110 115
 AGC TAC TGC TCC TTT GGT GAA GGA TCC GGT AGC GGA TCT GGT AGC GCT 437
 Ser Tyr Cys Ser Phe Gly Glu Gly Ser Gly Ser Gly Ser Gly Ser Ala
 120 125 130 135
 CCT GAT GTG CAG GAT TGC CCA GAA TGC ACG CTA CAG GAA AAC CCA TTC 485
 Pro Asp Val Gln Asp Cys Pro Glu Cys Thr Leu Gln Glu Asn Pro Phe
 140 145 150
 TTC TCC CAG CCG GGT GCC CCA ATA CTT CAG TGC ATG GGC TGC TGC TTC 533
 Phe Ser Gln Pro Gly Ala Pro Ile Leu Gln Cys Met Gly Cys Cys Phe
 155 160 165
 TCT AGA GCA TAT CCC ACT CCA CTA AGG TCC AAG AAG ACG ATG TTG GTC 581
 Ser Arg Ala Tyr Pro Thr Pro Leu Arg Ser Lys Lys Thr Met Leu Val
 170 175 180
 CAA AAG AAC GTC ACC TCA GAG TCC ACT TGC TGT GTA GCT AAA TCA TAT 629
 Gln Lys Asn Val Thr Ser Glu Ser Thr Cys Cys Val Ala Lys Ser Tyr
 185 190 195
 AAC AGG GTC ACA GTA ATG GGG GGT TTC AAA GTG GAG AAC CAC ACG GCG 677
 Asn Arg Val Thr Val Met Gly Gly Phe Lys Val Glu Asn His Thr Ala
 200 205 210 215
 TGC CAC TGC AGT ACT TGT TAT TA TCACAAATCT TAAGGTACC 719
 Cys His Cys Ser Thr Cys Tyr Tyr
 220
 (2) INFORMATION FOR SEQ ID NO: 27:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 223 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (v) FRAGMENT TYPE: internal
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 27
 Met Lys Thr Leu Gln Phe Phe Phe Leu Phe Cys Cys Trp Lys Ala Ile
 1 5 10 15
 Cys Cys Asn Ser Cys Glu Leu Thr Asn Ile Thr Ile Ala Ile Glu Lys
 20 25 30
 Glu Glu Cys Arg Phe Cys Ile Ser Ile Asn Thr Thr Trp Cys Ala Gly
 35 40 45
 Tyr Cys Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys
 50 55 60
 Ile Gln Lys Thr Cys Thr Phe Lys Glu Leu Val Tyr Glu Thr Val Arg
 65 70 75 80
 Val Pro Gly Cys Ala His His Ala Asp Ser Leu Tyr Thr Tyr Pro Val
 85 90 95
 Ala Thr Gln Cys His Cys Gly Lys Cys Asp Ser Asp Ser Thr Asp Cys
 100 105 110
 Thr Val Arg Gly Leu Gly Pro Ser Tyr Cys Ser Phe Gly Glu Gly Ser
 115 120 125
 Gly Ser Gly Ser Gly Ser Ala Pro Asp Val Gln Asp Cys Pro Glu Cys
 130 135 140
 Thr Leu Gln Glu Asn Pro Phe Phe Ser Gln Pro Gly Ala Pro Ile Leu
 145 150 155 160
 Gln Cys Met Gly Cys Cys Phe Ser Arg Ala Tyr Pro Thr Pro Leu Arg
 165 170 175
 Ser Lys Lys Thr Met Leu Val Gln Lys Asn Val Thr Ser Glu Ser Thr
 180 185 190
 Cys Cys Val Ala Lys Ser Tyr Asn Arg Val Thr Val Met Gly Gly Phe
 195 200 205
 Lys Val Glu Asn His Thr Ala Cys His Cys Ser Thr Cys Tyr Tyr
 210 215 220
 (2) INFORMATION FOR SEQ ID NO: 28:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 693 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 28
 GGTACCTTAA GATTTGTGAT AATAACAAGT ACTGCAGTGG CACGCCGTGT GGTTCTCCAC 60
 TTTGAAACCC CCCATTACTG TGACCCTGTT ATATGATTTA GCTACACAGC AAGTGGACTC 120
 TGAGGTGACG TTCTTTTGGA CCAACATCGT CTTCTTGGAC CTTAGTGGAG TGGGATATGC 180
 TCTAGAGAAG CAGCAGCCCA TGCACTGAAG TATTGGGGCA CCCGGCTGGG AGAAGAATGG 240
 GTTTTCCTGT AGCGTGCATT CTGGGCAATC CTGCACATCA GGAGCGCTAC CAGATCCGCT 300
 ACCGGATCCT TCACCAAAGG AGCAGTAGCT GGGCCCCAGG CCTCGCACAG TACAATCAGT 360
 GCTGTCGCTG TCACACTTGC CACAGTGACA CTGGGTGGCC ACTGGGTATG TATACAAGGA 420
 ATCTGCATGG TGAGCACAGC CGGGCACTCT CACTGTTTCA TATACCAGTT CCTTGAAGGT 480
 ACATGTTTTC TGGATTTTGG GCCTGGCTGG GTCCTTATAC ACCAGATCCC TGGTGTAGCA 540
 GTAGCCAGCA CACCAAGTGG TGTTGATGCT TATGCAGAAA CGACATTCTT CTTTCTCTAT 600
 TGCAATGGTG ATGTTGGTCA GCTCACAGCT ATTGCAGCAG ATTGCTTTCC AGCAACAGAA 660
 AAGGAAGAAA AACTGGAGTG TCTTCATCCT TGG 693
 (2) INFORMATION FOR SEQ ID NO: 29:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 707 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (ix) FEATURE:
 (A) NAME/KEY: Coding Sequence
 (B) LOCATION: 33...698
 (D) OTHER INFORMATION:
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 29
 ATGAAATCGA CGGAATCAGA CTCGAGCCAA GG ATG AAG ACA CTC CAG TTT TTC 53
 Met Lys Thr Leu Gln Phe Phe
 1 5
 TTC CTT TTC TGT TGC TGG AAA GCA ATC TGC TGC AAT AGC TGT GAG CTG 101
 Phe Leu Phe Cys Cys Trp Lys Ala Ile Cys Cys Asn Ser Cys Glu Leu
 10 15 20
 ACC AAC ATC ACC ATT GCA ATA GAG AAA GAA GAA TGT CGT TTC TGC ATA 149
 Thr Asn Ile Thr Ile Ala Ile Glu Lys Glu Glu Cys Arg Phe Cys Ile
 25 30 35
 AGC ATC AAC ACC ACT TGG TGT GCT GGC TAC TGC TAC ACC AGG GAT CTG 197
 Ser Ile Asn Thr Thr Trp Cys Ala Gly Tyr Cys Tyr Thr Arg Asp Leu
