Parasitic nematode transglutaminase proteins and uses thereof

The present invention relates to parasitic nematode transglutaminase proteins; to parasitic nematode transglutaminase nucleic acid molecules, including those that encode such transglutaminase proteins; to antibodies raised against such transglutaminase proteins; and to compounds that inhibit parasitic nematode transglutaminase activity. The present invention also includes methods to obtain such proteins, nucleic acid molecules, antibodies, and inhibitory compounds. Also included in the present invention are therapeutic compositions comprising such proteins, nucleic acid molecules, antibodies and/or inhibitory compounds as well as the use of such therapeutic compositions to protect animals from diseases caused by parasitic nematodes. This invention also relates to the surprising discovery that parasitic nematode transglutaminase proteins have protein disulfide isomerase activity. Accordingly, this invention relates further to inhibitors of the protein disulfide isomerase activity of said transglutaminases.

FIELD OF THE INVENTION
 The present invention relates to parasitic nematode transglutaminase
 nucleic acid molecules, proteins encoded by such nucleic acid molecules,
 antibodies raised against such proteins, and inhibitors of such proteins.
 The present invention also includes therapeutic compositions comprising
 such nucleic acid molecules, proteins, antibodies, inhibitors, and
 combinations thereof, as well as the use of these compositions to protect
 animals from diseases caused by parasitic nematodes.
 BACKGROUND OF THE INVENTION
 Parasitic nematode infections in animals, including humans, are typically
 treated by chemical drugs. One disadvantage with chemical drugs is that
 they must be administered often. For example, dogs susceptible to
 heartworm are typically treated monthly. Repeated administration of drugs,
 however, often leads to the development of resistant nematode strains that
 no longer respond to treatment. Furthermore, many of the chemical drugs
 cause harmful side effects in the animals being treated, and as larger
 doses become required due to the build up of resistance, the side effects
 become even greater. Moreover, a number of drugs only treat symptoms of a
 parasitic disease but are unable to prevent infection by the parasitic
 nematode.
 An alternative method to prevent parasitic nematode infection includes
 administering a vaccine against a parasitic nematode. Although many
 investigators have tried to develop vaccines based on specific antigens,
 it is well understood that the ability of an antigen to stimulate antibody
 production does not necessarily correlate with the ability of the antigen
 to stimulate an immune response capable of protecting an animal from
 infection, particularly in the case of parasitic nematodes. Although a
 number of prominent antigens have been identified in several parasitic
 nematodes, including in Dirofilaria, there is yet to be a commercially
 available vaccine developed for any parasitic nematode.
 The life cycle of parasitic nematodes generally includes development
 through four molts, the last two molts taking place in the host animal.
 Molting is a complex process involving a variety of different mechanisms.
 However, a lack of understanding of the basic biology, metabolism and
 biochemistry of parasitic nematodes has resulted in the identification of
 few targets for chemotherapy or vaccines.
 As an example of the complexity of parasitic nematodes, the life cycle of
 D. immitis, the nematode that causes heartworm, includes a variety of life
 forms, each of which presents different targets, and challenges, for
 immunization. Adult forms of the parasite are quite large and
 preferentially inhabit the heart and pulmonary arteries of an animal.
 Sexually mature adults, after mating, produce microfilariae which traverse
 capillary beds and circulate in the vascular system of the dog. One method
 of demonstrating infection in the dog is to detect the circulating
 microfilariae. If a dog is maintained in an insect-free environment, the
 life cycle of the parasite cannot progress. However, when microfilariae
 are ingested by a female mosquito during blood feeding on an infected dog,
 subsequent development of the microfilariae into larvae occurs in the
 mosquito. The microfilariae go through two larval stages (L1 and L2) and
 finally become mature third stage larvae (L3) which can then be
 transmitted back to the dog through the bite of the mosquito. It is this
 L3 stage, therefore, that accounts for the initial infection. As early as
 three days after infection, the L3 molt to the fourth larval (LA) stage,
 and subsequently to the fifth stage, or immature adults. The immature
 adults migrate to the heart and pulmonary arteries, where they mature and
 reproduce, thus producing the microfilariae in the blood. "Occult"
 infection with heartworm in dogs is defined as that wherein no
 microfilariae can be detected, but the existence of the adult heartworms
 can be determined through thoracic examination.
 Heartworrn not only is a major problem in dogs, which typically cannot even
 develop immunity upon infection (i.e., dogs can become reinfected even
 after being cured by chemotherapy), but is also becoming increasingly
 widespread in other companion animals, such as cats and ferrets. Heartworm
 infections have also been reported in humans. Other parasitic nematodeic
 infections are also widespread, and all require better treatment,
 including a preventative vaccine program. O. volvulus, for example, causes
 onchocerciasis (also known as river blindness) in humans. Up to 50 million
 people throughout the world are reported to be infected with O. volvulus,
 with over a million being blinded due to infection.
 Although many investigators have tried to develop vaccines based on
 specific antigens, it is well understood that the ability of an antigen to
 stimulate antibody production does not necessarily correlate with the
 ability of the antigen to stimulate an immune response capable of
 protecting an animal from infection, particularly in the case of parasitic
 nematodes. Although a number of prominent antigens have been identified in
 several parasitic nematodes, including in Dirofilaria and Onchocerca,
 there is yet to be an effective vaccine developed for any parasitic
 nematode.
 In just the past few years, there has developed an interest in the
 identification of larval stage-specific enzymes as potential targets for
 treatment or prevention of nematode diseases. Nematode
 transglutaminase-catalyzed reactions have recently been identified as
 possibly important for the growth, development and survival of nematodes,
 including Acanthocheilonema vitae, Brugia malayi, and Onchocerca volvulus.
 See, for example, Mehta, 1992, Mol. Biochem. Parasitol., 53, 1-16;
 Lustigman, 1995, Antimicrobial Agents and Chemother., 39:9, 1913-1919;
 Lustigman, 1993, Parasitology Today, 9:8, 294-297. However, until now, no
 compounds or methods based on specific known targets in parasitic nematode
 development have been designed for treating or preventing parasitic
 nematode disease.
 There remains a need to identify an efficacious composition that protects
 animals against diseases caused by parasitic nematodes and that,
 preferably, also protects animals from infection by such nematodes.
 SUMMARY OF THE INVENTION
 The present invention relates to novel products and processes for
 prevention and treatment of parasitic nematode infection. According to the
 present invention there are provided parasitic nematode transglutaminase
 proteins and mimetopes thereof; nematode nucleic acid molecules, including
 those that encode such proteins; antibodies raised against parasitic
 nematode transglutaminase proteins (i.e., anti-parasitic nematode
 transglutaminase antibodies); and other compounds that inhibit parasitic
 nematode transglutaminase activity or the protein disulfide isomerase
 activity of parasitic nematode transglutaminase (i.e, inhibitory compounds
 or inhibitors).
 The present invention also includes methods to obtain the proteins,
 mimetopes, nucleic acid molecules, antibodies and inhibitory compounds
 herein described. Also included in the present invention are therapeutic
 compositions comprising such proteins, mimetopes, nucleic acid molecules,
 antibodies, inhibitory compounds, or mixtures thereof, as well as the use
 of such therapeutic compositions to protect animals from diseases caused
 by parasitic nematodes.
 One embodiment of the present invention is an isolated nucleic acid
 molecule that hybridizes under stringent hybridization conditions with a
 parasitic nematode transglutaminase gene. Preferred parasitic nematode
 transglutaminase genes of the present invention are transglutaminase genes
 from Brugia malayi, Dirofilaria immitis, and Onchocerca volvulus. Such
 nucleic acid molecules are referred to as nematode transglutaminase
 nucleic acid molecules. A parasitic nematode transglutaminase gene
 preferably includes at least one of the following nucleic acid sequences:
 SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID
 NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:27, SEQ ID NO:29, SEQ ID
 NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:35, SEQ ID
 NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:42, SEQ ID
 NO:43, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:49, SEQ ID
 NO:50, SEQ ID NO:51, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:56, SEQ ID
 NO:57 or SEQ ID NO:59.
 Another embodiment of the present invention is an isolated nucleic acid
 molecule that hybridizes under stringent hybridization conditions with a
 Dirofilaria immitis (D. immitis) transglutaminase gene such nucleic acid
 molecules are referred to as Dirofilaria immitis (or D. immitis)
 transglutaminase nucleic acid molecules. A D. immitis transglutaminase
 gene preferably includes one of the following nucleic acid sequences: SEQ
 ID NO:5, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID
 NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:27, SEQ ID NO:29, SEQ ID
 NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:46, SEQ ID
 NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:53, SEQ ID
 NO:54 or SEQ ID NO:56. A preferred D. immitis transglutaminase protein
 includes at least a portion of a protein represented by SEQ ID NO:2, SEQ
 ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:11, SEQ ID NO:28 or SEQ ID
 NO:33, SEQ ID NO:47, SEQ ID NO:52 or SEQ ID NO:55.
 The present invention also relates to recombinant molecules, recombinant
 viruses and recombinant cells that include a transglutaminase nucleic acid
 molecule of the present invention. Also included are methods to produce
 such nucleic acid molecules, recombinant molecules, recombinant viruses
 and recombinant cells.
 Another embodiment of the present invention includes a non-native nematode
 transglutaminase protein encoded by a nucleic acid molecule that
 hybridizes under stringent hybridization conditions with a parasitic
 nematode transglutaminase gene. A preferred nematode transglutaminase
 protein is capable of eliciting an immune response when administered to an
 animal and/or of having parasitic nematode transglutaminase or protein
 disulfide isomerase (PDI) activity, or both. A preferred nematode
 transglutaminase protein is encoded by a nucleic acid molecule that
 hybridizes under stringent conditions with a nucleic acid molecule
 including either SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:12, SEQ ID NO:14, SEQ
 ID NO:29, SEQ ID NO:31, SEQ ID NO:34, SEQ ID NO:37, SEQ ID NO:39, SEQ ID
 NO:42, SEQ ID NO:45, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:53, SEQ ID
 NO:56 or SEQ ID NO:59. A preferred nematode transglutaminase protein
 includes at least a portion of a protein represented by SEQ ID NO:1, SEQ
 ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:11, SEQ ID
 NO:28, SEQ ID NO:33, SEQ ID NO:36, SEQ ID NO:41, SEQ ID NO:44, SEQ ID
 NO:47, SEQ ID NO:52, SEQ ID NO:55 or SEQ ID NO:58.
 Another embodiment of the present invention includes a non-native D.
 immitis transglutaminase protein encoded by a nucleic acid molecule that
 hybridizes under stringent conditions with a D. immitis transglutaminase
 gene. A preferred D. immitis transglutaminase protein is capable of
 eliciting an immune response when administered to an animal and/or of
 having parasitic nematode transglutaminase activity. A preferred D.
 immitis transglutaminase protein is encoded by a nucleic acid molecule
 that hybridizes under stringent conditions with a nucleic acid molecule
 including either SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:12, SEQ ID NO:14, SEQ
 ID NO:29, SEQ ID NO:31, SEQ ID NO:34, SEQ ID NO:48, SEQ ID NO:50, SEQ ID
 NO:53 or SEQ ID NO:56. A preferred D. immitis transglutaminase protein
 includes at least a portion of a protein represented by SEQ ID NO:2, SEQ
 ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:11, SEQ ID NO:28, SEQ ID
 NO:33, SEQ ID NO:47, SEQ ID NO:52 or SEQ ID NO:55.
 The present invention also relates to mimetopes of parasitic nematode
 transglutaminase proteins as well as to isolated antibodies that
 selectively bind to parasitic nematode transglutaminase proteins or
 mimctopes thereof. Also included are methods, including recombinant
 methods, to produce proteins, mimetopes and antibodies of the present
 invention.
 Another embodiment of the present invention is a method to identify a
 compound capable of inhibiting nematode transglutaminase activity. The
 method includes the steps of: (a) contacting an isolated nematode
 transglutaminase protein with a putative inhibitory compound under
 conditions in which, in the absence of the compound, the protein has
 nematode transglutaminase activity; and (b) determining if the putative
 inhibitory compound inhibits the nematode transglutaminase activity. Also
 included in the present invention is a test kit to identify a compound
 capable of inhibiting nematode transglutaminase activity. Such a test kit
 includes an isolated nematode transglutaminase protein having nematode
 transglutaminase activity and a means for determining the extent of
 inhibition of the nematode transglutaminase activity in the presence of a
 putative inhibitory compound.
 The present invention also includes an inhibitor of nematode
 transglutaminase activity identified by its ability to inhibit the
 activity of a nematode transglutaminase and by its inability to
 substantially inhibit mammalian transglutaminase. Examples of such
 inhibitors are substrate analogs of nematode transglutaminase, active site
 inhibitors of nematode transglutaminase, and antibodies that specifically
 recognize nematode transglutaminase.
 Another embodiment of the present invention is a method to identify a
 compound capable of inhibiting protein disulfide isomerase (PDI) activity.
 The method includes the steps of: (a) contacting an isolated nematode
 transglutaminase protein with a putative PDI inhibitory compound under
 conditions in which, in the absence of the compound, the protein has
 nematode PDI activity; and (b) determining if the putative inhibitory
 compound inhibits the nematode PDI activity. Also included in the present
 invention is a test kit to identify a compound capable of inhibiting
 nematode PDI activity. Such a test kit includes an isolated nematode PDI
 protein having nematode PDI activity and a means for determining the
 extent of inhibition of the nematode PDI activity in the presence of a
 putative inhibitory compound.
 The present invention also includes an inhibitor of nematode PDI activity
 identified by its ability to inhibit the PDI activity of a nematode
 transglutaminase protein and by its inability to substantially inhibit
 mammalian PDI. Examples of such inhibitors are substrate analogs of
 nematode PDI, active site inhibitors of nematode PDI, and antibodies that
 specifically recognize parasitic nematode transglutaminase.
 Yet another embodiment of the present invention is a therapeutic
 composition that is capable of protecting an animal from disease caused by
 a parasitic nematode. Such a therapeutic composition includes an excipient
 and one or more of the following protective compounds: an isolated
 nematode transglutaminase protein or a mimetope thereof; an isolated
 nucleic acid molecule that hybridizes under stringent hybridization
 conditions with a nematode transglutaminase gene; an isolated antibody
 that selectively binds to a nematode transglutaminase protein; an
 inhibitor of nematode transglutaminase protein activity identified by its
 ability to (a) inhibit nematode transglutaminase activity, and (b) not
 substantially inhibit mammalian transglutaminase activity; an inhibitor of
 nematode PDI protein activity identified by its ability to (a) inhibit
 nematode PDI activity, and (b) not substantially inhibit mammalian PDI
 activity; or any combinations thereof. A preferred therapeutic composition
 of the present invention also includes an adjuvant, a carrier, or both.
 Preferred nematode transglutaminase nucleic acid molecule compounds of the
 present invention include naked nucleic acid vaccines recombinant virus
 vaccines and recombinant cell vaccines. Also included in the present
 invention is a method to protect an animal from disease caused by a
 parasitic nematode comprising the step of administering to the animal at
 least one protective compound of the present invention.
 Yet another embodiment of the present invention is a method to produce a
 transglutaminase protein, the method comprising culturing a cell
 transformed with a nucleic acid molecule that hybridizes under stringent
 hybridization conditions with a nematode transglutaminase gene.
 DETAILED DESCRIPTION OF THE INVENTION
 The present invention provides for isolated parasitic nematode
 transglutaminase proteins, isolated parasitic nematode transglutaminase
 nucleic acid molecules, antibodies directed against parasitic nematode
 transglutaminase proteins, and other inhibitors of nematode
 transglutaminase activity. As used herein, the terms isolated parasitic
 nematode transglutaminase proteins and isolated parasitic nematode
 transglutaminase nucleic acid molecules refer to nematode transglutaminase
 proteins and nematode transglutaminase nucleic acid molecules derived from
 parasitic nematodes. The proteins and nucleic acid molecules of the
 present invention can be obtained from their natural source, or they can
 be produced using, for example, recombinant nucleic acid technology (also
 referred to herein as recombinant DNA technology) or chemical synthesis.
 The terms non-native parasitic nematode transglutaminase protein or
 non-native parasitic nematode protein, as used herein, refer to a
 parasitic nematode transglutaminase protein which is produced either
 synthetically or by transcribing a molecularly cloned or chemically
 synthesized parasitic nematode transglutaminase or nucleic acid molecule
 of the present invention (in other words, by recombinant DNA technology).
 Also included in the present invention is the use of these proteins,
 nucleic acid molecules, antibodies and other inhibitors as therapeutic
 compositions to protect animals from parasitic nematode diseases as well
 as in other applications, such as those disclosed below. An entirely
 unexpected finding with respect to nematode transglutaminase proteins of
 the present invention, herein disclosed for the first time, is that a
 nematode transglutaminase protein has protein disulfide isomerase (PDI)
 activity.