 40 45 50 55
 GTG TAT AAG GAC CCA GCC AGG CCC AAA ATC CAG AAA ACA TGT ACC TTC 245
 Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe
 60 65 70
 AAG GAA CTG GTA TAT GAA ACA GTG AGA GTG CCC GGC TGT GCT CAC CAT 293
 Lys Glu Leu Val Tyr Glu Thr Val Arg Val Pro Gly Cys Ala His His
 75 80 85
 GCA GAT TCC TTG TAT ACA TAC CCA GTG GCC ACC CAG TGT CAC TGT GGC 341
 Ala Asp Ser Leu Tyr Thr Tyr Pro Val Ala Thr Gln Cys His Cys Gly
 90 95 100
 AAG TGT GAC AGC GAC AGC ACT GAT TGT ACT GTG CGA GGC CTG GGG CCC 389
 Lys Cys Asp Ser Asp Ser Thr Asp Cys Thr Val Arg Gly Leu Gly Pro
 105 110 115
 AGC TAC TGC GGA TCC GGT AGC GGA TCT GGT AGC GCT CCT GAT GTG CAG 437
 Ser Tyr Cys Gly Ser Gly Ser Gly Ser Gly Ser Ala Pro Asp Val Gln
 120 125 130 135
 GAT TGC CCA GAA TGC ACG CTA CAG GAA AAC CCA TTC TTC TCC CAG CCG 485
 Asp Cys Pro Glu Cys Thr Leu Gln Glu Asn Pro Phe Phe Ser Gln Pro
 140 145 150
 GGT GCC CCA ATA CTT CAG TGC ATG GGC TGC TGC TTC TCT AGA GCA TAT 533
 Gly Ala Pro Ile Leu Gln Cys Met Gly Cys Cys Phe Ser Arg Ala Tyr
 155 160 165
 CCC ACT CCA CTA AGG TCC AAG AAG ACG ATG TTG GTC CAA AAG AAC GTC 581
 Pro Thr Pro Leu Arg Ser Lys Lys Thr Met Leu Val Gln Lys Asn Val
 170 175 180
 ACC TCA GAG TCC ACT TGC TGT GTA GCT AAA TCA TAT AAC AGG GTC ACA 629
 Thr Ser Glu Ser Thr Cys Cys Val Ala Lys Ser Tyr Asn Arg Val Thr
 185 190 195
 GTA ATG GGG GGT TTC AAA GTG GAG AAC CAC ACG GCG TGC CAC TGC AGT 677
 Val Met Gly Gly Phe Lys Val Glu Asn His Thr Ala Cys His Cys Ser
 200 205 210 215
 ACT TGT TAT TAT CAC AAA TCT TAAGGTACC 707
 Thr Cys Tyr Tyr His Lys Ser
 220
 (2) INFORMATION FOR SEQ ID NO: 30:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 222 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (v) FRAGMENT TYPE: internal
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 30
 Met Lys Thr Leu Gln Phe Phe Phe Leu Phe Cys Cys Trp Lys Ala Ile
 1 5 10 15
 Cys Cys Asn Ser Cys Glu Leu Thr Asn Ile Thr Ile Ala Ile Glu Lys
 20 25 30
 Glu Glu Cys Arg Phe Cys Ile Ser Ile Asn Thr Thr Trp Cys Ala Gly
 35 40 45
 Tyr Cys Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys
 50 55 60
 Ile Gln Lys Thr Cys Thr Phe Lys Glu Leu Val Tyr Glu Thr Val Arg
 65 70 75 80
 Val Pro Gly Cys Ala His His Ala Asp Ser Leu Tyr Thr Tyr Pro Val
 85 90 95
 Ala Thr Gln Cys His Cys Gly Lys Cys Asp Ser Asp Ser Thr Asp Cys
 100 105 110
 Thr Val Arg Gly Leu Gly Pro Ser Tyr Cys Gly Ser Gly Ser Gly Ser
 115 120 125
 Gly Ser Ala Pro Asp Val Gln Asp Cys Pro Glu Cys Thr Leu Gln Glu
 130 135 140
 Asn Pro Phe Phe Ser Gln Pro Gly Ala Pro Ile Leu Gln Cys Met Gly
 145 150 155 160
 Cys Cys Phe Ser Arg Ala Tyr Pro Thr Pro Leu Arg Ser Lys Lys Thr
 165 170 175
 Met Leu Val Gln Lys Asn Val Thr Ser Glu Ser Thr Cys Cys Val Ala
 180 185 190
 Lys Ser Tyr Asn Arg Val Thr Val Met Gly Gly Phe Lys Val Glu Asn
 195 200 205
 His Thr Ala Cys His Cys Ser Thr Cys Tyr Tyr His Lys Ser
 210 215 220
 (2) INFORMATION FOR SEQ ID NO: 31:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 681 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 31
 GGTACCTTAA GATTTGTGAT AATAACAAGT ACTGCAGTGG CACGCCGTGT GGTTCTCCAC 60
 TTTGAAACCC CCCATTACTG TGACCCTGTT ATATGATTTA GCTACACAGC AAGTGGACTC 120
 TGAGGTGACG TTCTTTTGGA CCAACATCGT CTTCTTGGAC CTTAGTGGAG TGGGATATGC 180
 TCTAGAGAAG CAGCAGCCCA TGCACTGAAG TATTGGGGCA CCCGGCTGGG AGAAGAATGG 240
 GTTTTCCTGT AGCGTGCATT CTGGGCAATC CTGCACATCA GGAGCGCTAC CAGATCCGCT 300
 ACCGGATCCG CAGTAGCTGG GCCCCAGGCC TCGCACAGTA CAATCAGTGC TGTCGCTGTC 360
 ACACTTGCCA CAGTGACACT GGGTGGCCAC TGGGTATGTA TACAAGGAAT CTGCATGGTG 420
 AGCACAGCCG GGCACTCTCA CTGTTTCATA TACCAGTTCC TTGAAGGTAC ATGTTTTCTG 480
 GATTTTGGGC CTGGCTGGGT CCTTATACAC CAGATCCCTG GTGTAGCAGT AGCCAGCACA 540
 CCAAGTGGTG TTGATGCTTA TGCAGAAACG ACATTCTTCT TTCTCTATTG CAATGGTGAT 600
 GTTGGTCAGC TCACAGCTAT TGCAGCAGAT TGCTTTCCAG CAACAGAAAA GGAAGAAAAA 660
 CTGGAGTGTC TTCATCCTTG G 681
 (2) INFORMATION FOR SEQ ID NO: 32:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 312 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (ix) FEATURE:
 (A) NAME/KEY: Coding Sequence
 (B) LOCATION: 1...303
 (D) OTHER INFORMATION:
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 32
 TGC GGA TCC GGT AGC GGA TCT GGT AGC GCT CCT GAT GTG CAG GAT TGC 48
 Cys Gly Ser Gly Ser Gly Ser Gly Ser Ala Pro Asp Val Gln Asp Cys
 1 5 10 15
 CCA GAA TGC ACG CTA CAG GAA AAC CCA TTC TTC TCC CAG CCG GGT GCC 96
 Pro Glu Cys Thr Leu Gln Glu Asn Pro Phe Phe Ser Gln Pro Gly Ala
 20 25 30
 CCA ATA CTT CAG TGC ATG GGC TGC TGC TTC TCT AGA GCA TAT CCC ACT 144
 Pro Ile Leu Gln Cys Met Gly Cys Cys Phe Ser Arg Ala Tyr Pro Thr
 35 40 45
 CCA CTA AGG TCC AAG AAG ACG ATG TTG GTC CAA AAG CAA GTC ACC TCA 192
 Pro Leu Arg Ser Lys Lys Thr Met Leu Val Gln Lys Gln Val Thr Ser
 50 55 60
 GAG TCC ACT TGC TGT GTA GCT AAA TCA TAT AAC AGG GTC ACA GTA ATG 240
 Glu Ser Thr Cys Cys Val Ala Lys Ser Tyr Asn Arg Val Thr Val Met
 65 70 75 80
 GGG GGT TTC AAA GTG GAG CAA CAC ACG GCG TGC CAC TGC AGT ACT TGT 288
 Gly Gly Phe Lys Val Glu Gln His Thr Ala Cys His Cys Ser Thr Cys
 85 90 95
 TAT TAT CAC AAA TCT TAAGGTACC 312
 Tyr Tyr His Lys Ser
 100
 (2) INFORMATION FOR SEQ ID NO: 33:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 101 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (v) FRAGMENT TYPE: internal
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 33
 Cys Gly Ser Gly Ser Gly Ser Gly Ser Ala Pro Asp Val Gln Asp Cys
 1 5 10 15
 Pro Glu Cys Thr Leu Gln Glu Asn Pro Phe Phe Ser Gln Pro Gly Ala
 20 25 30
 Pro Ile Leu Gln Cys Met Gly Cys Cys Phe Ser Arg Ala Tyr Pro Thr
 35 40 45
 Pro Leu Arg Ser Lys Lys Thr Met Leu Val Gln Lys Gln Val Thr Ser
 50 55 60
 Glu Ser Thr Cys Cys Val Ala Lys Ser Tyr Asn Arg Val Thr Val Met
 65 70 75 80
 Gly Gly Phe Lys Val Glu Gln His Thr Ala Cys His Cys Ser Thr Cys
 85 90 95
 Tyr Tyr His Lys Ser
 100
 (2) INFORMATION FOR SEQ ID NO: 34:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 317 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 34
 GTACCGGTAC CTTAAGATTT GTGATAATAA CAAGTACTGC AGTGGCACGC CGTGTGTTGC 60
 TCCACTTTGA AACCCCCCAT TACTGTGACC CTGTTATATG ATTTAGCTAC ACAGCAAGTG 120
 GACTCTGAGG TGACTTGCTT TTGGACCAAC ATCGTCTTCT TGGACCTTAG TGGAGTGGGA 180
 TATGCTCTAG AGAAGCAGCA GCCCATGCAC TGAAGTATTG GGGCACCCGG CTGGGAGAAG 240
 AATGGGTTTT CCTGTAGCGT GCATTCTGGG CAATCCTGCA CATCAGGAGC GCTACCAGAT 300
 CCGCTACCGG ATCCGCA 317
 (2) INFORMATION FOR SEQ ID NO: 35:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 575 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (ix) FEATURE:
 (A) NAME/KEY: Coding Sequence
 (B) LOCATION: 33...575
 (D) OTHER INFORMATION:
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 35
 ATGAAATCGA CGGAATCAGA CTCGAGCCAA GG ATG GAG ATG TTC CAG GGG CTG 53
 Met Glu Met Phe Gln Gly Leu
 1 5
 CTG CTG TTG CTG CTG CTG AGC ATG GGC GGG ACA TGG GCA TCC AAG GAG 101
 Leu Leu Leu Leu Leu Leu Ser Met Gly Gly Thr Trp Ala Ser Lys Glu
 10 15 20
 CCG CTT CGG CCA CGG TGC CGC CCC ATC CAA GCC ACC CTG GCT GTG GAG 149
 Pro Leu Arg Pro Arg Cys Arg Pro Ile Gln Ala Thr Leu Ala Val Glu
 25 30 35
 AAG GAG GGC TGC CCC GTG TGC ATC ACC GTC AAC ACC ACC ATC TGT GCC 197
 Lys Glu Gly Cys Pro Val Cys Ile Thr Val Asn Thr Thr Ile Cys Ala
 40 45 50 55
 GGC TAC TGC CCC ACC ATG ACC CGC GTG CTG CAG GGG GTC CTG CCG GCC 245
 Gly Tyr Cys Pro Thr Met Thr Arg Val Leu Gln Gly Val Leu Pro Ala
 60 65 70
 CTG CCT CAG GTG GTG TGC AAC TAC CGC GAT GTG CGC TTC GAG TCC ATC 293
 Leu Pro Gln Val Val Cys Asn Tyr Arg Asp Val Arg Phe Glu Ser Ile
 75 80 85
 CGG CTC CCT GGC TGC CCG CGC GGC GTG AAC CCC GTG GTC TCC TAC GCC 341
 Arg Leu Pro Gly Cys Pro Arg Gly Val Asn Pro Val Val Ser Tyr Ala
 90 95 100
 GTG GCT CTC AGC TGT CAA TGT GCA CTC TGC CGC CGC AGC ACC ACT GAC 389
 Val Ala Leu Ser Cys Gln Cys Ala Leu Cys Arg Arg Ser Thr Thr Asp
 105 110 115
 TGC GGG GGT CCC AAG GAC CAC CCC TTG ACC TGT GAT GAC CCC CGC TTC 437
 Cys Gly Gly Pro Lys Asp His Pro Leu Thr Cys Asp Asp Pro Arg Phe
 120 125 130 135
 CAG GAC TCC TCT TCC TCA AAG GCC CCT CCC CCC AGC CTT CCA AGC CCA 485
 Gln Asp Ser Ser Ser Ser Lys Ala Pro Pro Pro Ser Leu Pro Ser Pro
 140 145 150
 TCC CGA CTC CCG GGG CCC TCG GAC ACC CCG ATC CTC CCC CAA GGA TCC 533
 Ser Arg Leu Pro Gly Pro Ser Asp Thr Pro Ile Leu Pro Gln Gly Ser
 155 160 165