 Parasitic nematode transglutaminase proteins and nucleic acid molecules of
 the present invention have utility because they represent novel targets
 for anti-parasite vaccines and drugs. The products and processes of the
 present invention are advantageous because they enable the inhibition of
 crucial steps in nematode molting that involve nematode transglutaminase.
 While not being bound by theory, it is believed that nematode
 transglutaminase protein activity is essential for successful development
 of nematode larvae. In addition, the unexpected finding that nematode
 transglutaminase proteins have PDI activity supports the use of
 transglutaminase proteins of the present invention having PDI activity as
 targets for potential anti-parasite vaccines or therapeutics.
 One embodiment of the present invention is an isolated protein comprising a
 D. immitis transglutaminase protein. It is to be noted that the term "a"
 or "an" entity refers to one or more of that entity; for example, a
 protein refers to one or more proteins or at least one protein. The terms
 "a" (or "an"), "one or more" and "at least one" can be used
 interchangeably herein. It is also to be noted that the terms
 "comprising", "including", and "having" can be used interchangeably.
 Furthermore, a compound "selected from the group consisting of" refers to
 one or more of the compounds in the list that follows, including mixtures
 (i.e., combinations) of two or more of the compounds.
 According to the present invention, an isolated, or biologically pure,
 protein, is a protein that has been removed from its natural milieu.
 Accordingly, "isolated" and "biologically pure" do not necessarily reflect
 the extent to which the protein has been purified. An isolated protein of
 the present invention can be obtained from its natural source, can be
 produced using recombinant DNA technology or can be produced by chemical
 synthesis. When an isolated protein of the present invention is produced
 using recombinant DNA technology or produced by chemical synthesis, the
 protein is referred to herein as either an isolated protein or as a
 non-native protein.
 As used herein, an isolated parasitic nematode transglutaminase protein can
 be a full-length protein or any homolog of such a protein. An isolated
 protein of the present invention, including a homolog, can be identified
 in a straightforward manner by the protein's ability to elicit an immune
 response against parasitic nematode transglutaminase proteins, to exhibit
 transglutaminase activity, or to have any combination of these
 characteristics. Examples of parasitic nematode transglutaminase homologs
 include parasitic nematode transglutaminase proteins in which amino acids
 have been deleted (e.g., a truncated version of the protein, such as a
 peptide), inserted, inverted, substituted, derivatized (e.g., by
 glycosylation, phosphorylation, acetylation, myristoylation, prenylation,
 palmitoylation, amidation, addition of glycerophosphatidyl inositol), or
 any combination of the above, so that the homolog includes at least one
 epitope capable of eliciting an immune response against a parasitic
 nematode transglutaminase protein. In other words, when the homolog is
 administered to an animal as an immunogen, using techniques known to those
 skilled in the art, the animal will produce an immune response against at
 least one epitope of a natural parasitic nematode transglutaminase
 protein. The ability of a protein to effect an immune response can be
 measured using techniques known to those skilled in the art. Techniques to
 measure parasitic nematode transglutaminase activity are also known to
 those skilled in the at, and are described in the Examples.
 Parasitic nematode transglutaminase protein homologs can be the result of
 natural allelic variation or natural mutation. Nematode transglutaminase
 protein homologs of the present invention can also be produced using
 techniques known in the art including, but not limited to, direct
 modifications to the protein or modifications to the gene encoding the
 protein using, for example, classic or recombinant DNA techniques to
 effect random or targeted mutagenesis.
 Isolated proteins of the present invention have the further characteristic
 of being encoded by nucleic acid molecules that hybridize under stringent
 hybridization conditions to a gene encoding a D. immitis, a B. malayi or
 an O. volvulus nematode transglutaminase protein (i.e., to a D. immitis, a
 B. malayi or an O. volvulus nematode transglutaminase gene). As used
 herein, stringent hybridization conditions refer to standard hybridization
 conditions under which nucleic acid molecules, including oligonucleotides,
 are used to identify molecules having similar nucleic acid sequences.
 Stringent hybridization conditions typically permit isolation of nucleic
 acid molecules having at least about 70% nucleic acid sequence identity
 with the nucleic acid molecule being used as a probe in the hybridization
 reaction. Standard conditions are disclosed, for example, in Sambrook et
 al., 1989, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Labs
 Press. The reference Sambrook et al., ibid., is incorporated by reference
 herein in its entirety. Formulae to calculate the appropriate
 hybridization and wash conditions to achieve hybridization permitting 30%
 or less mismatch of nucleotides are disclosed, for example, in Meinkoth et
 al., 1984, Anal. Biochem. 138, 267-284; Meinkoth et al., ibid., is
 incorporated by reference herein in its entirety.
 As used herein, a parasitic nematode transglutaminase gene includes all
 nucleic acid sequences related to a natural parasitic nematode
 transglutaminase gene including, for example, regulatory regions that
 control production of the nematode transglutaminase protein encoded by
 that gene (such as, but not limited to, transcription, translation or
 post-translation control regions), as well as the coding region itself. A
 D. immitis gene can include nDiTG.sub.707, nDiTG,.sub.1472, nDiTG.sub.143,
 nDiTG.sub.1407, nDiTG.sub.1881 or nDiTG.sub.1494 ; a B. malayi gene can
 include nBmTG.sub.537 or nBmTG.sub.440, and an O. volvulus gene can
 include nOvTG.sub.537. In one embodiment, a parasitic nematode
 transglutaminase gene of the present invention includes the nucleic acid
 sequence SEQ ID NO:5, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:13, SEQ ID
 NO:27, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:35, SEQ ID NO:38, SEQ ID
 NO:40, SEQ ID NO:43, SEQ ID NO:46, SEQ ID NO:49, SEQ ID NO:51, SEQ ID
 NO:54 or SEQ ID NO:57, as well as the complement of these sequences (i.e.
 SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:29, SEQ ID
 NO:3 1, SEQ ID NO:34, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:42, SEQ ID
 NO:45, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:56 or SEQ ID
 NO:59, respectively). The nucleic acid sequence SEQ ID NO:8 represents the
 deduced sequence of the coding strand of the apparent coding region of a
 cDNA (complementary DNA) molecule denoted herein as nDiTG.sub.705, the
 production of which is disclosed in the Examples. The complement of SEQ ID
 NO:8 (represented herein by SEQ ID NO:9) refers to the nucleic acid
 sequence of the strand complementary to the strand having SEQ ID NO:8, the
 sequence of which can easily be determined from SEQ ID NO:8 by those
 skilled in the art. Likewise, a nucleic acid sequence complement of any
 nucleic acid sequence of the present invention refers to the nucleic acid
 sequence of the nucleic acid strand that is complementary to (i.e., can
 form a double helix with) the strand for which the sequence is cited.
 Nucleic acid sequence SEQ ID NO:13 represents the deduced sequence of the
 coding strand of a cDNA nucleic acid molecule denoted herein as
 nDiTG.sub.1107, the production of which is disclosed in the Examples. The
 complement of SEQ ID NO:13 is represented herein by SEQ ID NO:14.
 It should be noted that because nucleic acid and amino acid sequencing
 technology is not entirely error-free, SEQ ID NO:5, SEQ ID NO:8, SEQ ID
 NO:10, SEQ ID NO:13, SEQ ID NO:27, SEQ ID NO:30, SEQ ID NO:32, SEQ ID
 NO:35, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:43, SEQ ID NO:46. SEQ ID
 NO:49, SEQ ID NO:51, SEQ ID NO:54 and SEQ ID NO:57, as well as other
 nucleic acid and protein sequences presented herein, represent apparent
 nucleic acid sequences of the nucleic acid molecules encoding a parasitic
 nematode transglutaminase protein of the present invention, and apparent
 amino acid sequences of the proteins of the present invention,
 respectively.
 In another embodiment, a nematode transglutaminase gene can be an allelic
 variant that includes a similar but not identical sequence to SEQ ID NO:5,
 SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:12, SEQ ID
 NO:13, SEQ ID NO:14, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:30, SEQ ID
 NO:31, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:37, SEQ ID
 NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:43, SEQ ID
 NO:45, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID
 NO:51, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:57 or SEQ ID
 NO:59. An allelic variant of a nematode transglutaminase gene including
 SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID
 NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:27, SEQ ID NO:29, SEQ ID
 NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:35, SEQ ID
 NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:42, SEQ ID
 NO:43, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:49, SEQ ID
 NO:50, SEQ ID NO:51, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:56, SEQ ID
 NO:57 or SEQ ID NO:59, is a gene that occurs at essentially the same locus
 (or loci) in the genome as the gene including SEQ ID NO:5, SEQ ID NO:7,
 SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:13, SEQ ID
 NO:14, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID
 NO:32, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:38, SEQ ID
 NO:39, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:45, SEQ ID
 NO:46, SEQ ID NO:49, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID
 NO:53, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:57 or SEQ ID NO:59, but
 which, due to natural variations caused by, for example, mutation or
 recombination, has a similar but not identical sequence. Allelic variants
 typically encode proteins having similar activity to that of the protein
 encoded by the gene to which they are being compared. Allelic variants can
 also comprise alterations in the 5' or 3' untranslated regions of the gene
 (e.g., in regulatory control regions). Allelic variants are well known to
 those skilled in the art and would be expected to be found within a given
 parasitic nematode, or among a group of two or more parasitic nematodes,
 because of the diploid nematode genome.
 The minimum size of a nematode transglutaminase protein homolog of the
 present invention is a size sufficient to be encoded by a nucleic acid
 molecule capable of forming a stable hybrid (i.e., hybridize under
 stringent hybridization conditions) with the complementary sequence of a
 nucleic acid molecule encoding the corresponding natural protein. The size
 of the nucleic acid molecule encoding such a protein homolog is dependent
 on nucleic acid composition and percent homology between the nucleic acid
 molecule and a complementary sequence. It should also be noted that the
 extent of homology required to form a stable hybrid can vary depending on
 whether the homologous sequences are interspersed throughout the nucleic
 acid molecules or are clustered (i.e., localized) in distinct regions on
 the nucleic acid molecules. The minimum size of nucleic acid molecules
 that can form stable hybrids under standard hybridization conditions is
 typically at least about 12 to about 15 nucleotides in length if the
 nucleic acid molecules are GC-rich, and at least about 15 to about 17
 bases in length if they are AT-rich. Therefore, the minimum size of a
 nucleic acid molecule used to encode a nematode transglutaminase protein
 homolog of the present invention is from about 12 to about 18 nucleotides
 in length. Accordingly, the minimum size of a nematode transglutaminase
 protein homolog of the present invention is from about 4 to about 6 amino
 acids in length. There is no limit, other than a practical limit, on the
 maximum size of a nucleic acid molecule of the present invention because
 nucleic acid molecules of the present invention can include a portion of a
 gene, an entire gene, multiple genes, or portions thereof. The preferred
 size of a protein encoded by a nucleic acid molecule of the present
 invention depends on whether a full-length, fusion, multivalent, or
 functional portion of a protein is desired.
 Suitable parasitic nematodes from which to isolate nematode
 transglutaminase proteins of the present invention (including isolation of
 the natural protein or production of the natural or non-native protein by
 recombinant or synthetic techniques) include filarioid, ancylostomatoid,
 ascaridoid, diochtophymatoid, dracunculoid, metastrongyloid, oxyuroid,
 physalopteroid, rhabtitoid, spiruroid, strongyloid, thelazioid,
 trichinelloid, and trichostrongyloid nematodes. Particularly preferred
 nematodes are those of the genera Dirofilaria, Onchocerca, Brugia,
 Acanthocheilonema, Aelurostrongylus, Ancylostoma, Angiostrongylus,
 Ascaris, Bunostomum, Capillaria, Chabertia, Cooperia, Crenosoma,
 Dictyocaulus, Dioctophyme, Dipetalonema, Dracunculus, Enterobius,
 Filaroides, Haemonchus, Lagochilascaris, Loa, Mansonella, Muellerius,
 Necator, Nematodirus, Oesophagostomum, Ostertagia, Parafilaria,
 Parascaris, Physaloptera, Protostrongylus, Setaria, Spirocerca,
 Stephanofilaria, Strongyloides, Strongylus, Thelazia, Toxascaris,
 Toxoeara, Trichinella, Trichostrongylus, Trichuris, Uncinaria, and
 Wuchereria. Particularly preferred are filarioid nematodes including
 Dirofilaria, Onchocerca, Brugia, Acanthocheilonema, Dipetalonema, Loa,
 Mansonella, Parafilaria, Setaria, Stephanofilaria, and Wuchereria, with D.
 immitis, B. malayi, O. volvulus and T. canis being even more preferred,
 and D. immitis being particularly preferred.
 A preferred parasitic nematode transglutaminase protein of the present
 invention is a compound that is not substantially toxic to host animals
 (that is, does not substantially inhibit host animal transglutaminase; the
 term, "does not substantially inhibit" as used herein can be used
 interchangeably with the term, "inability to substantially interfere"; a
 compound that does not substantially inhibit host animal transglutaminase
 activity is one that, when administered to a host animal, the host animal
 shows no significant adverse effects attributable to the compound) and
 which, when administered to an animal in an effective manner, is capable
 of protecting that animal from disease caused by a parasitic nematode. In
 accordance with the present invention, the ability of a nematode
 transglutaminase protein of the present invention to protect an animal
 from disease by a parasitic nematode refers to the ability of that protein
 to, for example, treat, ameliorate or prevent disease caused by parasitic
 nematodes. In particular, the phrase, "protect an animal from disease by a
 parasitic nematode," refers to reducing the potential for parasitic
 nematode population expansion in the host animal by inhibiting parasitic
 nematode molting and subsequent growth. Nematode molting is an essential
 step in the life cycle and development of all nematodes, and characterizes
 the progression of the nematode larvae through the development of larval
 stages to the adult. A host animal, as used herein, is an animal in which
 a parasitic nematode can live and multiply. In one embodiment, a nematode
 transglutaminase protein of the present invention can elicit an immune
 response (including a humoral or cellular immune response, or both)
 against a parasitic nematode.
 Suitable nematodes to target with therapeutic compounds of the present
 invention include any nematodes that are essentially incapable of molting,
 or are inhibited in the ability to molt, in a host animal when a nematode
 transglutaminase protein of the present invention, or inhibitor of such a
 protein, has been administered to that animal. Accordingly, a nematode to
 target includes any nematode that produces a protein having one or more
 epitopes that can be neutralized by either a humoral or a cellular immune
 response, or both, elicited by a nematode transglutaminase protein of the
 present invention, or that produces a protein that can be targeted by a
 compound that otherwise inhibits nematode transglutaminase activity,
 thereby resulting in the decreased ability of the nematode to cause
 disease in an animal. Preferred nematodes to target include parasitic
 nematodes disclosed herein as being useful in the production or isolation
 of parasitic nematode transglutaminase proteins of the present invention.
 The present invention also includes mimetopes of parasitic nematode
 transglutaminase proteins of the present invention. As used herein, a
 mimetope of a parasitic nematode transglutaminase protein of the present
 invention refers to any compound that is able to mimic the activity of
 such a parasitic nematode transglutaminase protein (e.g., has the ability
 to elicit an immune response against a parasitic nematode transglutaminase
 protein of the present invention or ability to inhibit parasitic nematode
 transglutaminase activity). The ability to mimic the activity of a
 parasitic nematode transglutaminase protein is likely to be the result of
 a structural similarity between the parasitic nematode transglutaminase
 protein and the mimetope. It is to be noted, however, that the mimetope
 need not have a structure similar to a parasitic nematode transglutaminase
 protein as long as the mimetope functionally mimics the protein. Mimetopes
 can be, but are not limited to: peptides that have been modified to
 decrease their susceptibility to degradation; anti-idiotypic and/or
 catalytic antibodies, or fragments thereof; non-proteinaceous immunogenic
 portions of an isolated protein (e.g., carbohydrate structures); synthetic
 or natural organic or inorganic molecules, including nucleic acids; and/or
 any other peptidomimetic compounds. Mimetopes of the present invention can
 be designed using computer-generated structures of parasitic nematode
 transglutaminase proteins of the present invention. Mimetopes can also be
 obtained by generating random samples of molecules, such as
 oligonucleotides, peptides or other organic molecules, and screening such
 samples by affinity chromatography techniques using the corresponding
 binding partner, (e.g., an anti- parasitic nematode transglutaminase
 antibody). A preferred mimetope is a peptidomimetic compound that is
 structurally and/or functionally similar to a parasitic nematode
 transglutaminase protein of the present invention, particularly to the
 active site of the parasitic nematode transglutaminase protein.