 GGT AGC GGA TCT GGT AGC GCT CCT GAT GTG CAG GAT TGC CCA 575
 Gly Ser Gly Ser Gly Ser Ala Pro Asp Val Gln Asp Cys Pro
 170 175 180
 (2) INFORMATION FOR SEQ ID NO: 36:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 181 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (v) FRAGMENT TYPE: internal
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 36
 Met Glu Met Phe Gln Gly Leu Leu Leu Leu Leu Leu Leu Ser Met Gly
 1 5 10 15
 Gly Thr Trp Ala Ser Lys Glu Pro Leu Arg Pro Arg Cys Arg Pro Ile
 20 25 30
 Gln Ala Thr Leu Ala Val Glu Lys Glu Gly Cys Pro Val Cys Ile Thr
 35 40 45
 Val Asn Thr Thr Ile Cys Ala Gly Tyr Cys Pro Thr Met Thr Arg Val
 50 55 60
 Leu Gln Gly Val Leu Pro Ala Leu Pro Gln Val Val Cys Asn Tyr Arg
 65 70 75 80
 Asp Val Arg Phe Glu Ser Ile Arg Leu Pro Gly Cys Pro Arg Gly Val
 85 90 95
 Asn Pro Val Val Ser Tyr Ala Val Ala Leu Ser Cys Gln Cys Ala Leu
 100 105 110
 Cys Arg Arg Ser Thr Thr Asp Cys Gly Gly Pro Lys Asp His Pro Leu
 115 120 125
 Thr Cys Asp Asp Pro Arg Phe Gln Asp Ser Ser Ser Ser Lys Ala Pro
 130 135 140
 Pro Pro Ser Leu Pro Ser Pro Ser Arg Leu Pro Gly Pro Ser Asp Thr
 145 150 155 160
 Pro Ile Leu Pro Gln Gly Ser Gly Ser Gly Ser Gly Ser Ala Pro Asp
 165 170 175
 Val Gln Asp Cys Pro
 180
 (2) INFORMATION FOR SEQ ID NO: 37:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 549 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 37
 TGGGCAATCC TGCACATCAG GAGCGCTACC AGATCCGCTA CCGGATCCTT GGGGGAGGAT 60
 CGGGGTGTCC GAGGGCCCCG GGAGTCGGGA TGGGCTTGGA AGGCTGGGGG GAGGGGCCTT 120
 TGAGGAAGAG GAGTCCTGGA AGCGGGGGTC ATCACAGGTC AAGGGGTGGT CCTTGGGACC 180
 CCCGCAGTCA GTGGTGCTGC GGCGGCAGAG TGCACATTGA CAGCTGAGAG CCACGGCGTA 240
 GGAGACCACG GGGTTCACGC CGCGCGGGCA GCCAGGGAGC CGGATGGACT CGAAGCGCAC 300
 ATCGCGGTAG TTGCACACCA CCTGAGGCAG GGCCGGCAGG ACCCCCTGCA GCACGCGGGT 360
 CATGGTGGGG CAGTAGCCGG CACAGATGGT GGTGTTGACG GTGATGCACA CGGGGCAGCC 420
 CTCCTTCTCC ACAGCCAGGG TGGCTTGGAT GGGGCGGCAC CGTGGCCGAA GCGGCTCCTT 480
 GGATGCCCAT GTCCCGCCCA TGCTCAGCAG CAGCAACAGC AGCAGCCCCT GGAACATCTC 540
 CATCCTTGG 549
 (2) INFORMATION FOR SEQ ID NO: 38:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 837 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (ix) FEATURE:
 (A) NAME/KEY: Coding Sequence
 (B) LOCATION: 33...827
 (D) OTHER INFORMATION:
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 38
 ATGAAATCGA CGGAATCAGA CTCGAGCCAA GG ATG GAG ATG TTC CAG GGG CTG 53
 Met Glu Met Phe Gln Gly Leu
 1 5
 CTG CTG TTG CTG CTG CTG AGC ATG GGC GGG ACA TGG GCA TCC AAG GAG 101
 Leu Leu Leu Leu Leu Leu Ser Met Gly Gly Thr Trp Ala Ser Lys Glu
 10 15 20
 CCG CTT CGG CCA CGG TGC CGC CCC ATC AAT GCC ACC CTG GCT GTG GAG 149
 Pro Leu Arg Pro Arg Cys Arg Pro Ile Asn Ala Thr Leu Ala Val Glu
 25 30 35
 AAG GAG GGC TGC CCC GTG TGC ATC ACC GTC AAC ACC ACC ATC TGT GCC 197
 Lys Glu Gly Cys Pro Val Cys Ile Thr Val Asn Thr Thr Ile Cys Ala
 40 45 50 55
 GGC TAC TGC CCC ACC ATG ACC CGC GTG CTG CAG GGG GTC CTG CCG GCC 245
 Gly Tyr Cys Pro Thr Met Thr Arg Val Leu Gln Gly Val Leu Pro Ala
 60 65 70
 CTG CCT CAG GTG GTG TGC AAC TAC CGC GAT GTG CGC TTC GAG TCC ATC 293
 Leu Pro Gln Val Val Cys Asn Tyr Arg Asp Val Arg Phe Glu Ser Ile
 75 80 85
 CGG CTC CCT GGC TGC CCG CGC GGC GTG AAC CCC GTG GTC TCC TAC GCC 341
 Arg Leu Pro Gly Cys Pro Arg Gly Val Asn Pro Val Val Ser Tyr Ala
 90 95 100
 GTG GCT CTC AGC TGT CAA TGT GCA CTC TGC CGC CGC AGC ACC ACT GAC 389
 Val Ala Leu Ser Cys Gln Cys Ala Leu Cys Arg Arg Ser Thr Thr Asp
 105 110 115
 TGC GGG GGT CCC AAG GAC CAC CCC TTG ACC TGT GAT GAC CCC CGC TTC 437
 Cys Gly Gly Pro Lys Asp His Pro Leu Thr Cys Asp Asp Pro Arg Phe
 120 125 130 135
 CAG GAC TCC TCT TCC TCA AAG GCC CCT CCC CCC AGC CTT CCA AGC CCA 485
 Gln Asp Ser Ser Ser Ser Lys Ala Pro Pro Pro Ser Leu Pro Ser Pro
 140 145 150
 TCC CGA CTC CCG GGG CCC TCG GAC ACC CCG ATC CTC CCC CAA GGA TCC 533
 Ser Arg Leu Pro Gly Pro Ser Asp Thr Pro Ile Leu Pro Gln Gly Ser
 155 160 165
 GGT AGC GGA TCT GGT AGC GCT CCT GAT GTG CAG GAT TGC CCA GAA TGC 581
 Gly Ser Gly Ser Gly Ser Ala Pro Asp Val Gln Asp Cys Pro Glu Cys
 170 175 180
 ACG CTA CAG GAA AAC CCA TTC TTC TCC CAG CCG GGT GCC CCA ATA CTT 629