 One embodiment of a parasitic nematode transglutaminase protein of the
 present invention is a fusion protein that includes a parasitic nematode
 transglutaminase protein-containing domain attached to one or more fusion
 segments. Suitable fusion segments for use with the present invention
 include, but are not limited to, segments that can: enhance a protein's
 stability; act as an immunopotentiator to enhance an immune response
 against a nematode transglutaminase protein; assist in purification of a
 nematode transglutaminase protein (e.g., by affinity chromatography); or
 any combination of the above listed functions. A suitable fusion segment
 can be a domain of any size that has the desired function (e.g., imparts
 increased stability, imparts increased immunogenicity to a protein, or
 simplifies purification of a protein). Fusion segments can be joined to
 amino or carboxyl termini, or both, of the nematode
 transglutaminase-containing domain of the protein and can be susceptible
 to cleavage in order to enable straightforward recovery of a nematode
 transglutaminase protein. Fusion proteins are preferably produced by
 culturing a recombinant cell transformed with a fusion nucleic acid
 molecule that encodes a protein including the fusion segment attached to
 either or both of the carboxyl or amino terminal ends of a nematode
 transglutaminase-containing domain. Preferred fusion segments include a
 metal binding domain (e.g., a poly-histidine segment); an immunoglobulin
 binding domain (e.g., Protein A; Protein G; T cell; B cell; Fc receptor;
 or complement protein antibody-binding domains); a sugar binding domain
 (e.g., a maltose-binding domain); a "tag" domain (e. g., in at least a
 portion of .beta.-galactoside, a strep tag peptide, other domains that can
 be purified using compounds that bind to the domain, such as monoclonal
 antibodies), or any combination of the above listed fusion segments. More
 preferred fusion segments include metal binding domains, such as a
 poly-histidine segment; a maltose-binding domain; a strep tag peptide,
 such as that available from Biometra in Tampa, Fla.; and an S10 peptide.
 In another embodiment, a parasitic nematode transglutaminase protein of the
 present invention also includes at least one additional protein segment
 that is capable of protecting an animal from one or more diseases such a
 multivalent protective protein can be produced by culturing a cell
 transformed with a nucleic acid molecule comprising two or more nucleic
 acid domains joined together in such a manner that the resulting nucleic
 acid molecule is expressed as a multivalent protective compound containing
 at least two protective compounds, or portions thereof, capable of
 protecting an animal from diseases caused, for example, by at least one
 other infectious agent.
 Examples of multivalent protective compounds include, but are not limited
 to, a parasitic nematode transglutaminase protein of the present invention
 attached to one or more compounds protective against one or more other
 infectious agents, particularly an agent that infects humans, cats, dogs,
 cattle, sheep pigs, goats or horses, such as, but not limited to: viruses
 (e.g., adenoviruses, caliciviruses, coronaviruses, distemper viruses,
 hepatitis viruses, herpesviruses, immunodeficiency viruses, infectious
 peritonitis viruses, leukemia viruses, oncogenic viruses, panleukopenia
 viruses, papilloma viruses, parainfluenza viruses, parvoyiruses, rabies
 viruses, and reoviruses, as well as other cancer-causing or cancer-related
 viruses); bacteria (e.g., Actinomyces, Bacillus, Bacteroides, Bordetella,
 Bartonella, Borrelia, Brucella, Campylobacter, Capnocytophaga,
 Clostridium, Corynebacterium, Coxiella, Dermatophilus, Enterococcus,
 Ehrlichia, Escherichia, Francisella, Fusobacterium, Haemobartonella,
 Helicobacter, Klebsiella, L-form bacteria, Leptospira, Listeria,
 Mycobacteria, Mycoplasma, Neorickettsia, Nocardia, Pasteurella,
 Peptococcus, Peptostreptococcus, Proteus, Pseudomonas, Rickettsia,
 Rochalimaea, Salmonella, Shigella, Staphylococcus, Streptococcus, and
 Yersinia; fungi and fungal-related microorganisms (e.g., Absidia,
 Acremonium, Alternaria, Aspergillus, Basidiobolus, Bipolaris, Blastomyces,
 Candida, Chlamydia, Coccidioides, Conidiobolus, Cryptococcus, Curvalaria,
 Epiderinophyton, Exophiala, Geotrichum, Histoplasma, Madurella,
 Malassezia, Microsporum, Moniliella, Mortierella, Mueor, Paecilomyces,
 Penicillium, Phialemonium, Phialophora, Prototheca, Pseudallescheria,
 Pseudomicrodochium, Pythium, Rhinosporidium, Rhizopus, Scolecobaidium,
 Sporothrix, Stemphylium, Trichophyton, Trichosporon, and Xylohypha); and
 other parasites (e.g., Babesia, Balantidium, Besnoitia, Cryptosporidium,
 Eimeria, Encephalitozoon, Entamoeba, Giardia, Hammondia, Hepatozoon,
 Isospora, Leishmania, Microsporidia, Neospora, Nosema, Pentatrichomonas,
 Plasmodium, Pneumocystis, Sarcocystis, Schistosoma, Theileria, Toxoplasma,
 and Trypanosoma, as well as other nematode parasites, including, but not
 limited to those disclosed herein). In one embodiment, a parasitic
 nematode transglutaminase protein of the present invention is attached to
 one or more additional compounds protective against parasitic nematode
 disease. In another embodiment one or more protective compounds, such as
 those listed above, can be included in a multivalent vaccine comprising a
 parasitic nematode transglutaminase protein of the present invention and
 one or more other protective molecules as separate compounds.
 A preferred isolated protein of the present invention is a protein encoded
 by a nucleic acid molecule that hybridizes under stringent hybridization
 conditions with nucleic acid molecule nDiTG.sub.707, nDiTG.sub.705,
 nDiTG.sub.1472, nDiTG.sub.1107, nDiTG.sub.143, nDiTG.sub.45,
 nDiTG.sub.120, nDiTG.sub.1407, nDiTG.sub.1881, nDitG.sub.1494,
 nDiTG.sub.1416, nBmTG.sub.440, nBmTG.sub.417, nBmTG.sub.339, nBmTG.sub.537
 or nOvTG.sub.137. A further preferred isolated protein is encoded by a
 nucleic acid molecule that hybridizes under stringent hybridization
 conditions with a nucleic acid molecule having nucleic acid sequence SEQ
 ID NO:7, SEQ ID NO:9, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:29, SEQ ID
 NO:31, SEQ ID NO:34, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:42, SEQ ID
 NO:45, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:56 or SEQ ID
 NO:59.
 Translation of SEQ ID NO:5 suggests that nucleic acid molecule
 nDiTG.sub.707 encodes a partial-length parasitic nematode transglutaminase
 protein of about 235 amino acids, referred to herein as PDiTG.sub.235,
 represented by SEQ ID NO:6, assuming an open reading frame having a first
 codon spanning from about nucleotide 1 through about nucleotide 3 of SEQ
 ID NO:5. The coding region encoding PDiTG.sub.235 is represented by
 nucleic acid molecule nDiTG.sub.705, having the nucleic acid sequence
 represented by SEQ ID NO:8 (the coding strand) and SEQ ID NO:9 (the
 complementary strand). The deduced amino acid sequence (represented by SEQ
 ID NO:6) suggests a protein having a molecular weight of about 27.2
 kilodaltons (kD) and an estimated pI of about 5.07.
 The amino acid sequence of PDiTG.sub.235 includes a thioredoxin family
 active site from residues about 24 to 30. Thioredoxins participate in
 various redox reactions through the reversible oxidation of an active
 center disulfide bond Holmgren, A., 1985 Annual Review of Biochemistry,
 54, 237-271. A number of eukaryotic proteins contain domains
 evolutionarily related to thioredoxin.
 Translation of SEQ ID NO:10 suggests that nucleic acid molecule nDiTG
 .sub.472 encodes a partial-length parasitic nematode transglutaminase
 protein of about 368 amino acids, referred to herein as PDiTG.sub.368,
 represented by SEQ ID NO:11, assuming an open reading frame having a first
 codon spanning from about nucleotide 2 through about nucleotide 4 of SEQ
 ID NO:10, and a putative stop codon spanning from about nucleotide 1105
 through nucleotide 1107 of SEQ ID NO:10. The coding region encoding
 PDiTG.sub.368 (including a putative stop codon) is represented by nucleic
 acid molecule nDiTG.sub.1107, having the nucleic acid sequence represented
 by SEQ ID NO:13 (the coding strand) and SEQ ID NO:14 (the complementary
 strand). The deduced amino acid sequence SEQ ID NO:11 suggests a protein
 having a molecular weight of about 42.6 kD and an estimated pI of about
 5.71.
 The amino acid sequence of PDiTG.sub.368 (i.e., SEQ ID NO:11) includes: i)
 a thioredoxin family active site detected from residues 268 to 274; ii) an
 endoplasmic reticulum (ER) targeting sequence from residues 365 to 368
 (KEEL)(proteins that permanently reside in the lumen of ER seem to be
 distinguished from newly synthesized secretory proteins by the presence of
 the C-terminal sequence Lys-Asp-Glu-Leu (KDEL); see, for example, Munro et
 al., 1987, Cell 48,899-907; Pelham, 1990, Trends in Biochemical Sciences,
 15,483-486; and iii) a tachykinin family signature from residues 186 to
 202 (tachykinins are a group of biologically active peptides that excite
 neurons, evoke behavioral responses, are potent vasodilators, and contract
 many smooth muscles; see, for example, Maggio, 1988, Annual Review of
 Neurosciences, 11,13-28.
 More preferred parasitic nematode transglutaminase proteins of the present
 invention include proteins comprising amino acid sequences that are at
 least about 80%, preferably at least about 85%, more preferably at least
 about 90%, and even more preferably at least about 95% identical to amino
 acid sequence SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, or SEQ ID NO:4. These
 sequences are described in the Examples. Even more preferred parasitic
 nematode transglutaminase proteins of the present invention include
 proteins comprising amino acid sequences that are at least about 50%,
 preferably at least about 60%, more preferably at least about 70%, more
 preferably at least about 80%, more preferably at least about 90%, and
 even more preferably at least about 95% identical to amino acid sequence
 SEQ ID NO:6, SEQ ID NO:11, SEQ ID NO:28, SEQ ID NO:33, SEQ ID NO:36, SEQ
 ID NO:41, SEQ ID NO:44, SEQ ID NO:47, SEQ ID NO:52, SEQ ID NO:55 or SEQ ID
 NO:58.
 More preferred parasitic nematode transglutaminase proteins of the present
 invention include proteins encoded by a nucleic acid molecule comprising
 at least a portion of nDiTG.sub.707, nDiTG.sub.705, nDiTG.sub.1472,
 nDiTG.sub.1107, nDiTG.sub.143, nDiTG.sub.45, nDiTG.sub.120,
 nDiTG.sub.1407, nDiTG.sub.1881, nDiTG.sub.1494, nDiTG.sub.1416,
 nBmTG.sub.440, nBmTG.sub.417, nBmTG.sub.339, nBmTG.sub.537 and
 nOvTG.sub.537, or at least a portion of allelic variants of these nucleic
 acid molecules. In one embodiment, a preferred nematode transglutaminase
 protein of the present invention is encoded by at least a portion of SEQ
 ID NO:5, SEQ ID NO:8, SEQ ID NO:10, or SEQ ID NO:13, SEQ ID NO:27, SEQ ID
 NO:30, SEQ ID NO:32, SEQ ID NO:35, SEQ ID NO:38, SEQ ID NO:40, SEQ ID
 NO:41, SEQ ID NO:46, SEQ ID NO:49, SEQ ID NO:51, SEQ ID NO:54 or SEQ ID
 NO:57, and has an amino acid sequence that includes at least a portion of
 SEQ ID NO:6, SEQ ID NO:11, SEQ ID NO:28, SEQ ID NO:33, SEQ ID NO:36, SEQ
 ID NO:41, SEQ ID NO:44, SEQ ID NO:47, SEQ ID NO:52, SEQ ID NO:55 or SEQ ID
 NO:58. Also preferred is a protein encoded by an allelic variant of a
 nucleic acid molecule comprising at least a portion of SEQ ID NO:5, SEQ ID
 NO:8, SEQ ID NO:10, or SEQ ID NO:13, SEQ ID NO:27, SEQ ID NO:30, SEQ ID
 NO:32, SEQ ID NO:35, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:43, SEQ ID
 NO:46, SEQ ID NO:49, SEQ ID NO:51, SEQ ID NO:54 or SEQ ID NO:57.
 Particularly preferred proteins of the present invention are those
 comprising an amino acid sequence selected from the group consisting of
 SEQ ID NO:1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4,SEQ ID NO:6, SEQ ID
 NO:11, SEQ ID NO:28, SEQ ID NO:33, SEQ ID NO:36, SEQ ID NO:41, SEQ ID
 NO:44, SEQ ID NO:47, SEQ ID NO:52, SEQ ID NO:55 or SEQ ID NO:58, and
 proteins encoded by an allelic variant of a nucleic acid molecule encoding
 any of these amino acid sequences. Also preferred is an isolated D.
 immitis transglutaminase protein. An isolated D. immitis transglutaminase
 protein of the present invention can be either native or can be chemically
 synthesized or produced in a cell transformed with a nucleic acid molecule
 encoding a D. immitis transglutaminase protein.
 Another embodiment of the present invention is an isolated nucleic acid
 molecule that hybridizes under stringent hybridization conditions with a
 parasitic nematode transglutaminase gene, and particularly with a D.
 immitis, B. malayi or O. volvulus transglutaminase gene. The identifying
 characteristics of such a gene are herein described. A nucleic acid
 molecule of the present invention can include an isolated natural
 parasitic nematode transglutaminase gene or a homolog thereof, the latter
 of which is described in more detail below. A nucleic acid molecule of the
 present invention can include one or more regulatory regions, full-length
 or partial coding regions, or any combinations thereof. The minimum size
 of a nucleic acid molecule of the present invention is the minimum size
 that can form a stable hybrid with a parasitic nematode transglutaminase
 gene under stringent hybridization conditions. Suitable and preferred
 parasitic nematodes are disclosed above.
 In accordance with the present invention, an isolated nucleic acid molecule
 is a nucleic acid molecule that has been removed from its natural milieu
 (i.e., that has been subjected to human manipulation) and can include DNA,
 RNA, or derivatives of either DNA or RNA. As used herein, the term,
 "isolated," does not reflect the extent to which the nucleic acid molecule
 has been purified. An isolated parasitic nematode transglutaminase nucleic
 acid molecule of the present invention can be isolated from its natural
 source or can be produced using recombinant DNA technology (e.g.,
 polymerase chain reaction (PCR) amplification, cloning) or chemical
 synthesis. Isolated nematode transglutaminase nucleic acid molecules can
 include, for example, natural allelic variants and nucleic acid molecules
 modified by nucleotide insertions, deletions, substitutions, inversions,
 variants created during PCR amplification, or any combination of the above
 modifications. According to the present invention, acceptable
 modifications to nematode transglutaminase nucleic acid molecules do not
 substantially interfere with the nucleic acid molecule's ability to encode
 a nematode transglutaminase protein of the present invention or to form
 stable hybrids under stringent conditions with natural parasitic nematode
 transglutaminase gene isolates.
 A parasitic nematode transglutaminase nucleic acid molecule homolog can be
 produced using a number of methods known to those skilled in the art (see,
 for example, Sambrook et al., ibid.). For example, nucleic acid molecules
 can be modified using a variety of techniques including, but not limited
 to, classic mutagenesis and recombinant DNA techniques (e.g.,
 site-directed mutagenesis, chemical treatment, restriction enzyme
 cleavage, ligation of nucleic acid fragments, and PCR amplification), or
 synthesis of oligonucleotide mixtures and ligation of mixture groups to
 "build" a mixture of nucleic acid molecules and combinations thereof.
 Nucleic acid molecule homologs can be selected by hybridization with a
 nematode transglutaminase gene or by screening expression products of the
 nematode transglutaminase nucleic acid molecule homologs for the function
 of a protein encoded by the nucleic acid molecule (e.g., the ability to
 elicit an immune response against at least one epitope of a parasitic
 nematode transglutaminase protein or parasitic nematode transglutaminase
 activity).
 An isolated nucleic acid molecule of the present invention can include a
 nucleic acid sequence that encodes at least one parasitic nematode
 transglutaminase protein of the present invention; examples of such
 proteins are herein disclosed. Although the phrase "nucleic acid molecule"
 primarily refers to the physical nucleic acid molecule and the phrase
 "nucleic acid sequence" primarily refers to the sequence of nucleotides in
 the nucleic acid molecule, the two phrases can be used interchangeably,
 especially with respect to a nucleic acid molecule, or a nucleic acid
 sequence, being capable of encoding a parasitic nematode transglutaminase
 protein.
 A preferred nucleic acid molecule of the present invention, when
 administered to an animal, is substantially not toxic to the animal and is
 capable of protecting that animal from disease caused by a parasitic
 nematode. As will be disclosed in more detail below, such a nucleic acid
 molecule can be, or encode, an antisense RNA, a molecule capable of triple
 helix formation, a ribozyme, or other nucleic acid-based drug compound. In
 additional embodiments, a nucleic acid molecule of the present invention
 can encode a protective protein (e.g., a nematode transglutaminase protein
 of the present invention), the nucleic acid molecule being delivered to
 the animal, for example, by direct injection (i.e, as a composition
 comprising a naked nucleic acid molecule of the present invention) or in a
 vehicle such as a recombinant virus vaccine or a recombinant cell vaccine.
 One embodiment of the present invention is a parasitic nematode
 transglutaminase nucleic acid molecule that hybridizes under stringent
 hybridization conditions with nucleic acid molecule nDiTG.sub.707, and
 preferably with a nucleic acid molecule having nucleic acid sequence SEQ
 ID NO:5 or SEQ ID NO:7. Such a nucleic acid molecule would also hybridize
 with nDiTG.sub.705, and thus would also hybridize with SEQ ID NO:8 or SEQ
 ID NO:9. Comparison of nucleic acid sequence SEQ ID NO:5 (i.e., the
 nucleic acid sequence of the coding strand of nDiTG.sub.707) with nucleic
 acid sequences reported in GenBank.TM. indicates that SEQ ID NO:5 showed
 the most homology (i.e., about 37% identity) with human clone 
 (GenBank.TM. accession number J05016), a protein disulfide isomerase
 related to protein (Erp72) mRNA.
 Another embodiment of the present invention is a parasitic nematode
 transglutaminase nucleic acid molecule that hybridizes under stringent
 hybridization conditions with nucleic acid molecule nDiTG.sub.1427, and
 preferably with a nucleic acid molecule having nucleic acid sequence SEQ
 ID NO:10 or SEQ ID NO:12. Such a nucleic acid molecule would also
 hybridize with nDiTG.sub.1107, and thus would also hybridize with SEQ ID
 NO:13 or SEQ ID NO:14. Comparison of nucleic acid sequence SEQ ID NO:10
 (i.e., the nucleic acid sequence of the coding strand of nDiTG.sub.1427)
 with nucleic acid sequences reported in GenBank.TM. indicates that SEQ ID
 NO:10 showed the most homology (i.e., about 63% sequence identity) with a
 human epithelial cell mRNA for ER-60 protease (GenBank.TM. accession
 number D83485), spanning from nucleotide about 1143 to about 1458 of the
 ER-60 protease.
 Preferred parasitic nematode transglutaminase nucleic acid molecules
 include nucleic acid molecules having a nucleic acid sequence that is at
 least about 70%, preferably at least about 75%, more preferably at least
 about 80%, more preferably at least about 85%, even more preferably at
 least about 90% and even more preferably at least about 95% identical to
 nucleic acid sequence SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9,
 SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:27, SEQ
 ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:34, SEQ ID
 NO:35, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID
 NO:42, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:48, SEQ ID
 NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:53, SEQ ID NO:54, SEQ ID
 NO:56, SEQ ID NO:57 or SEQ ID NO:59.
 Another preferred embodiment of the present invention includes at least a
 portion of a nucleic acid sequence SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:8,
 SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ
 ID NO:27, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID
 NO:34, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID
 NO:40, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:46, SEQ ID
 NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:53, SEQ ID
 NO:54, SEQ ID NO:56, SEQ ID NO:57 or SEQ ID NO:59 that is capable of
 hybridizing with a nematode transglutaminase gene of the present
 invention, as well as allelic variants thereof. Such nucleic acid
 molecules can include nucleotides in addition to those included in the
 sequences listed above, such as, but not limited to, a full-length gene, a
 full-length coding region, a nucleic acid molecule encoding a fusion
 protein, or a nucleic acid molecule encoding a multivalent protective
 compound. Particularly preferred nucleic acid molecules include
 nDiTG.sub.707, nDiTG.sub.705, nDiTG.sub.1472, nDiTG.sub.1107,
 nDiTG.sub.143, nDiTG.sub.120, nDiTG.sub.1407, nDiTG.sub.1881,
 nDiTG.sub.1494, nDiTG.sub.1416, nBmTG.sub.440, nBmTG.sub.417,
 nBmTG.sub.339, nBmTG.sub.537 or nOvTG.sub.537, and allelic variants of
 these nucleic acid molecules. Also particularly preferred nucleic acid
 molecules include those including SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:8,
 SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ
 ID NO:27, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID
 NO:34, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID
 NO:40, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:46, SEQ ID
 NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:53, SEQ ID
 NO:54, SEQ ID NO:56, SEQ ID NO:57 or SEQ ID NO:59, and allelic variants of
 these preferred nucleic acid molecules.
 The present invention also includes a nucleic acid molecule encoding a
 protein having at least a portion of SEQ ID NO:6, SEQ ID NO:11, SEQ ID
 NO:28, REQ ID NO:33, SEQ ID NO:36, SEQ ID NO:41, SEQ ID NO:44, SEQ ID
 NO:47, SEQ ID NO:52, SEQ ID NO:55 or SEQ ID NO:58, including allelic
 variants of these sequences and nucleic acid molecules that have been
 modified to accommodate codon usage properties of the cells in which such
 nucleic acid molecules are to be expressed. Particularly preferred are
 nucleic acid molecules that encode amino acid sequences including those
 represented by SEQ ID NO:6, SEQ ID NO:11, SEQ ID NO:28, SEQ ID NO:33, SEQ
 ID NO:36, SEQ ID NO:41, SEQ ID NO:44, SEQ ID NO:47, SEQ ID NO:52, SEQ ID
 NO:55 or SEQ ID NO:58, and allelic variants of these nucleic acid
 molecules.
 Knowing the nucleic acid sequences of certain parasitic nematode
 transglutaminase nucleic acid molecules of the present invention allows
 one skilled in the art to, for example, (a) make copies of those nucleic
 acid molecules, (b) obtain nucleic acid molecules including at least a
 portion of such nucleic acid molecules (e.g., nucleic acid molecules
 including full-length genes, full-length coding regions, regulatory
 control sequences, truncated coding regions), and (c) obtain parasitic
 nematode transglutaminase nucleic acid molecules from other parasitic
 nematodes. Such nucleic acid molecules can be obtained in a variety of
 ways including screening appropriate expression libraries with antibodies
 of the present invention; traditional cloning techniques using
 oligonucleotide probes of the present invention to screen appropriate
 libraries DNA, or RNA; and PCR amplification of appropriate libraries,
 DNA, or RNA using oligonucleotide primers of the present invention.
 Preferred libraries to screen or from which to amplify nucleic acid
 molecule include adult and larval stage parasitic nematode cDNA libraries
 as well as genomic DNA libraries. Similarly, preferred DNA or RNA sources
 to screen or from which to amplify nucleic acid molecules include adult
 and larval stage parasitic nematode cDNA, adult and larval mRNA, and
 genomic DNA. Techniques to clone and amplify genes are disclosed, for
 example, in Sambrook et al., ibid, as well as in the Examples section.
 The present invention also includes nucleic acid molecules that are
 oligonucleotides capable of hybridizing, under stringent hybridization
 conditions, with complementary regions of other, preferably longer,
 nucleic acid molecules of the present invention such as those comprising
 parasitic nematode transglutaminase genes or other parasitic nematode
 transglutaminase nucleic acid molecules. Oligonucleotides of the present
 invention can be RNA, DNA, or derivatives of either. The minimum size of
 such oligonucleotides is the size required for formation of a stable
 hybrid between an oligonucleotide and a complementary sequence on a
 nucleic acid molecule of the present invention. Minimal size
 characteristics are disclosed herein. The present invention includes
 oligonucleotides that can be used as, for example, probes to identify
 nucleic acid molecules, primers to produce nucleic acid molecules or
 therapeutic reagents to inhibit nematode transglutaminase protein
 production or activity (e.g., as antisense-, triplex formation-, ribozyme-
 and/or RNA drug-based reagents). The present invention also includes the
 use of such oligonucleotides to protect animals from disease using one or
 more of such technologies. Appropriate oligonucleotide-containing
 therapeutic compositions can be administered to an animal using techniques
 known to those skilled in the art.
 One embodiment of the present invention includes a recombinant vector,
 which includes at least one isolated nucleic acid molecule of the present
 invention, inserted into any vector capable of delivering the nucleic acid
 molecule into a cell. Such a vector contains heterologous nucleic acid
 sequences, that is nucleic acid sequences that are not naturally found
 adjacent to nucleic acid molecules of the present invention and that
 preferably are derived from a species other than the species from which
 the nucleic acid molecule(s) are derived. The vector can be either RNA or
 DNA, either prokaryotic or eukaryotic, and typically is a virus or a
 plasmid. Recombinant vectors can be used in the cloning, sequencing,
 and/or otherwise manipulation of parasitic nematode transglutaminase
 nucleic acid molecules of the present invention.
 One type of recombinant vector, referred to herein as a recombinant
 molecule, comprises a nucleic acid molecule of the present invention
 operatively linked to an expression vector. The phrase operatively linked
 refers to insertion of a nucleic acid molecule into an expression vector
 in a manner such that the molecule is able to be expressed when
 transformed into a cell. As used herein, an expression vector is a DNA or
 RNA vector that is capable of transforming a cell and of effecting
 expression of a specified nucleic acid molecule. Preferably, the
 expression vector is also capable of replicating within the cell.
 Expression vectors can be either prokaryotic or eukaryotic, and are
 typically viruses (including viral genomes) or plasmids. Expression
 vectors of the present invention include any vectors that function (i.e.,
 direct gene expression) in recombinant cells of the present invention,
 including in bacterial, fungal, endoparasite, insect, other animal, and
 plant cells. Preferred expression vectors of the present invention can
 direct gene expression in bacterial, yeast, insect and mammalian cells and
 more preferably in the cell types disclosed herein.
 In particular, expression vectors of the present invention contain
 regulatory sequences such as transcription control sequences, translation
 control sequences, origins of replication, and other regulatory sequences
 that are compatible with the recombinant cell and that control the
 expression of nucleic acid molecules of the present invention. In
 particular, recombinant molecules of the present invention include
 transcription control sequences. Transcription control sequences are
 sequences that control the initiation, elongation, and termination of
 transcription. Particularly important transcription control sequences are
 those that control transcription initiation, such as promoter, enhancer,
 operator and repressor sequences. Suitable transcription control sequences
 include any transcription control sequence that can function in at least
 one of the recombinant cells of the present invention. A variety of such
 transcription control sequences are known to those skilled in the art.
 Preferred transcription control sequences include those that function in
 bacterial, yeast, insect and mammalian cells, such as, but not limited to,
 tac, lac, trp, trc, oxy-pro, omp/lpp, rrnB, bacteriophage lambda(such as
 lambda p.sub.L and lambda p.sub.R and fusions that include such
 promoters), bacteriophage T7, T7lac, bacteriophage T3, bacteriophage SP6,
 bacteriophage SP01 , metallothionein, alpha-mating factor, Pichia alcohol
 oxidase, alphavirus subgenomic promoters (such as Sindbis virus subgenomic
 promoters), antibiotic resistance gene, baculovirus, Heliothis zea insect
 virus, vaccinia virus, herpesvirus, raccoon poxvirus, other poxvirus,
 adenovirus, cytomegalovirus (such as intermediate early promoters), simian
 virus 40, retrovirus, actin, retroviral long terminal repeat, Rous sarcoma
 virus, heat ghock, phosphate and nitrate transcription control sequences
 as well as other sequences capable of controlling gene expression in
 prokaryotic or eukaryotic cells. Additional suitable transcription control
 sequences include tissue-specific promoters and enhancers as well as
 lymphokine-inducible promoters (e.g., promoters inducible by interferons
 or interleukins). Transcription control sequences of the present invention
 can also include naturally occurring transcription control sequences
 naturally associated with parasitic nematodes, for example D. immitis.
 Suitable and preferred nucleic acid molecules to include in recombinant
 vectors of the present invention are as disclosed herein. Particularly
 preferred nucleic acid molecules to include in recombinant vectors, and
 particularly in recombinant molecules, include nDiTG.sub.707,
 nDiTG.sub.705, nDiTG.sub.1472, nDiTG.sub.1107, nDiTG.sub.143,
 nDiTG.sub.120, nDiTG.sub.45, nDiTG.sub.1407, nDiTG.sub.1881,
 nDiTG.sub.1494, nDiTG.sub.1416, nBmTG.sub.440, nBmTG.sub.417,
 nBmTG.sub.339, nBmTG.sub.537 or nOvTG.sub.537.
 Recombinant molecules of the present invention may also (a) contain
 secretory signals (i.e., signal segment nucleic acid sequences) to enable
 an expressed nematode transglutaminase protein of the present invention to
 be secreted from the cell that produces the protein and/or (b) contain
 fusion sequences that lead to the expression of nucleic acid molecules of
 the present invention as fusion proteins. Examples of suitable signal
 segments include any signal segment capable of directing the secretion of
 a protein of the present invention. Preferred signal segments include, but
 are not limited to, tissue plasminogen activator (t-PA), interferon,
 interleukin, growth hormone, histocompatibility and viral envelope
 glycoprotein signal segments, as well as natural signal segments. Suitable
 fusion segments encoded by fusion segment nucleic acids are disclosed
 herein, In addition, a nucleic acid molecule of the present invention can
 be joined to a fusion segment that directs the encoded protein to the
 proteosome, such as a ubiquitin fusion segment. Recombinant molecules may
 also include intervening and/or untranslated sequences surrounding and/or
 within the nucleic acid sequences of nucleic acid molecules of the present
 invention. An example of a preferred intervening sequence for eukaryotic
 gene expression os cytomegalovirus intron A.
 Another embodiment of the present invention includes a recombinant cell
 transformed with one or more recombinant molecules of the present
 invention. Transformation of a nucleic acid molecule into a cell can be
 accomplished by any method by which a nucleic acid molecule can be
 inserted into the cell. Transformation techniques include, but are not
 limited to, transfection, electroporation, microinjection, lipofection,
 adsorption, and protoplast fusion. A recombinant cell may remain
 unicellular or may grow into a tissue, organ or a multicellular organism.
 A nucleic acid molecule of the present invention that has been transformed
 into a cell is referred to herein as a transformed nucleic acid molecule.
 Transformed nucleic acid molecules of the present invention can remain
 extrachromosomal or can integrate into one or more sites within a
 chromosome of the transformed (i.e., recombinant) cell in such a manner
 that their ability to be expressed is retained. Preferred nucleic acid
 molecules with which to transform a cell include parasitic nematode
 transglutaminase nucleic acid molecules disclosed herein. Particularly
 preferred nucleic acid molecules with which to transform a cell include
 nDiTG.sub.705, nDiTG.sub.1107, nDiTG.sub.120, nDiTG.sub.1407,
 nDiTG.sub.1494, nBmTG.sub.417, nBmTG.sub.537 or nOvTG.sub.537. Also
 preferred are nDiTG.sub.1881, nDiTG.sub.707, nDiTG.sub.1472,
 nDiTG.sub.143, nDiTG.sub.45, nDiTG.sub.1416, nBmTG.sub.339 and
 nBmTG.sub.440.
 Suitable cells to transform include any cell that can be transformed with a
 nucleic acid molecule of the present invention. A transformed cell of the
 present invention is also herein referred to as a recombinant cell.
 Suitable cells can be either untransformed cells or cells that are already
 transformed with at least one nucleic acid molecule (e.g., nucleic acid
 molecules encoding one or more proteins of the present invention, other
 proteins useful in the production of multivalent vaccines, or a
 combination thereof). Suitable cells for transformation according to the
 present invention can be either a) endogenously (i.e., naturally) capable
 of producing parasitic nematode transglutaminase proteins of the present
 invention, or b) capable of producing such proteins after transformation
 with at least one nucleic acid molecule of the present invention. Cells of
 the present invention can be any cell capable of producing at least one
 protein of the present invention, and include bacterial, fungal (including
 yeast), insect, other nematode, other and plant cells. Preferred cells for
 transformation by nucleic acid molecules of the present invention include
 bacterial, mycobacterial, yeast, parasite, insect and mammalian cells.