 Thr Leu Gln Glu Asn Pro Phe Phe Ser Gln Pro Gly Ala Pro Ile Leu
 185 190 195
 CAG TGC ATG GGC TGC TGC TTC TCT AGA GCA TAT CCC ACT CCA CTA AGG 677
 Gln Cys Met Gly Cys Cys Phe Ser Arg Ala Tyr Pro Thr Pro Leu Arg
 200 205 210 215
 TCC AAG AAG ACG ATG TTG GTC CAA AAG CAA GTC ACC TCA GAG TCC ACT 725
 Ser Lys Lys Thr Met Leu Val Gln Lys Gln Val Thr Ser Glu Ser Thr
 220 225 230
 TGC TGT GTA GCT AAA TCA TAT AAC AGG GTC ACA GTA ATG GGG GGT TTC 773
 Cys Cys Val Ala Lys Ser Tyr Asn Arg Val Thr Val Met Gly Gly Phe
 235 240 245
 AAA GTG GAG CAA CAC ACG GCG TGC CAC TGC AGT ACT TGT TAT TAT CAC 821
 Lys Val Glu Gln His Thr Ala Cys His Cys Ser Thr Cys Tyr Tyr His
 250 255 260
 AAA TCT TAAGTTAACC 837
 Lys Ser
 265
 (2) INFORMATION FOR SEQ ID NO: 39:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 265 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (v) FRAGMENT TYPE: internal
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 39
 Met Glu Met Phe Gln Gly Leu Leu Leu Leu Leu Leu Leu Ser Met Gly
 1 5 10 15
 Gly Thr Trp Ala Ser Lys Glu Pro Leu Arg Pro Arg Cys Arg Pro Ile
 20 25 30
 Asn Ala Thr Leu Ala Val Glu Lys Glu Gly Cys Pro Val Cys Ile Thr
 35 40 45
 Val Asn Thr Thr Ile Cys Ala Gly Tyr Cys Pro Thr Met Thr Arg Val
 50 55 60
 Leu Gln Gly Val Leu Pro Ala Leu Pro Gln Val Val Cys Asn Tyr Arg
 65 70 75 80
 Asp Val Arg Phe Glu Ser Ile Arg Leu Pro Gly Cys Pro Arg Gly Val
 85 90 95
 Asn Pro Val Val Ser Tyr Ala Val Ala Leu Ser Cys Gln Cys Ala Leu
 100 105 110
 Cys Arg Arg Ser Thr Thr Asp Cys Gly Gly Pro Lys Asp His Pro Leu
 115 120 125
 Thr Cys Asp Asp Pro Arg Phe Gln Asp Ser Ser Ser Ser Lys Ala Pro
 130 135 140
 Pro Pro Ser Leu Pro Ser Pro Ser Arg Leu Pro Gly Pro Ser Asp Thr
 145 150 155 160
 Pro Ile Leu Pro Gln Gly Ser Gly Ser Gly Ser Gly Ser Ala Pro Asp
 165 170 175
 Val Gln Asp Cys Pro Glu Cys Thr Leu Gln Glu Asn Pro Phe Phe Ser
 180 185 190
 Gln Pro Gly Ala Pro Ile Leu Gln Cys Met Gly Cys Cys Phe Ser Arg
 195 200 205
 Ala Tyr Pro Thr Pro Leu Arg Ser Lys Lys Thr Met Leu Val Gln Lys
 210 215 220
 Gln Val Thr Ser Glu Ser Thr Cys Cys Val Ala Lys Ser Tyr Asn Arg
 225 230 235 240
 Val Thr Val Met Gly Gly Phe Lys Val Glu Gln His Thr Ala Cys His
 245 250 255
 Cys Ser Thr Cys Tyr Tyr His Lys Ser
 260 265
 (2) INFORMATION FOR SEQ ID NO: 40:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 835 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: double
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 40
 TCCGGATTAG CTTGAGATGG ATCCGGTTAA CTTAAGATTT GTGATAATAA CAAGTACTGC 60
 AGTGGCACGC CGTGTGTTGC TCCACTTTGA AACCCCCCAT TACTGTGACC CTGTTATATG 120
 ATTTAGCTAC ACAGCAAGTG GACTCTGAGG TGACTTGCTT TTGGACCAAC ATCGTCTTCT 180
 TGGACCTTAG TGGAGTGGGA TATGCTCTAG AGAAGCAGCA GCCCATGCAC TGAAGTATTG 240
 GGGCACCCGG CTGGGAGAAG AATGGGTTTT CCTGTAGCGT GCATTCTGGG CAATCCTGCA 300
 CATCAGGAGC GCTACCAGAT CCGCTACCGG ATCCTTGGGG GAGGATCGGG GTGTCCGAGG 360
 GCCCCGGGAG TCGGGATGGG CTTGGAAGGC TGGGGGGAGG GGCCTTTGAG GAAGAGGAGT 420
 CCTGGAAGCG GGGGTCATCA CAGGTCAAGG GGTGGTCCTT GGGACCCCCG CAGTCAGTGG 480
 TGCTGCGGCG GCAGAGTGCA CATTGACAGC TGAGAGCCAC GGCGTAGGAG ACCACGGGGT 540
 TCACGCCGCG CGGGCAGCCA GGGAGCCGGA TGGACTCGAA GCGCACATCG CGGTAGTTGC 600
 ACACCACCTG AGGCAGGGCC GGCAGGACCC CCTGCAGCAC GCGGGTCATG GTGGGGCAGT 660
 AGCCGGCACA GATGGTGGTG TTGACGGTGA TGCACACGGG GCAGCCCTCC TTCTCCACAG 720
 CCAGGGTGGC ATTGATGGGG CGGCACCGTG GCCGAAGCGG CTCCTTGGAT GCCCATGTCC 780
 CGCCCATGCT CAGCAGCAGC AACAGCAGCA GCCCCTGGAA CATCTCCATC CTTGG 835
 (2) INFORMATION FOR SEQ ID NO: 41:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 27 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 41
 GGAGGAAGGG TGGTCGACCT CTCTGGT 27
 (2) INFORMATION FOR SEQ ID NO: 42:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 27 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 42
 CACATCAGGA GCTTGTGGGA GGATCGG 27
 (2) INFORMATION FOR SEQ ID NO: 43:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 27 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 43
 ATCCTCCCAC AAGCTCCTGA TGTGCAG 27
 (2) INFORMATION FOR SEQ ID NO: 44:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 30 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 44