 More preferred cells include Salmonella, Escherichia, Bacillus, Listeria,
 Saccharomyces, Spodoptera, Mycobacteria, Trichoplusia, BHK (baby hamster
 kidney) cells, MDCK cells (normal dog kidney cell line for canine
 herpesvirus cultivation), CRFK cells (normal cat kidney cell line for
 feline heipesvirus cultivation), CV-1 cells (African monkey kidney cell
 line used, for example, to culture raccoon poxvirus), COS (e.g., COS-7)
 cells, and Vero cells. Particularly preferred cells for transformation are
 Escherichia coli, including E. coli K-12 derivatives; Salmonella typhi;
 Salmonella typhimurium, including attenuated strains such as UK-1 .sub.x
 3987 and SR-11 .sub.x 4072; Spodopterafrugiperda; Trichoplusia ni; BHK
 cells; MDCK cells; CRFK cells; CV-1 cells; COS cells; Vero cells; and
 non-tumorigenic mouse myoblast G8 cells (e.g., ATCC CRL 1246). Additional
 appropriate mammalian cells suitable for transformation by nucleic acid
 molecules of the present invention include other kidney cell lines, other
 fibroblast cell lines (e.g., human, murine or chicken embryo fibroblast
 cell lines), myeloma cell lines, Chinese hamster ovary cells, mouse NIH3T3
 cells, LMTIK.sup.31 cells and/or HeLa cells. In one embodiment, the
 proteins may be expressed as heterologous proteins in myeloma cell lines
 employing immunoglobulin promoters.
 A recombinant cell is preferably produced by transforming a suitable cell
 with one or more recombinant molecules, each comprising one or more
 nucleic acid molecules of the present invention operatively linked to an
 expression vector containing one or more transcription control sequences.
 The phrase operatively linked refers to insertion of a nucleic acid
 molecule into an expression vector in a manner such that the molecule is
 able to be expressed when transformed into a suitable cell as described
 above.
 A recombinant molecule of the present invention is a molecule that can
 include at least one of any parasitic nematode transglutaminase nucleic
 acid molecule herein described, operatively linked to at least one of any
 transcription control sequence capable of effectively regulating
 expression of the nucleic acid molecule(s) in the cell suitable for
 transformation, examples of which are disclosed herein.
 A recombinant cell of the present invention includes any cell transformed
 with at least one of any nucleic acid molecule of the present invention.
 Suitable and preferred nucleic acid molecules as well as suitable and
 preferred recombinant molecules with which to transform cells are
 disclosed herein.
 Recombinant cells of the present invention can also be co-transformed with
 one or more recombinant molecules including parasitic nematode
 transglutaminase nucleic acid molecules encoding one or more proteins of
 the present invention and one or more other nucleic acid molecules
 encoding other protective compounds, as disclosed herein (e.g., to produce
 multivalent vaccines).
 Recombinant DNA technologies can be used to improve expression of
 transformed nucleic acid molecules by manipulating, for example, the
 number of copies of the nucleic acid molecules within a transformed cell,
 the efficiency with which those nucleic acid molecules are transcribed,
 the efficiency with which the resultant transcripts are translated, and
 the efficiency of post-translational modifications. Recombinant techniques
 useful for increasing the expression of nucleic acid molecules of the
 present invention include, but are not limited to, operatively linking
 nucleic acid molecules of the present invention to nucleic acid molecules
 that direct the production of a high-copy number of plasmids, integration
 of the nucleic acid molecules into one or more chromosomes in the
 transformed cell, addition of vector stability sequences to plasmids
 containing nucleic acid sequences of the present invention, substitutions
 or modifications of transcription control signals (e.g., promoters,
 operators, enhancers), substitutions or modifications of translational
 control signals (e.g., ribosome binding sites, Shine-Dalgarno sequences),
 modification of nucleic acid molecules of the present invention to
 correspond to the codon usage of the transformed cell, deletion of
 sequences that destabilize transcripts, and use of control signals that
 temporally separate recombinant cell growth from recombinant enzyme
 production during fermentation. The activity of an expressed recombinant
 protein of the present invention may be improved by fragmenting,
 modifying, or derivatizing nucleic acid molecules encoding such a protein.
 Isolated nematode transglutaminase proteins of the present invention can be
 produced in a variety of ways, including production and recovery of
 natural proteins, production and recovery of recombinant proteins, and
 chemical synthesis of the proteins. In one embodiment, an isolated
 parasitic nematode transglutaminase protein of the present invention is
 produced by culturing a cell capable of expressing the protein under
 conditions effective to produce the protein, and recovering the protein. A
 preferred cell to culture is a recombinant cell of the present invention.
 Effective culture conditions include, but are not limited to, effective
 media, bioreactor, temperature, pH and oxygen conditions that permit
 protein production. An effective medium refers to any medium in which a
 cell is cultured to produce a parasitic nematode transglutaminase protein
 of the present invention. Such medium typically comprises an aqueous
 medium having assimilable carbon, nitrogen and phosphate sources, and
 appropriate salts, minerals, metals and other nutrients, such as vitamins.
 Cells of the present invention can be cultured in conventional
 fermentation bioreactors, shake flasks, test tubes, microtiter dishes, and
 petri plates. Culturing can be cared out at a temperature, pH and oxygen
 content appropriate for a recombinant cell. Such culturing conditions are
 within the expertise of one of ordinary skill in the art.
 Depending on the vector and transformed cell system used for production,
 resultant proteins of the present invention may either remain within the
 recombinant cell; be secreted into the fermentation medium; be secreted
 into a space between two cellular membranes, such as the periplasmic space
 in E. coli; or be retained on the outer surface of a cell or viral
 membrane. The phrase "recovering the protein", as well as similar phrases,
 can refer to collecting the whole fermentation medium containing the
 protein and need not imply additional steps of separation or purification.
 Proteins of the present invention can be purified using a variety of
 standard protein purification techniques, such as, but not limited to,
 affinity chromatography, immunoaffinity chromatography,
 thermoprecipitation, ammonium gulphate precipitaion, ion exchange
 chromatography, filtration, electrophoresis, hydrophobic interaction
 chromatography, gel filtration chromatography, reverse phase
 chromatography, concanavalin A chromatography, chromatofocusing and
 differential solubilization. Proteins of the present invention are
 preferably retrieved in "substantially pure" form. As used herein,
 "substantially pure" refers to a purity that allows for the effective use
 of the protein as a therapeutic composition or diagnostic. A therapeutic
 composition for animals, for example, should exhibit no substantial
 toxicity and preferably should be capable of stimulating the production of
 antibodies in a treated animal.
 The present invention also includes isolated (i.e., removed from their
 natural Milieu) antibodies that selectively bind to a parasitic nematode
 transglutaminase protein of the present invention or a mimetope thereof
 (e.g., anti-parasitic nematode transglutaminase antibodies). As used
 herein, the term "selectively binds to" a nematode transglutaminase
 protein refers to the ability of antibodies of the present invention to
 preferentially bind to specified proteins and mimetopes thereof of the
 present invention. Binding can be measured using a variety of methods
 standard in the art including enzyme immunoassays (e.g., ELISA),
 immunoblot assays, etc.; see, for example, Sambrook et al., ibid. An
 anti-parasitic nematode transglutaminase antibody preferably selectively
 binds to a parasitic nematode transglutaminase protein in such a way as to
 reduce the activity of that protein.
 Isolated antibodies of the present invention can include antibodies in
 serum, or antibodies that have been purified to varying degrees.
 Antibodies of the present invention can be polyclonal or monoclonal, or
 can be functional equivalents such as antibody fragments and
 genetically-engineered antibodies, including single chain antibodies or
 chimeric antibodies that can bind to more than one epitope.
 A preferred method to produce antibodies of the present invention includes
 (a) administering to an animal an effective amount of a protein (ranging
 in size from a peptide to a full length protein) or mimetope thereof of
 the present invention to produce the antibodies and (b) recovering the
 antibodies. In another method, antibodies of the present invention are
 produced recombinantly using techniques as disclosed to produce parasitic
 nematode transglutaminase proteins of the present invention. Antibodies
 raised against defined proteins or mimetopes can be advantageous because
 such antibodies are not substantially contaminated with antibodies against
 other substances that might otherwise cause interference in a diagnostic
 assay or side effects if used in a therapeutic composition.
 Antibodies of the present invention have a variety of potential uses that
 are within the scope of the present invention. For example, such
 antibodies can be used (a) as therapeutic compounds to passively immunize
 an animal in order to protect the animal from parasitic nematodes
 susceptible to treatment by such antibodies, (b) as reagents in assays to
 detect infection by such nematodes, (c) as tools to screen expression
 libraries, (d) as tools to recover desired proteins of the present
 invention from a mixture of proteins and other contaminants, and (e) for
 any combination of the above listed uses. Furthermore, antibodies of the
 present invention can be used to target cytotoxic agents to parasitic
 nematodes of the present invention in order to directly kill such
 nematodes. Targeting can be accomplished by conjugating (i.e., stably
 joining) such antibodies to the cytotoxic agents using techniques known to
 those skilled in the art. Suitable cytotoxic agents are known to those
 skilled in the art.
 One embodiment of the present invention is a therapeutic composition that,
 when administered to an animal in an effective manner, is capable of
 protecting that animal from disease caused by a parasitic nematode.
 Therapeutic compositions of the present invention include an excipient and
 at least one of the following protective compounds, an isolated native
 nematode transglutaminase protein; an isolated non-native nematode
 transglutaminase protein; a mimetope of a nematode transglutaminase
 protein; an isolated nucleic acid molecule that hybridizes under stringent
 hybridization conditions with a nematode transglutaminase gene; an
 isolated antibody that selectively binds to a nematode transglutaminase
 protein, an inhibitor of nematode transglutaminase protein activity
 identified by its ability to inhibit nematode transglutaminase activity
 and its inability to substantially interfere with host animal
 transglutaminase activity, or a mixture thereof (i.e., combination of at
 least two of the compounds). The term "inability to substantially
 interfere with" host animal transglutaminase activity, as used herein,
 refers to the failure of a nematode transglutaminase inhibitor compound to
 inhibit host animal transglutaminase activity to such a degree that such
 an inhibitor is not substantially toxic to a host animal when it is
 administered to that animal. The inability to interfere with host animal
 transglutaminase activity can be identified by transglutaminase assay in
 vitro, as described in the Examples section. Candidate inhibitors can also
 be tested for toxicity in standard animal studies. Preferred parasitic
 nematodes to target are herein disclosed. Examples of proteins, nucleic
 acid molecules, antibodies and inhibitors of the present invention are
 disclosed herein.
 The present invention also includes a therapeutic composition comprising at
 least one nemtatode transglutaminase-based compound of the present
 invention in combination with at least one additional compound protective
 against one or more infectious agents. Examples of such compounds and
 infectious agents are disclosed herein.
 Therapeutic compositions of the present invention can be administered to
 any animal susceptible to such therapy, preferably to mammals and birds,
 and more preferably to dogs, cats, humans, ferrets, horses, cattle, sheep,
 goats and pigs as well as other pets, food animals, work animals or zoo
 animals. Preferred animals to protect against parasitic nematode disease
 include dogs, cats, humans and ferrets, with dogs, cats and humans being
 particularly preferred.
 Suitable inhibitors of nematode transglutaminase activity include compounds
 that interact directly with a nematode transglutaminase protein active
 site, thereby inhibiting transglutaminase activity, usually by binding to
 or otherwise interacting with or otherwise modifying the nematode
 transglutaminase active site. Nematode transglutaminase inhibitors can
 also interact with other regions of the nematode transglutaminase protein
 to inhibit transglutaminase activity, for example, by allosteric
 interaction. Inhibitors of nematode transglutaminase can be relatively
 small compounds, or they can be quite large, as in the case of
 anti-parasitic nematode transglutaminase antibodies. Preferably, a
 nematode transglutaminase inhibitor of the present invention is identified
 by its ability to inhibit the activity of a nematode transglutaminase, and
 further by its failure to substantially inhibit the activity of host
 animal transglutaminase. Methods for measuring inhibition of
 transglutaminase activity, useful for determining inhibition of either
 nematode or host animal transglutaminase activity, are described in the
 Examples section.
 Inhibitors of a nematode transglutaminase can be used directly as compounds
 in compositions of the present invention to treat host animals, provided
 that such compounds do not substantially inhibit the activity of the host
 animal transglutaminase.
 Inhibitors of a nematode transglutaminase protein can also be used to
 identify preferred types of nematode transglutaminase proteins to target
 using compositions of the present invention, for example by affinity
 chromatography. For example, an inhibitor of the present invention could
 be bound to a gel or a filter, or another substrate, and larval or adult
 nematode extracts could be contacted with the bound inhibitor. Those
 compounds in either larval or adult nematode extracts that bound to or
 otherwise interacted with the inhibitor could then be separated from the
 bound inhibitor and further analyzed for nematode transglutaminase
 activity.
 Preferred inhibitors of a nematode transglutaminase of the present
 invention include, but are not limited to, nematode transglutaminase
 substrate analogs and other molecules that bind to a nematode
 transglutaminase (e.g., to an allosteric site) in such a manner that
 nematode transglutaminase activity of the nematode transglutaminase is
 inhibited. A nematode transglutaminase substrate analog refers to a
 compound that interacts with (e.g., binds to, associates with, modifies)
 the active site of a nematode transglutaminase protein. A preferred
 nematode transglutaminase substrate analog inhibits nematode
 transglutaminase activity. Nematode transglutaminase substrate analogs can
 be any inorganic or organic composition, and can be, but are not limited
 to, peptides, nucleic acids, and peptidomimetic compounds. Nematode
 transglutaminase substrate analogs can be, but need not be, structurally
 similar to a nematode transglutaminase protein's natural substrate
 provided they can interact with the active site of that nematode
 transglutaminase protein. Nematode transglutaminase substrate analogs can
 be designed using computer-generated structures of nematode
 transglutaminase proteins of the present invention or computer structures
 of nematode transglutaminase proteins' natural substrates. Substrate
 analogs Can also be obtained by generating random samples of molecules
 (for example, oligonucleotides, peptides, peptidomimetic compounds, or
 other inorganic or organic molecules), and screening such samples by
 affinity chromatography techniques using the corresponding binding
 partner, (e.g., a nematode transglutaminase or anti-nematode
 transglutaminase substrate antibody). A preferred nematode
 transglutaminase substrate analog is a peptidomimetic compound (i.e., a
 compound that is structurally or functionally similar to a natural
 substrate of a nematode transglutaminase of the present invention,
 particularly to the region of the substrate that interacts with the
 nematode transglutaminase active site, but that inhibits nematode
 transglutaminase activity upon interacting with the nematode
 transglutaminase active site).
 Parasitic nematode transglutaminase peptides, mimetopes and substrate
 analogs, as well as other protective compounds (nucleic acid molecules,
 proteins, antibodies, for example), can be used directly as compounds in
 compositions of the present invention to treat animals as long as such
 compounds are not harmful to the animals being treated. Methods to test
 the safety of such compounds are disclosed herein.
 In accordance with the present invention, a host animal (i.e., an animal
 that is infected with or is capable of being infected by a parasitic
 nematode) is treated by administering to the animal a therapeutic
 composition of the present invention in such a manner that the composition
 itself ((e.g., an inhibitor of a nematode transglutaminase protein,
 mimetope, a nematode transglutaminase synthesis suppressor (i.e., a
 compound that decreases the production of nematode transglutaminase in the
 nematode), a nematode transglutaminase mimetope or an anti-parasitic
 nematode transglutaminase antibody)) or a product generated by the animal
 in response to administration of the composition (e.g., antibodies
 produced in response to a parasitic nematode transglutaminase protein or
 nucleic acid molecule vaccine, or conversion of an inactive inhibitor
 "prodrug" to an active inhibitor of a nematode transglutaminase protein)
 contacts the nematode, thereby reducing transglutaminase activity in the
 nematode. A host animal is preferably treated in such a way that the
 compound or product thereof enters the bodily fluids (e.g., blood and
 lymph systems) and/or tissues of the animal. Parasitic nematodes are then
 exposed to the composition or product when they are present in the host
 animal. For example, nematode transglutaminase protein inhibitors
 administered to an animal are, administered in such a way that the
 inhibitors enter the blood and tissues of the animal where parasitic
 nematodes will come in contact with the inhibitors. In another embodiment,
 when a parasitic nematode transglutaminase protein, mimetopes or nucleic
 acid molecule vaccine is administered to a host animal, the treated animal
 mounts an immune response resulting in the production of antibodies
 against the parasitic nematode transglutaminase protein (i.e.,
 anti-parasitic nematode transglutaminase antibodies) that circulate in the
 animal's blood stream and/or other bodily fluids thereby coming into
 contact with parasitic nematodes.
 In order to protect an animal from disease caused by a parasitic nematode
 of the present invention, a therapeutic composition of the present
 invention is administered to the animal in an effective manner such that
 the composition is capable of protecting that animal from a disease caused
 by a parasitic nematode. Therapeutic compositions of the present invention
 can be administered to animals prior to infection in order to prevent
 infection (i.e., as a preventative vaccine), or can be administered to
 animals after infection in order to treat disease caused by the parasitic
 nematode (i.e., as a therapeutic vaccine), or both techniques may be used.
 Therapeutic compositions of the present invention preferably are formulated
 in an excipient that the animal to be treated can tolerate. Examples of
 such excipients include water, saline, Ringer's solution, dextrose
 solution, Hank's solution, and other aqueous physiologically balanced salt
 solutions. Nonaqueous vehicles, such as fixed oils, sesame oil, ethyl
 oleate, or triglycerides may also be used. Other useful formulations
 include suspensions containing viscosity enhancing agents, such as sodium
 carboxymethylcellulose, sorbitol, or dextran. Excipients can also contain
 minor amounts of additives, such as substances that enhance isotonicity
 and chemical stability. Examples of buffers include phosphate buffer,
 bicarbonate buffer and Tris buffer, while examples of preservatives
 include, m-or o-cresol, formalin and benzyl alcohol. Standard formulations
 can either be liquid injectables or solids that can be taken up in a
 suitable liquid as a suspension or solution for injection. Thus, in a
 non-liquid formulation, the excipient can comprise dextrose, human serum
 albumin, preservatives, etc., to which sterile water or saline can be
 added prior to administration.
 In one embodiment of the present invention, a therapeutic composition can
 include an adjuvant. Adjuvants are agents that are capable of enhancing
 the immune response of an animal to a specific antigen. Suitable adjuvants
 include, but are not limited to, cytokines, chemokines, and compounds that
 induce the production of cytokines and chemokines (e.g., granulocyte
 macrophage colony stimulating factor (GM-CSF), granulocyte colony
 stimulating factor (G-CSF), macrophage colony stimulating factor (M-CSF),
 colony stimulating factor (CSF), erythropoietin (EPO), interleukin 2
 (IL-2), interleukin-3 (IL-3), interleukin 4 (IL-4), interleukin 5 (IL-5),
 interleukin 6 (IL-6), interleukin 7 (IL-7), interleukin 8 (IL-8),
 interleukin 10 (IL-10), interleukin 12 (IL-12), interferon gamma,
 interferon gamma inducing factor I (IGIF), transforming growth factor
 beta, RANTES (regulated upon activation, normal T-cell expressed and
 presumably secreted), macrophage inflammatory proteins (e.g., MIP-1 alpha
 and MIP-1 beta), and leishmania elongation initiating factor (LEIF));
 bacterial components (e.g., endotoxing, in particular superantigens,
 exotoxins and cell wall components); aluminum-based salts; calcium-based
 salts; silica; polynucleotides; toxoids; serum proteins, viral coat
 proteins; block copolymer adjuvants (e.g., Hunter's Titermax.TM. adjuvant
 (Vaxcel.TM., Inc. Norcross, Ga.), Ribi adjuvants (Ribi ImmunoChem
 Research, Inc., Hamilton, Mont.): and saponins and their derivatives
 (e.g., Quil A (Superfos Biosector A/S, Denmark). Protein adjuvants of the
 present invention can be delivered in the form of the protein themselves
 or of nucleic acid molecules encoding such proteins using the methods
 described herein. In addition to the foregoing adjuvants, when an isolated
 nucleic acid molecule of the present invention is used as a protective
 compound in the therapeutic composition, one or more DNA adjuvants can be
 operatively linked to that nucleic acid molecule using molecular biology
 techniques known to those skilled in the art.
 In one embodiment of the present invention, a therapeutic composition can
 include a carrier. Carriers include compounds that increase the half-life
 of a therapeufic composition in the treated animal. Suitable carriers
 include, but are not limited to, polymeric controlled release vehicles,
 biodegradable implants, liposomes, bacteria, viruses, other cells, oils,
 esters, and glycols.
 One embodiment of the present invention is a controlled release formulation
 that is capable of slowly releasing a composition of the present invention
 into an animal. As used herein, a controlled release formulation comprises
 a composition of the present invention in a controlled release vehicle.
 Suitable Controlled release vehicles include, but are not limited to,
 biocompatible polymers, other polymeric matrices, capsules, microcapsules,
 microparticles, gels (including hydrogels), bolus preparations, osmotic
 pumps, diffusion devices, liposomes, lipospheres, and transdermal delivery
 systems. Other controlled release formulations of the present invention
 include liquids that, upon administration to an animal, form a solid or a
 gel in situ. Preferred controlled release formulations are biodegradable
 (i.e., bioerodible).
 A preferred controlled release formulation of the present invention is
 capable of releasing a composition of the present invention into the blood
 of the treated animal at a constant rate sufficient to attain dose levels
 of the composition effective to protect an animal from disease caused by
 parasitic nematodes. The therapeutic composition is preferably released
 over a period of time ranging from about 1 to about 12 months. A
 controlled release formulation of the present invention is capable of
 effecting a treatment preferably for at least about 1 month, more
 preferably for at least about 3 months, even more preferably for at least
 about 6 months, even more preferably for at least about 9 months, and even
 more preferably for at least about 12 months.
 Acceptable protocols to administer therapeutic compositions in an effective
 manner include the specification of individual dose size, number of doses,
 frequency of dose administration, and mode of administration,
 Determination of such protocols can be accomplished by those skilled in
 the art. A suitable single dose is a dose that is capable of protecting an
 animal from disease when administered one or more times over a suitable
 time period. For example, a preferred single dose of a protein, mimetope
 or antibody therapeutic composition is from about 1 microgram (.mu.g) to
 about 10 milligrams (mg) of the therapeutic composition per kilogram body
 weight of the animal. Booster vaccinations can be administered from about
 2 weeks to several years after the original administration. Booster
 administrations preferably are administered when the immune response of
 the animal becomes insufficient to protect the animal from disease. A
 preferred administration schedule is one in which from about 10 .mu.g to
 about 1 mg of the therapeutic composition per kg body weight of the animal
 is administered from about one to about two times over a time period of
 from about 2 weeks to about 12 months. Modes of administration can
 include, but are not limited to, subcutaneous, intradermal, intravenous,
 intranasal, oral, intraocular, transdermal and intramuscular routes.
 According to one embodiment, a nucleic acid molecule of the present
 invention can be administered to a host animal in a fashion enabling
 expression of that nucleic acid molecule into a protective protein or
 protective RNA (e.g., antisense RNA, ribozyme, triple helix forms or RNA
 drug) in the host animal. Nucleic acid molecules can be delivered to an
 animal using a variety of methods including, but not limited to, (a)
 administering a naked (i.e., not packaged in a viral coat or cellular
 membrane) nucleic acid vaccine (e.g., as naked DNA or RNA molecules, such
 as is taught, for example in Wolff et al., 1990, Science 247, 1465-1468)
 or (b) administering a nucleic acid molecule packaged as a recombinant
 virus vaccine or as a recombinant cell vaccine (i.e., the nucleic acid
 molecule is delivered by a viral or cellular vehicle)).
 A naked nucleic acid vaccine of the present invention includes a nucleic
 acid molecule of the present invention and preferably includes a
 recombinant molecule of the present invention that preferably is
 replication, or otherwise amplification, competent. A naked nucleic acid
 vaccine of the present invention can comprise one or more nucleic acid
 molecules of the present invention in the form of, for example, a
 bicistronic recombinant molecule, having, for example, one or more
 internal entry sites. Preferred naked nucleic acid vaccines include at
 least a portion of a viral genome (i.e., a viral vector). Preferred viral
 vectors include those based on alphaviruses, poxviruses, adenoviruses,
 herpesviruses, and retroviruses, with those based on alphaviruses (such as
 Sindbis or Semliki virus), species-specific herpesviruses and
 species-specific poxviruses being particularly preferred. Any suitable
 transcription control sequence can be used, including those disclosed as
 suitable for protein production. Particularly preferred transcription
 control sequence include cytomegalovirus intermediate early (preferably in
 conjunction with intron-A), Rous Sarcoma Virus long terminal repeat, and
 tissue-specific transcription control sequences, as well as transcription
 control sequences endogenous to viral vectors if viral vectors are used.
 The incorporation of "strong" poly(A) sequences are also preferred.
 Naked nucleic acid vaccines of the present invention can be administered in
 a variety of ways, with intramuscular, subcutaneous, intradermal,
 transdermal, intranasal, intraocular and oral routes of administration
 being preferred. A preferred single dose of a naked nucleic acid vaccines
 ranges from about 1 nanogram (ng) to about 100 .mu.g, depending on the
 route of administration and method of delivery, as can be determined by
 those skilled in the art. Suitable delivery methods include, for example,
 by injection, as drops, by aerosolization and by topical application.
 Naked DNA of the present invention can be contained in an aqueous
 excipient (e.g., phosphate buffered saline) alone or in a carrier (e.g.,
 lipid-based vehicles).
 A recombinant virus vaccine of the present invention includes a recombinant
 molecule of the present invention that is packaged in a viral coat and
 that can be expressed in an animal after administration. Preferably, the
 recombinant molecule is packaging-deficient, encodes an attenuated virus,
 or both. A number of recombinant viruses can be used including, but not
 limited to, those based on alphaviruses, poxviruses, adenoviruses,
 herpesviruses, and retroviruses. Preferred recombinant virus vaccines are
 those based on alphaviruses (such as Sindbis virus), raccoon poxviruses,
 species-specific herpesviruses and species-specific poxviruses. An example
 of methods to produce and use alphavirus recombinant virus vaccines is
 disclosed in PCT Publication No. WO 94/17813, by Xiong et al., published
 Aug. 18, 1994, which is incorporated by reference herein in its entirety.
 An example of methods to produce and use racoon poxvirus recombinant virus
 vaccines is disclosed in U.S. Pat. No. 5,266,314, to Esposito, et al.,
 issued November 30, 1993, which is incorporated by reference herein in its
 entirety.
 When administered to an animal, a recombinant virus vaccine of the present
 invention infects cells within the immunized animal and directs the
 production of a protective protein or RNA nucleic acid molecule that is
 capable of protecting the animal from disease caused by a parasitic
 nematode as disclosed herein. For example, a recombinant virus vaccine
 comprising a parasitic nematode transglutaminase nucleic acid molecule of
 the present invention is administered according to a protocol that results
 in the animal producing a sufficient immune response to protect itself
 from disease caused by a parasitic nematode. A preferred single dose of a
 recombinant virus vaccine of the present invention is from about
 1.times.10.sup.4 to about 1.times.10.sup.7 virus plaque forming units
 (pfu) per kilogram body weight of the animal. Administration protocols are
 similar to those described herein for protein-based vaccines, with
 subcutaneous, intramuscular, intranasal and oral administration routes
 being preferred.
 A recombinant cell vaccine of the present invention includes recombinant
 cells of the present invention that express at least one protein of the
 present invention. Preferred recombinant cells for this embodiment include
 Salmonellia, E. coli, Ligteria, Mycobactenum, S. frugiperda, yeast,
 (including Saccharomyces cerevisiae), BHK, CV-1, myoblast G8, COS (e.g.,
 COS-7), Vero, MDCK and CRFK recombinant cells. Recombinant cell vaccines
 of the present invention can be administered in a variety of ways but have
 the advantage that they can be administered orally, preferably at doses
 ranging from about 10.sup.8 to about 10.sup.12 cells per kilogram body
 weight. Administration protocols are similar to those described herein for
 protein-based vaccines. Recombinant cell vaccines can comprise whole
 cells, cells stripped of cell walls or cell lysates.
 The efficacy of a therapeutic composition of the present invention to
 protect an animal from disease caused by a parasitic nematode can be
 tested in a variety of ways including, but not limited to, detection of
 protective antibodies (using, for example, proteins or mimetopes of the
 present invention), detection of cellular immunity within the treated
 animal, or challenge of the treated animal with the parasitic nematode to
 determine whether the treated animal is resistant to disease. Challenge
 studies can include implantation of chambers including parasitic nematode
 larvae into the treated animal, or direct administration of larvae to the
 treated animal, or both. In one embodiment, therapeutic compositions can
 be tested in animal models such as mice. Such techniques are known to
 those skilled in the art.
 One preferred embodiment of the present invention is the use of parasitic
 nematode transglutaminase proteins, nucleic acid molecules, antibodies and
 inhibitory compounds of the present invention, to protect an animal from
 heartworm. It is particularly preferred to prevent L3 that are delivered
 to the animal by the mosquito intermediate host from maturing into adult
 worms. Preferred therapeutic compositions are those that are able to
 inhibit at least one step in the portion of the parasite's development
 cycle that includes L3, third molt, L4, fourth molt, immature adult prior
 to entering the host animal's tissues or circulatory system. In dogs, this
 portion of the development cycle is about 70 days. Particularly preferred
 therapeutic compositions include nematode transglutaminase-based
 therapeutic compositions of the present invention, particularly because D.
 immitis transglutaminase is necessary for D. immitis larval molting and
 development, as disclosed herein. These preferred therapeutic compositions
 include nematode transglutaminase nucleic acid molecules, nematode
 tranglutaminase proteins and mimetopes thereof, anti-nematode
 transglutaminase antibodies, and inhibitors of nematode transglutaminase
 activity that fail to substantially inhibit host animal transglutaminase
 activity. Particularly preferred are D. immitis forms of any of the
 therapeutic compositions of the present invention. Therapeutic
 compositions are administered to animals in a manner effective to protect
 the animals heartworm. Additional protection may be obtained by
 administering additional protective compounds, including other nematode
 proteins, nucleic acid molecules, antibodies and inhibitory compounds, as
 disclosed herein and elsewhere.
 One therapeutic composition of the present invention includes an inhibitor
 of nematode transglutaminase activity that does not substantially inhibit
 host animal transglutaminase activity. In other words, in one embodiment,
 a therapeutic composition of the present invention includes a compound
 capable of substantially interfering with the function of a nematode
 transglutaminase susceptible to inhibition by an inhibitor of nematode
 transglutaminase activity. The term, "substantially interfering with the
 function of nematode transglutaminase," as used herein, refers to the
 ability of an inhibitor compound to interfere with a nematode
 transglutaminase activity to such a degree that development of heartworm
 in a host animal is impaired. For example, an isolated protein or mimetope
 thereof, is administered in an amount and manner that elicits (i.e.,
 stimulates) an immune response that is sufficient to protect the animal
 from the disease. Similarly, an antibody of the present invention, when
 administered to an animal in an effective manner, is administered in an
 amount so as to be present in the animal at a titer that is sufficient to
 protect the animal from the disease, at least temporarily. Oligonucleotide
 nucleic acid molecules of the present invention can also be adminstered in
 an effective manner, thereby reducing expression of parasitic nematode
 transglutaminase proteins in order to interfere with development of
 parasitic nematodes targeted in accordance with the present invention.
 An inhibitor of nematode transglutaminase activity can be identified using
 parasitic nematode transglutaminase proteins of the present invention. One
 embodiment of the present invention is a method to identify a compound
 that is capable of inhibiting nematode transglutaminase activity, but that
 does not substantially inhibit host animal transglutaminase activity. Such
 a method includes the steps of (a) contacting (e.g., combining, mixing) an
 isolated nematode transglutaminase protein with a putative inhibitory
 compound under conditions in which, in the absence of the compound, the
 protein has nematode transglutaminase activity; (b) determining if the
 putative inhibitory compound inhibits the nematode transglutaminase
 activity; and (c) repeating steps (a) and (b), but substituting host
 animal transglutaminase for nematode transglutaminase. Putative inhibitory
 compounds to screen for include small organic molecules, antibodies
 (including fragments and mimetopes thereof) and substrate analogs. Methods
 to determine nematode and host animal transglutaminase activities are
 known to those skilled in the art; see, for example, citations in the
 background section and references included therein.
 The present invention also includes a test kit to identify a compound
 capable of inhibiting nematode transglutaminase activity of a parasitic
 nematode. Such a test kit includes an isolated nematode transglutaminase
 protein having transglutaminase activity and a means for determining the
 extent of inhibition of transglutaminase activity in the presence of
 (i.e., effected by) a putative inhibitory compound. Compounds determined
 to inhibit nematode transglutaminase activity are also screened to
 identify those that are not substantially toxic to host animals.
 Nematode transglutaminase inhibitors isolated by the method or by the test
 kit described, or by both, can be used to inhibit any nematode
 transglutaminase that is susceptible to such an inhibitor. Preferred
 parasitic nematode transglutaminase proteins to inhibit are those produced
 by D. immitis, B. malayi or O. volvulus. A particularly preferred
 transglutaminase inhibitor of the present invention is capable of
 protecting an animal from heartworm. Effective amounts and dosing regimens
 can be determined using techniques known to those skilled in the art.