 TGAGTCGACA TGATAATTCA GTGATTGAAT 30
 (2) INFORMATION FOR SEQ ID NO: 45:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 55 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 45
 ATGAAATCGA CGGAATCAGA CTCGAGCCAA GGATGGAGAT GTTCCAGGGG CTGCT 55
 (2) INFORMATION FOR SEQ ID NO: 46:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 51 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 46
 GCTACCAGAT CCGCTACCGG ATCCTTGGGG GAGGATCGGG GTGTCCGAGG G 51
 (2) INFORMATION FOR SEQ ID NO: 47:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 48 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 47
 GGATCCGGTA GCGGATCTGG TAGCGCTCCT GATGTGCAGG ATTGCCCA 48
 (2) INFORMATION FOR SEQ ID NO: 48:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 60 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 48
 TCCGGATTAG CTTGAGATGG ATCCGGTACC TTAAGATTTG TGATAATAAC AAGTACTGCA 60
 (2) INFORMATION FOR SEQ ID NO: 49:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 32 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 49
 ATGAAATCGA CGGAATCAGA CTCGAGCCAA GG 32
 (2) INFORMATION FOR SEQ ID NO: 50:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 33 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 50
 TCCGGATTAG CTTGAGATGG ATCCGGTACC TTA 33
 (2) INFORMATION FOR SEQ ID NO: 51:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 20 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 51
 Met Glu Met Phe Gln Gly Leu Leu Leu Leu Leu Leu Leu Ser Met Gly
 1 5 10 15
 Gly Thr Trp Ala
 20
 (2) INFORMATION FOR SEQ ID NO: 52:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 8 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 52
 Gly Ser Gly Ser Gly Ser Gly Ser
 1 5
 (2) INFORMATION FOR SEQ ID NO: 53:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 41 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 53
 GCTACCGGAT CCCCGCGGGT CATCACAGGT CAAGGGGTGG T 41
 (2) INFORMATION FOR SEQ ID NO: 54:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 56 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 54
 ATGAAATCGA CGGAATCAGA CTCGAGCCAA GGAATGGAGA TGCTCCAGGG GCTGCT 56
 (2) INFORMATION FOR SEQ ID NO: 55:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 51 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 55
 GCTACCAGAT CCGCTACCGG ATCCTTGGGG GTGGTCACAG GTCAAGGGGT G 51
 (2) INFORMATION FOR SEQ ID NO: 56:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 20 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 56
 Met Glu Met Leu Gln Gly Leu Leu Leu Leu Leu Leu Leu Ser Met Gly
 1 5 10 15
 Gly Ala Trp Ala
 20
 (2) INFORMATION FOR SEQ ID NO: 57:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 57 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 57
 ATGAAATCGA CGGAATCAGA CTCGAGCCAA GGATGAAGAC ACTCCAGTTT TTCTTCC 57
 (2) INFORMATION FOR SEQ ID NO: 58:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 46 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 58
 ACCAGATCCG CTACCGGATC CTTCTTTCAT TTCACCAAAG GAGCAG 46
 (2) INFORMATION FOR SEQ ID NO: 59:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 18 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 59
 Met Lys Thr Leu Gln Phe Phe Phe Leu Phe Cys Cys Trp Lys Ala Ile
 1 5 10 15
 Cys Cys
 (2) INFORMATION FOR SEQ ID NO: 60:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 111 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 60
 GCTACCGGAT CCTTCTTTCA TTTCACCAAA GGAGCAGTAG CTGGGCCCCA GGCCTCGCAC 60
 AGTACAATCA GTGCTGTCGC TGTCGCAGAG TGCACATTGA CAGCTGACAG C 111
 (2) INFORMATION FOR SEQ ID NO: 61:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 87 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 61
 GCTACCGGAT CCTTCTTTCA TTTCACCAAA GGAGCAGTAG CTGGGCCCCA GGCCTCGCAC 60
 AGTGCAGTCA GTGGTGCTGC GGCGGCA 87
 (2) INFORMATION FOR SEQ ID NO: 62:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 78 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 62
 GCTACCGGAT CCTTCACCAA AGGAGCAGTA GCTGGGCCCC AGGCCTCGCA CAGTGCAGTC 60
 AGTGGTGCTG CGGCGGCA 78
 (2) INFORMATION FOR SEQ ID NO: 63:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 78 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 63
 GCTACCGGAT CCCCGCGGGT CATCGCAGTA GCTGGGCCCC AGGCCTCGCA CAGTGCAGTC 60
 AGTGGTGCTG CGGCGGCA 78
 (2) INFORMATION FOR SEQ ID NO: 64:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 70 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 64
 TGCTTCTCTA GAGCATATCC CACTCCACTA AGGTCCAAGA AGACGATGTT GGTCCAAAAG 60
 CAAGTCACCT 70
 (2) INFORMATION FOR SEQ ID NO: 65:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 73 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 65
 GTACCGGTAC CTTAAGATTT GTGATAATAA CAAGTACTGC AGTGGCACGC CGTGTGTTGC 60
 TCCACTTTGA AAC 73
 (2) INFORMATION FOR SEQ ID NO: 66:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 44 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 66
 CGGGGTAGGT TCGGTGGGAC CGACACCTCT TCCTCCCGAC GGGG 44
 (2) INFORMATION FOR SEQ ID NO: 67:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 48 base pairs
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 67
 CTACCACCAC AACTGCCACT ACGTGTGCCC CGTCGGGAGG AAGAGGTG 48
 (2) INFORMATION FOR SEQ ID NO: 68:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 145 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 68
 Ser Lys Glu Pro Leu Arg Pro Arg Cys Arg Pro Ile Asn Ala Thr Leu
 1 5 10 15
 Ala Val Glu Lys Glu Gly Cys Pro Val Cys Ile Thr Val Asn Thr Thr
 20 25 30
 Ile Cys Ala Gly Tyr Cys Pro Thr Met Thr Arg Val Leu Gln Gly Val
 35 40 45
 Leu Pro Ala Leu Pro Gln Val Val Cys Asn Tyr Arg Asp Val Arg Phe
 50 55 60
 Glu Ser Ile Arg Leu Pro Gly Cys Pro Arg Gly Val Asn Pro Val Val
 65 70 75 80
 Ser Tyr Ala Val Ala Leu Ser Cys Gln Cys Ala Leu Cys Arg Arg Ser
 85 90 95
 Thr Thr Asp Cys Gly Gly Pro Lys Asp His Pro Leu Thr Cys Asp Asp
 100 105 110
 Pro Arg Phe Gln Asp Ser Ser Ser Ser Lys Ala Pro Pro Pro Ser Leu
 115 120 125
 Pro Ser Pro Ser Arg Leu Pro Gly Pro Ser Asp Thr Pro Ile Leu Pro
 130 135 140
 Gln
 145
 (2) INFORMATION FOR SEQ ID NO: 69:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 114 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 69
 Ser Lys Glu Pro Leu Arg Pro Arg Cys Arg Pro Ile Asn Ala Thr Leu
 1 5 10 15
 Ala Val Glu Lys Glu Gly Cys Pro Val Cys Ile Thr Val Asn Thr Thr
 20 25 30
 Ile Cys Ala Gly Tyr Cys Pro Thr Met Thr Arg Val Leu Gln Gly Val
 35 40 45
 Leu Pro Ala Leu Pro Gln Val Val Cys Asn Tyr Arg Asp Val Arg Phe
 50 55 60
 Glu Ser Ile Arg Leu Pro Gly Cys Pro Arg Gly Val Asn Pro Val Val
 65 70 75 80
 Ser Tyr Ala Val Ala Leu Ser Cys Gln Cys Ala Leu Cys Arg Arg Ser
 85 90 95
 Thr Thr Asp Cys Gly Gly Pro Lys Asp His Pro Leu Thr Cys Asp Asp
 100 105 110
 Pro Arg
 (2) INFORMATION FOR SEQ ID NO: 70:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 93 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 70
 Ser Lys Glu Pro Leu Arg Pro Arg Cys Arg Pro Ile Asn Ala Thr Leu
 1 5 10 15
 Ala Val Glu Lys Glu Gly Cys Pro Val Cys Ile Thr Val Asn Thr Thr
 20 25 30
 Ile Cys Ala Gly Tyr Cys Pro Thr Met Thr Arg Val Leu Gln Gly Val
 35 40 45
 Leu Pro Ala Leu Pro Gln Val Val Cys Asn Tyr Arg Asp Val Arg Phe
 50 55 60
 Glu Ser Ile Arg Leu Pro Gly Cys Pro Arg Gly Val Asn Pro Val Val
 65 70 75 80
 Ser Tyr Ala Val Ala Leu Ser Cys Gln Cys Ala Leu Cys
 85 90
 (2) INFORMATION FOR SEQ ID NO: 71:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 114 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 71
 Ser Arg Glu Pro Leu Arg Pro Trp Cys His Pro Ile Asn Ala Ile Leu
 1 5 10 15
 Ala Val Glu Lys Glu Gly Cys Pro Val Cys Ile Thr Val Asn Thr Thr
 20 25 30
 Ile Cys Ala Gly Tyr Cys Pro Thr Met Met Arg Val Leu Gln Ala Val
 35 40 45
 Leu Pro Pro Leu Pro Gln Val Val Cys Thr Tyr Arg Asp Val Arg Phe
 50 55 60
 Glu Ser Ile Arg Leu Pro Gly Cys Pro Arg Gly Val Asp Pro Val Val
 65 70 75 80
 Ser Phe Pro Val Ala Leu Ser Cys Arg Cys Gly Pro Cys Arg Arg Ser
 85 90 95
 Thr Ser Asp Cys Gly Gly Pro Lys Asp His Pro Leu Thr Cys Asp His
 100 105 110
 Pro Gln
 (2) INFORMATION FOR SEQ ID NO: 72:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 111 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 72