 Another therapeutic composition of the present invention includes an
 inhibitor of nematode PDI activity that does not substantially inhibit
 host animal PDI activity. In other words, in one embodiment, a therapeutic
 composition of the present invention includes a compound capable of
 substantially interfering with the function of nematode transglutaminase
 PDI activity susceptible to inhibition by an inhibitor of nematode PDI
 activity. The term, "substantially interfering with the function of
 nematode transglutaminase PDI activity," as used herein, refers to the
 ability of an inhibitor compound to interfere with a nematode PDI activity
 to such a degree that development of heartworm in a host animal is
 impaired.
 An inhibitor of nematode PDI activity can be identified using parasitic
 nematode transglutaminase proteins of the present invention. One
 embodiment of the present invention is a method to identify a compound
 that is capable of inhibiting nematode PDI activity, but that does not
 substantially inhibit host animal PDI activity. Such a method includes the
 steps of (a) contacting (e.g., combining, mixing) an isolated nematode
 transglutaminase protein (having PDI activity) with a putative inhibitory
 compound under conditions in which, in the absence of the compound, the
 protein has nematode PDI activity; (b) determining if the putative
 inhibitory compound inhibits the nematode PDI activity; and (c) repeating
 steps (a) and (b), but substituting a host animal PDI for nematode PDI.
 Putative inhibitory compound to screen for include small organic
 molecules, antibodies (including fragments and mimetopes thereof) and
 substrate analogs. Methods to determine nematode and host animal PDI
 activities are known to those skilled in the art; see, for example,
 citations in the background section and references included therein.
 The present invention also includes a test kit to identify a compound
 capable of inhibiting PDI activity of a parasitic nematode. Such a test
 kit includes an isolated nematode transglutaminase protein having PDI
 activity and a means for determining the extent of inhibition of PDI
 activity in the presence of (i.e., effected by) a putative inhibitory
 compound. Compounds determined to inhibit nematode PDI activity are also
 screened to identify those that are not substantially toxic to host
 animals.
 Nematode PDI inhibitors isolated by the method or by the test kit
 described, or by both, can be used to inhibit any nematode PDI that is
 susceptible to such an inhibitor. Preferred parasitic transglutaminase
 proteins to inhibit are those produced by D. immitis, B. malayi or O.
 volvulus. A particularly preferred PDI inhibitor of the present invention
 is capable of protecting an animal from heartworm. Effective amounts and
 dosing regimens can be determined using techniques known to those skilled
 in the art.
 It is also within the scope of the present invention to use isolated
 proteins, mimetopes, nucleic acid molecules and antibodies of the present
 invention as diagnostic reagents to detect infection by parasitic
 nematodes. Such diagnostic reagents can be supplemented with additional
 compounds that can detect other phases of the parasite's life cycle.
 Methods to use such diagnostic reagents to diagnose parasitic nematode
 infection are well known to those skilled in the at. Suitable and
 preferred parasitic nematodes to detect are those to which therapeutic
 compositions of the present invention are targeted. A particularly
 preferred parasitic nematode to detect using diagnostic reagents of the
 present invention is D. immitis.

The following examples are provided for the purposes of illustration and
 are not intended to limit the scope of the present invention.
 EXAMPLES
 It is to be noted that these Examples include a number of molecular
 biology, microbiology, immunology and biochemistry techniques familiar to
 those skilled in the art. Disclosure of such techniques can be found, for
 example, in Sambrook et al., ibid., Ausubel, et al.,1993, Current
 Protocols in Molecular Biology, Greene/Wiley Interscience, New York, N.Y.,
 and related references. Ausubel, et al, ibid. is incorporated by reference
 herein in its entirety. DNA and protein sequence analyses were carried out
 using the PC/GENE.TM. sequence analysis program (available from
 Intelligenetics, Inc., Mountainview, Calif.) and the Wisconsin Package.TM.
 Version 9.0 (available from the Genetics Computer Group (GCG), Madison,
 Wis.). It should also be noted that because nucleic acid sequencing
 technology, and in particular the sequencing of PCR products, is not
 entirely error-free, that the nucleic acid and deduced protein sequences
 presented herein represent apparent nucleic acid sequences of the nucleic
 acid molecules encoding D. immitis, B. malayi, and O. volvulus
 transglutaminase proteins of the present invention.
 Example 1
 This example describes a novel N-terminal amino acid sequence of a
 transglutaminase protein purified from Brugia malayi. This example further
 describes the use of a protein encoded by that sequence to purify and
 partially characterize a rare and novel transglutaminase protein from D.
 immitis.
 Purification and partial characterization of a novel transglutaminase
 protein from B. malayi has been previously described See, Singh, et al.,
 1994, Eur J. Biochem., 225, 625-634 (incorporated herein by reference).
 The amino acid sequence of this protein, referred to as SEQ ID NO:1, is
 herein disclosed for the first time as follows:
 (D)(G)DVMKFTDADFKE(G)IK(X)(Y)(D)
 The amino acids in brackets are the most probable amino acids at those
 positions, and the amino acid (X) at position 18 could not be detected.
 A protein molecule corresponding to the N-terminal sequence of the
 previously described 56-kD transglutaminase of B. malayi was synthesized
 commercially and is herein denoted as PBmTG.sub.20. The amino acid
 sequence of this protein represents amino acids from about position 3
 (amino acid residue A, or aspartic acid) through about position 17 (amino
 acid residue K, or lysine). A cysteine residue was added to the N-terminus
 of the synthetic peptide (immediately before the aspartic acid residue at
 about position 3) for the convenience of its conjugation with the carrier
 protein keyhold limpet hemocyanin (KLH) via
 maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), as follows. 5.0 mg of
 KLH in 50 mM phosphate buffer, pH 8.0, was reacted with MBS (dissolved in
 dimethyl sulfoxide) at a molar ratio of 1 KLH:40 MBS. The solution was
 stirred for 30 min at room temperature. The unreacted MBS was removed by
 gel filtration, and 5.0 mg of peptide hapten was added to the
 MBS-activated KLH in 50 mM phosphate buffer, pH 7.5. The solution was
 stirred at room temperature for 3 hr. Unconjugated peptide was removed by
 gel filtration. The conjugation efficiency was 40%.
 Anti-B. malayi transglutaminase peptide PBmTG.sub.20 antiserum was produced
 as follows. A rabbit was immunized subcutaneously, first with
 approximately 150 .mu.g of the conjugated peptide mixed with Complete
 Freund's Adjuvant, and then with five subsequent immunizations of the same
 dose mixed in Incomplete Freund's Adjuvant. Bleeding and immunization were
 performed at alternate weeks Unused antisera were preserved in 0.1% sodium
 azide at 4.degree. C. For immobilizing the anti-peptide antibodies on
 Affigel-10 (available from Bio-Rad Laboratories, Hercules, Calif.), the
 immunoglobulin G (IgG) fraction from this antisera was collected by 40%
 ammonium sulfate precipitation. Ammonium ions were removed on a NAP-25
 column (Sephadex G-25 available from Pharmacia Biotechnology, Piscataway,
 N.J.) preequilibrated with 100 mM (3-[N-morpholino]propanesulfonic acid)
 (MOPS) buffer, pH 7.5 (buffer A) to obtain a desalted IgG fraction.
 A crude D. immitis extract preparation was prepared as follows. All
 operations were performed at 4.degree. C. unless otherwise mentioned.
 Thirty-two frozen adult female worms of D. immitis (available from TRA
 laboratories, Athens, Ga.) were homogenized twice in a Pyrex homogenizer
 in 20 mM Tris-HCl (pH 8.5) containing 0.1% Triton X-100, 2 mM
 1,4-dithiothreitol, 1 mM EDTA, 1 mM phenylmethylsulfonyl fluoride (PMSF),
 and 0.1 mM N-tosyl-L-lysine chloromethane, The resulting 40 ml of
 homogenate was sonicated as described in Singh et al., ibid. The extract
 was frozen and thawed between sonications to maximize the solubilization
 of membrane-bound enzyme. The extract was centrifuged at 15,000 g for 20
 min, and the supernatant (36 ml) was collected for further purification.
 Anti-B. malayi peptide PmTG.sub.20, antiserum produced as described above,
 was found to react with a 56-kD protein band in a western blot of a D.
 immitis extract. This reactivity of anti-PBmTG.sub.20 antiserum could be
 completely inhibited in the presence of excess synthetic peptide. In order
 to monitor the progress of the purification process, Western blots were
 performed on samples of the extract after each major step in the
 purification process as follows: Sodium dodecyl sulfate
 (SDS)-polyacrylamide (10%) gel electrophoresis was performed according to
 the method of Laemmli (1970). Western blotting was performed by
 transferring the protein bands to the nitrocellulose paper (0.47 .mu.M,
 available from Schleicher & Schuell, Keene, N.H.) using a Semiphor dry
 blot apparatus (available from Hoefer Scientific Instruments, San
 Francisco, Calif.). All solutions used for membrane processing were made
 in phosphate buffered saline (PBS), and incubations were done at room
 temperature unless otherwise noted. The membrane was blocked with 5%
 nonfat dry milk for 1 hr. and incubated for 1 hr with 1000-fold diluted
 anti-PBmTG.sub.20 antiserum in 5% nonfat dry milk. After two washes with
 100 ml of PBST (PBS containing 0.1% Tween 20) for 20 min each, the
 membrane was incubated for 1 hr with 5000-fold diluted alkaline
 phosphatase-linked anti-rabbit IgG (available from Kirkegaard and Perry
 Laboratories, Gaithersburg, Md.) in 5% nonfat dry milk. After two washes
 in 100 ml of PBST for 20 min each, the membrane was treated with alkaline
 phosphatase color development reagent (available from Bio-Rad
 Laboratories, Hercules, Calif.) as per manufacturer's instructions.
 Following crude extract preparation, the first step in D. immitis
 transglutaminase protein purification was thermoprecipitation and ammonium
 sulfate precipitation as follows. The crude extract from adult female
 worms was subjected to thermo-precipitation at 55.degree. C. in a water
 bath for 10 min with constant shaking. The precipitate was discarded by
 centrifugation at 15,000 g for 20 min, and the supernatant (31 ml) was
 precipitated at a 60% ammonium sulfate cutoff. The precipitate was
 collected by centrifugation (15,000 g for 30 min) and was dissolved in 2.5
 ml of buffer A. The ammonium ions in the preparation were removed by
 passing the preparation through an NAP-25 column preequilibrated with
 buffer A. The final volume of the D. immitis preparation obtained from the
 NAP-25 column was 3.5 ml.
 The next step in D. immitis transglutaminase protein purification,
 immunoaffinity chromatography, was accomplished as follows. The
 immunoglobulin fraction was conjugated to Affigel-10 according to the
 manufacturer's instructions. Specifically, 3.5 ml of the desalted IgG
 fraction containing anti-B. malayi transglutaminase PBmTG.sub.20
 (containing 17.5 mg of protein), obtained as described above in this
 Example, was added to 1 ml of Affigel-10 that was previously washed with
 cold deionized water. The suspension was incubated and rotated overnight
 at 4.degree. C. Next day, the unbound IgG was removed by repeated washing
 with buffer A.
 The 3.5 ml D. immitis preparation obtained after ammonium sulfate
 precipitation and desalting was incubated and rotated with the IgG-bound
 Affigel-10 overnight at 4.degree. C. The slurry was then packed in a
 column, and the gel was washed extensively with buffer A. Nonspecifically
 bound proteins were removed by washing the gel with 0.5% Triton X-100 in
 buffer A to remove the nonspecific hydrophobic interactions. This step was
 necessary before the specific elution of transglutaminase at pH 2.8. The
 gel was washed again with buffer A. D. immitis transglutaminase was eluted
 with 3 ml of 100 mM glycine-HCl buffer (pH 2.8) with a flow rate of 10
 ml/hr. The pH of the D. immitis transglutaminase-containing collected
 fraction was immediately adjusted to pH 8.0 by adding 300 .mu.l of 1 M
 sodium bicarbonate; the collected fraction was then subjected to overnight
 dialysis against 100 mM Tris-HCI buffer (pH 8.5). The dialyzed fraction
 was concentrated to 0.5 ml in a Centricon-10 tube (available from
 Pharmacia Biotechnology Piscataway, N.J.), and used for further
 characterization.
 The eluted protein was enzymatically active and gave a single major band of
 56-kD when subjected to eletrophoresis under denaturing conditions. The
 same 56 kD band was detected by western blot analysis (described below)
 when the anti-B. malayi transglutaminase peptide PBmTG.sub.20 antibody was
 used to detect protein.
 A summary of the steps used in the purification of transglutaminase from D.
 immitis is shown in Table 1. The starting transglutaminase activity in 224
 mg of initial soluble protein obtained from 32 adult female worms was
 extremely low. The specific activity in the crude extract obtained from D.
 immitis was at least 5 times lower than that previously reported for B.
 malayi transglutaminase preparation (Singh et al., ibid.).
 Transglutaminase activity was determined in a microtiter plate assay
 according to a recently published procedure; see, Slaughter et al., 1992,
 Anal. Biochem. 205, 166-171 (incorporated herein by reference). One
 milliunit (mU) transglutaminase activity is defined as the V.sub.max
 (.DELTA.A.sub.405 /min) generated in a microtiter plate assay by 0.74
 .mu.g of purified guinea pig liver transglutaminase (available from Sigma
 Chemical Co., T-5398). The effects of pH and temperature on the
 transglutaminase activity and stability as well as the effects of
 inhibitors, metal ions and other cofactors on the enzyme activity were
 determined as described by Singh et al., ibid. The amount of protein was
 estimated according to the Bradford method (see Bradford, 1976, Anal.
 Biochem., 72, 248-254), using reagents available from Bio-Rad
 Laboratories, Hercules, Calif.
 TABLE 1
 Summary of steps used for the purification of transglutaminase from
 D. immitis adult worms.
 Cumu-
 Total Specific lative
 Total Total activ- activity fold
 protein volume ity (mU/ purifi- Yield
 Steps (.mu.g) (ml) (mU) mg) cation (%)
 1. Crude 224,200 36.0 42.6 0.19 1.0 100
 exract
 2. Thermo- 129,634 31.0 35.0 0.27 1.4 82
 precipitation
 3. (NH.sub.4).sub.2 SO.sub.4 11,157 3.5 26.8 2.33 12.2 63
 precipitation
 4. Immuno- 2.1 0.5 4.2 2032.0 10,694.0 10
 affinity
 chroma-
 tography
 The D. immitis transglutaminase protein preparation protocol presented
 herein resulted in a high degree of purification of D. immitis
 transglutaminase protein. The final product was approximately 5 times
 purer than that previously reported for B. malayi transglutaminase
 purified by the lengthy conventional protocol of Singh et al., ibid. The
 specific activity of the purified D. immitis enzyme was 2.0 U/mg protein,
 and is very close to that previously reported for B. malayi
 transglutaminase. Although the enzyme was stable over a wide pH range
 (data not shown), it was most active in the basic pH range, between pH 8
 and pH 9.5, as are the other known transglutaminases. In contrast to
 mammalian. transglutaminases, the D. immitis enzyme, like the
 transglutaminase isolated from B. malayi (see, Singh, et al., ibid.) was
 active and stable at high temperatures (data not shown).
 The effects of various reagents on the activity of the transglutaminase
 purified from adult D. immitis worms are shown In Table 2. The enzyme
 required calcium for its activity, and chelating agents like EGTA and EDTA
 completely blocked the activity. Dithiothreitol and mercaptoethanol
 increased the enzyme activity substantially, whereas iodoacetamide
 decreased the activity drastically, suggesting that the enzyme requires at
 least one cysteine residue at the active site, like most of the
 transglutaminases; see, for example, Folk et al., 1977, Adv. Protein Chem.
 31, 1-133. The effect of iodoacetamide was severe when the enzyme was
 pretreated with calcium ions, suggesting that calcium ions open the active
 site for high molecular weight substrates like casein. The enzyme was
 inhibited competitively by amine donor substrate analogues like monodansyl
 cadaverine and putrescine, and by the active-site inhibitor cystamine.
 High concentrations of sodium and potassium ions, Tris and the end product
 of the reaction, ammonia, reversibly inhibited the enzyme. The observation
 that Cbz-Gln-Gly affects the enzyme activity only slightly (Table 2)
 suggests that this compound is a poor amine acceptor substrate for the
 enzyme. In contrast to mammalian tissue type transglutaminageg (Folk et
 al., ibid.; Bergamini et al., 1987, Biochim. Biophys. Acta 916, 149-151;
 Achyuthan et al., 1987, J. Biol. Chem. 262, 1901-1906; Bergamini, 1988,
 FEBS Lett. 239, 255-258; Lee et al., 1989, Biochem. Biophys. Res. Commun.
 162, 1370-1375), this enzyme was not affected adversely by micromolar
 concentrations of GTP. This suggests that GTP is not involved in the
 regulation of this enzyme as in nematode, transglutaminase from B. malayi
 (Singh et al., ibid.) and Limulus hemocyte transglutaminase (Tokunaga et
 al., 1993, J. Biol. Chem. 268, 252-261).