 Asn Ser Cys Glu Leu Thr Asn Ile Thr Ile Ala Val Glu Lys Glu Gly
 1 5 10 15
 Cys Gly Phe Cys Ile Thr Ile Asn Thr Thr Trp Cys Ala Gly Tyr Cys
 20 25 30
 Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln
 35 40 45
 Lys Thr Cys Thr Phe Lys Glu Leu Val Tyr Glu Thr Val Arg Val Pro
 50 55 60
 Gly Cys Ala His His Ala Asp Ser Leu Tyr Thr Tyr Pro Val Ala Thr
 65 70 75 80
 Gln Cys His Cys Gly Lys Cys Asp Ser Asp Ser Thr Asp Cys Thr Val
 85 90 95
 Arg Gly Leu Gly Pro Ser Tyr Cys Ser Phe Gly Glu Met Lys Glu
 100 105 110
 (2) INFORMATION FOR SEQ ID NO: 73:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 108 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 73
 Asn Ser Cys Glu Leu Thr Asn Ile Thr Ile Ala Val Glu Lys Glu Gly
 1 5 10 15
 Cys Gly Phe Cys Ile Thr Ile Asn Thr Thr Trp Cys Ala Gly Tyr Cys
 20 25 30
 Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln
 35 40 45
 Lys Thr Cys Thr Phe Lys Glu Leu Val Tyr Glu Thr Val Arg Val Pro
 50 55 60
 Gly Cys Ala His His Ala Asp Ser Leu Tyr Thr Tyr Pro Val Ala Thr
 65 70 75 80
 Gln Cys His Cys Gly Lys Cys Asp Ser Asp Ser Thr Asp Cys Thr Val
 85 90 95
 Arg Gly Leu Gly Pro Ser Tyr Cys Ser Phe Gly Glu
 100 105
 (2) INFORMATION FOR SEQ ID NO: 74:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 104 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 74
 Asn Ser Cys Glu Leu Thr Asn Ile Thr Ile Ala Val Glu Lys Glu Gly
 1 5 10 15
 Cys Gly Phe Cys Ile Thr Ile Asn Thr Thr Trp Cys Ala Gly Tyr Cys
 20 25 30
 Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln
 35 40 45
 Lys Thr Cys Thr Phe Lys Glu Leu Val Tyr Glu Thr Val Arg Val Pro
 50 55 60
 Gly Cys Ala His His Ala Asp Ser Leu Tyr Thr Tyr Pro Val Ala Thr
 65 70 75 80
 Gln Cys His Cys Gly Lys Cys Asp Ser Asp Ser Thr Asp Cys Thr Val
 85 90 95
 Arg Gly Leu Gly Pro Ser Tyr Cys
 100
 (2) INFORMATION FOR SEQ ID NO: 75:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 24 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 75
 Asp Ser Asp Ser Thr Asp Cys Thr Val Arg Gly Leu Gly Pro Ser Tyr
 1 5 10 15
 Cys Ser Phe Gly Glu Met Lys Glu
 20
 (2) INFORMATION FOR SEQ ID NO: 76:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 17 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 76
 Thr Val Arg Gly Leu Gly Pro Ser Tyr Cys Ser Phe Gly Glu Met Lys
 1 5 10 15
 Glu
 (2) INFORMATION FOR SEQ ID NO: 77:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 14 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 77
 Thr Val Arg Gly Leu Gly Pro Ser Tyr Cys Ser Phe Gly Glu
 1 5 10
 (2) INFORMATION FOR SEQ ID NO: 78:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 9 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 78
 Thr Val Arg Gly Leu Gly Pro Ser Tyr
 1 5
 (2) INFORMATION FOR SEQ ID NO: 79:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 92 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 79
 Ala Pro Asp Val Gln Asp Cys Pro Glu Cys Thr Leu Gln Glu Asn Pro
 1 5 10 15
 Phe Phe Ser Gln Pro Gly Ala Pro Ile Leu Gln Cys Met Gly Cys Cys
 20 25 30
 Phe Ser Arg Ala Tyr Pro Thr Pro Leu Arg Ser Lys Lys Thr Met Leu
 35 40 45
 Val Gln Lys Asn Val Thr Ser Glu Ser Thr Cys Cys Val Ala Lys Ser
 50 55 60
 Tyr Asn Arg Val Thr Val Met Gly Gly Phe Lys Val Glu Asn His Thr
 65 70 75 80
 Ala Cys His Cys Ser Thr Cys Tyr Tyr His Lys Ser
 85 90
 (2) INFORMATION FOR SEQ ID NO: 80:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 4 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 80
 Gly Ser Gly Ser
 1
 (2) INFORMATION FOR SEQ ID NO: 81:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 6 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 81
 Gly Ser Gly Ser Gly Ser
 1 5
 (2) INFORMATION FOR SEQ ID NO: 82:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 10 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 82
 Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser
 1 5 10
 (2) INFORMATION FOR SEQ ID NO: 83:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 4 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: unknown
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 83
 Asp Asp Pro Arg