 TABLE 2
 Effect of ions, inhibitors and other reagents on D. immitis
 transglutaminase activity
 Transglutaminase
 Concentration activity.dagger.
 Reageant* (mM) (% of control)
 Control.dagger-dbl. -- 100
 NaCl 500 48
 KCl 500 54
 (NH.sub.4).sub.2 SO.sub.4 10 0
 EDTA 10 0
 EGTA 10 0
 Iodoacetamide (-Ca.sup.2++).sctn. 10 61
 Iodoacetamide (+Ca.sup.2++).paragraph. 10 27
 Tris-HCl (pH 8.5) 250 66
 Tris-HCl (pH 8.5) 500 40
 N.alpha.-CBZ-Gln-Gly 10 92
 Monodansyl cadaverine 1 9
 Putrescine 1 14
 Cystamine 1 52
 GTP 0.1 100
 GTP 1 95
 *The effect of metals, ions and other reagents on transglutaminase activity
 was determined in the presence of CaCl.sub.2 and dithiothreitol.
 .dagger.The results shown are the average values from two independent
 experiments each performed in triplicate. Standard deviation from the mean
 was less than 5%.
 .dagger-dbl.Control tubes contained 10 mM CaCl.sub.2 and 10 mM
 dithiothreitol.
 .sctn.Iodoacetamide was preincubated with the enzyme in the absence of
 calcium overnight at 4.degree. C., and the activity was determined in the
 presence of 10 mM each of calcium and dithiothreitol after removal of
 iodoacetamide by dialysis.
 .paragraph.Iodoacetamide was preincubated with the enzyme in the presence
 of 10 mM calcium overnight at 4.degree. C., and the activity was
 determined in the presence of 10 mM each of calcium and dithiothreitol
 after removal of iodoacetamide by dialysis.
 Example 2
 This Example evaluated the effect of a number of transglutaminsae
 inhibitors on D. immitis larval viability in an in vitro larval culture
 system.
 The following transglutaminase inhibitors were tested at the indicated
 final concentrations in the culture system:
 (a) Monodansyl cadaverine (MDC), a known high affinity substrate analog,
 was tested at concentrations of 25, 50, 75, 85 and 100 .mu.M;
 (b) Cystamine, a transglutaminase active site inhibitor, was tested at
 concentrations of 25, 50, 75, 85 and 100 .mu.M;
 (c) Iodoacetamide was tested at concentrations of 2.5, 5 and 10 .mu.M.
 All inhibitors are available from Sigma Chemical Co, St. Louis, Mo.
 Inhibitors were made in NI media (50% NCTC+50% IMDM, available from
 GibcoBRL, Gaithersburg, Md.) containing antibiotics and 20% SeruMax
 (available from Sigma Chemical Co.).
 The general protocol for the larval viability assays was as follows:
 Briefly, 50 D. immitis L.sub.3 larva were cultured for 6 days in vitro in
 1 ml of NI media containing antibiotics and 20% SeruMax. In some assays,
 transglutaminase inhibitors were added on different days of culture, and
 in other assays the inhibitors were present for only 24 hours of culture.
 The cultures were examined microscopically every 24 hours until day 6 when
 the cultures were terminated. The number of larvae that molted were
 determined by counting shed cuticles.
 Results of these studies are presented below in Tables 3, 4, and 5. All
 transglutaminase inhibitors tested in the present study reduced in a
 dose-dependent manner the molting of D. immitis L.sub.3 larvae to L.sub.4
 larvae (Table 3).
 TABLE 3
 Effect of TGase inhibitors on molting of D. immitis L.sub.3
 Concentration
 Inhibitor (.mu.M) Percent molted
 Monodansylcadaverine 0 84
 (MDC) 25 75
 50 63
 75 28
 85 2.5
 100 0
 Cystamine 0 84
 25 61
 50 62
 75 17
 85 1
 100 0
 Iodoacetamide 0 84
 2.5 65
 5 3
 10 0
 MDC and cystamine at 100 .mu.M concentration completely inhibited the
 molting process; Iodoacetamide at a final concentration of 10 .mu.M was
 able to inhibit the molting of L.sub.3 to L.sub.4. In each case, complete
 inhibition of D. immitis molting required the presence of inhibitors
 during the first 24-48 hr of the molting process (Tables 4 and 5). The
 transglutaminase active site inhibitor (cystamine) was a very effective
 inhibitor of larval molting even when added on day 2 during the culture
 (Table 5).
 TABLE 4
 Presence of TGase inhibitors during first 24 hr of D. immitis L.sub.3
 culture -
 Effect on molting
 Concentration
 Inhibitor (.mu.M) Percent molted
 Monodansylcadaverine 0 68
 (MDC) 50 64
 100 41
 Cystamine 0 68
 50 68
 100 13
 Iodoacetamide 0 68
 10 3
 TABLE 4
 Presence of TGase inhibitors during first 24 hr of D. immitis L.sub.3
 culture -
 Effect on molting
 Concentration
 Inhibitor (.mu.M) Percent molted
 Monodansylcadaverine 0 68
 (MDC) 50 64
 100 41
 Cystamine 0 68
 50 68
 100 13
 Iodoacetamide 0 68
 10 3
 Example 3
 This Example demonstrates that soluble adult and larval D. immitis parasite
 extracts contain transglutaminase activity.
 Larval and adult male and female heartworm parasites were separately
 homogenized in buffer B (20 mM Tris/HCl pH 8.5, containing 2 mM
 1,4-dithiothreitol, 2 mM EDTA, 1 mM phenylmethylulfonyl fluoride, 0.1 mM
 N-tosyl-L-lysine chloromethane and 0.1 mM N-tosyl-L-phenylalanine
 chloromethane; all available from Sigma) for 20 min on ice. The crude
 extracts thug obtained were sonicated continuously for three 1-min
 periods, with 5-min intervals between each sonication, using a pre-chilled
 small probe of the W-380 Ultrasonic Processor (available from Heat
 Systems-Ultrasonics, Farmingdale, N.Y.). The third sonication was done in
 the presence of 0.1% Triton X-100. The suspensions were centrifuged at
 15,000.times.g for 20 min. The supernatant thus obtained (referred to
 herein as the parasite extracts, or crude parasite extracts) was used to
 assay for transglutaminase activity.
 Transglutaminase activity was determined in a microtiter plate assay as
 described above in Example 1. In brief, the microtiter plates were coated
 with 1% dimethylcasein (available from Sigma) at room temperature
 overnight; uncoated sites were blocked with 1% nonfat dry milk. The
 reaction mixtures contained in total volumes of 200 .mu.l each: 100 mM
 Tris/HCl pH 8.5, 10 mM CaCl.sub.2, 10 mM dithiothreitol, 1 mM amine donor
 substrate 5(biotinamido) pentylamine (BPT), (available from Sigma), and
 crude parasite extracts. The reactions were performed at 37.degree. C. for
 2 hours and transglutaminase-catalyzed conjugation of BPT into
 dimethylcasein was determined by streptavidin-peroxidase and
 orthophenyldiamine as a reporter system. The enzyme activity (expressed as
 mU) in extracts was determined relative to the activity of purified guinea
 pig liver transglutaminase (available from Sigma) tested in the same
 microtiter plate. The results of this assay are given in Table 6. There
 was detectable transglutaminase activity both in larval and adult
 extracts. The activity in males was lower than in females for the same
 amount of protein tested.
 TABLE 6
 Transglutaminase enzyme activity in D. immitis larvae and adults
 Amount Total activity
 Parasite stage used (mU)
 0 hr L.sub.3 100 L.sub.3 38.9
 48 hr L.sub.3 100 L.sub.3 42.3
 6 day L.sub.4 100 L.sub.4 27.6
 Male adult 60 .mu.g 9.0
 Female adult 60 .mu.g 50.0
 Example 4
 This Example describes the identification of native D. immitis
 transglutaminase (DiTG) by immunoblot analysis. Rabbit anti-B. malayi
 transglutaminase peptide PBmTG.sub.20 antisera, produced as described in
 Example 1, was used to identify a native D. immitis transglutaminase
 protein in D. immitis extracts as follows.
 The materials in crude extracts from D. immitis larvae and adult male and
 female worms were separated by running 5 .mu.g protein per lane on a
 12-well 10% Tris-glycine SDS-PAGE gel at 200 volts for 1 hour, and then
 transferred to a nitrocellulose membrane by standard methods. After
 transfer, the membrane was blocked in 5% dry milk for 1 hr at 37.degree.
 C. The membrane was then incubated with rabbit anti-B. malayi
 transglutaminase peptide PBmTG.sub.20 antibody at a dilution of 1:2500 in
 Tris buffered saline. After 1 hr incubation at room temperature, the blot
 was washed, and antibody binding resolved using a peroxidase-labeled
 rabbit IgG secondary antibody and the substrate nitroblue tetrazolium
 chloride, 5-bromo-4-chloro-3-indolylphosphate p-toluidine salt (NBT/BCIP)
 (available from Gibco BRL, Gaithersburg, Md). Using this antibody,
 immunoblot analysis of D. immitis adult male, female and larval extracts
 identified a 56 kD native D. immitis protein (DiTG) similar to the size of
 native Brugia protein (Singh et al., ibid.).
 Example 5
 This Example describes the amino acid sequence analysis of the 56 kD D.
 immitis transglutaminase.
 The native 56 kD D. immitis transglutaminase protein from adult female D.
 immitis parasite extracts was separated by two dimensional SDS-PAGE. The
 first dimension was an isoelectric focusing gel using a non-equilibrium pH
 gradient containing ampholines of pI 5-8 (available from Pharmacia
 Biotech, Uppsala, Sweden). The second dimension was run on an 8%
 Tris-glycine gel; the resulting protein spots were transferred to PVDF
 membrane, and the spot corresponding to D. immitis transglutaninase was
 excised. 17 such spots were then used for N-terminal sequence analysis
 using an automated protein sequencer (ABI437A, available from Applied
 Biosystems, Inc., Foster City, Calif.).
 For internal amino acid sequence analysis, spots containing D. immitis
 transglutaminase were excised from Coomassie blue stained preparative two
 dimensional SDS-PAGE gels of female D. immitis parasite extract. 48 such
 spots were pooled and then subjected to trypsin digestion in the gel. The
 digested protein sample was then separated using high pressure liquid
 chromatography (HPLC). Digested proteins were then sequenced as described
 above. Preparation and sequencing of the internal protein fragments were
 performed by the Harvard Microchemistry Facility, Cambridge, Mass.
 The results of the amino acid sequence analysis of D. immitis
 transglutaminase are given below. A partial N-terminal amino acid sequence
 of about 29 amino acids was determined and is represented herein as SEQ ID
 NO:2:
 DGDVMKFTDADFKEGIKPYDVLLVKFYAP
 A homology search of a non-redundant protein sequence database was
 performed on this amino acid sequence through the National Center for
 Biotechnology Information (NCBI) (National Library of Medicine, National
 Institute of Health, Baltimore, Md.) using the BLAST network. This
 database includes SwissProt+PIR+SPupdate+GenPept+GPUpdate+PDB databases.
 The search was performed using SEQ ID NO:2 and showed significant homology
 to probable protein disulfide isomerases (PDIs) spanning from amino acid
 residue 1 through 29 of SEQ ID NO:2. The highest scoring match of the
 homology search at the amino acid level was GenBank.TM. accession number
 Z37139, Caenorabditis elegans clone C14B1.1. SEQ ID NO:2 showed about 44%
 identity to residues 24 to 50 of the clone C14B1.1. SEQ ID NO:2 also
 showed a near sequence identity to the B. malayi peptide, PBmTG.sub.20,
 SEQ ID NO:1.
 The two internal D. immitis transglutaminase amino acid sequences obtained
 as described above were characterized as follows: A partial internal amino
 acids sequence of about 14 amino acids was determined and is represented
 herein as SEQ ID NO:3:
 YQYDLLPMFVVYGK
 A homology search of a non-redundant protein sequence database was
 performed on SEQ ID NO:3 through the NCBI using the BLAST network as
 described above. This database includes
 SwissProt+PIR+SPupdate+GenPept+GPUpdates+PDB. Results of the search showed
 no significant homology of SEQ ID NO:3 to other proteins in the database.
 Another partial internal amino acid sequence of about 19 amino acids was
 determined and is represented herein as SEQ ID NO:4:
 MDATANDVPPPFQVQGFPT
 A homology search of a non-redundant protein sequence database was
 performed on this amino acid sequence using the BLAST network through the
 NCBI, as described above. The search was performed using SEQ ID NO:4 and
 showed significant homology to probable PDIs spanning from amino acid
 residue 1 through 19 of SEQ ID NO:4. The highest scoring match of the
 homology search at the amino acid level was GenBank.TM. accession number
 PC1298 (chicken nuclear matrix 57 K protein). SEQ ID NO:4 showed about 78%
 identity to residues 42 to 60 of this chicken nuclear matrix protein
 sequence.
 Example 6
 This Example describes the isolation and sequencing of a nucleic acid
 molecule encoding a D. immitis transglutaminase protein.
 A D. immitis transglutaminase nucleic acid molecule of about 707
 nucleotides, denoted nDiTG.sub.707, was identified by polymerase chain
 reaction (PCR) amplification from D. immitis first strand cDNA reverse
 transcribed from adult female mRNA as follows. The following primers were
 used to PCR amplify the D. immitis transglutaminase nucleic acid molecule
 from the cDNA template: A sense primer spanning nucleotides encoding amino
 acid residue number about 5 through amino acid residue number about 15 of
 SEQ ID NO:2, and having the nucleic acid sequence 5'
 ATGAARTTYACNGAYGCNGAYTTYAARGARGG 3' (denoted herein as SEQ ID NO:15); and
 an anti-sense primer spanning nucleotides encoding amino acid residue
 number about 8 through amino acid residue number about 14 of SEQ ID NO:3
 and having the nucleic acid sequence 5' TTNCCRTANACNACRAACAT 3' (denoted
 herein as SEQ ID NO:16).
 The PCR amplified D. immitis transglutaminase nucleic acid molecule,
 referred to herein as nDiTG.sub.707, was separated from the rest of the
 PCR reaction products on a 1% agarose gel at 60 v for 2 hr. After
 separation of the PCR products, the band of interest was excised from the
 agarose gel. The gel slice was then processed to release the DNA using the
 QIAquick kit (available from Qiagen, Chatsworth, Calif.) as per
 manufacturer's instructions. The purified DNA was then cloned into TA
 cloning vector (available from Invitrogen, San Diego, Calif.) as per the
 manufacturer's instructions and submitted for automated sequence analysis.
 The sequences of the two complementary strands of nDiTG.sub.707 are
 presented as SEQ ID NO:5 and SEQ ID NO:7.
 Translation of SEQ ID NO:5 yields a protein of about 235 amino acids,
 denoted PDiTG.sub.235, the amino acid sequence of which is presented in
 SEQ ID NO:6. The nucleic acid molecule encoding PDiTG.sub.235 is referred
 to herein as nDiTG.sub.705, the nucleic acid sequence of which is
 represented in SEQ ID NO:8 (the coding strand) and SEQ ID NO:9 (the
 complementary strand). Based on its amino acid sequence, PDiTG.sub.235 has
 a predicted molecular weight of about 27.2 kD and an estimated pI of about
 5.07.
 Amino acid sequence of PDiTG.sub.235 (i.e. SEQ ID NO:6) was analyzed using
 the PC/GENE.TM. (available from Intelligenetics, Inc., Mountainview,
 Calif.) sequence analysis program for sites and signatures. A thioredoxin
 family active site was detected from residues about 24 to 30. Thioredoxins
 participate in various redox reactions through the reversible oxidation of
 an active center disulfide bond; see, for example, Holmgren, ibid. A
 number of eukaryotic proteins contain similar domains evolutionarily
 related to thioredoxin.
 A homology search of a non-redundant protein sequence database was
 performed through the NCBI using the BLAST network, as described above.
 The search performed using SEQ ID NO:6 showed that this sequence has
 significant homology to protein disulfide isomerases (PDI), and
 PDI-related proteins, of eukaryotic orgin, The homology spans from about
 amino acid 1 through about amino acid 235 of SEQ ID NO:6. The highest
 scoring match of the homology search at the amino acid level was
 GenBank.TM. accession number P38658, Schistosoma mansoni, probable PDI
 ER-60 precursor. SEQ ID NO:6 showed about 37% identity to P38658. At the
 nucleotide level, the coding regions represented in SEQ ID NO:8, from
 nucleotide 7 to 246, were similar to that of the human clone 
 (GenBank.TM. accession number J05016), PDI-related protein (Erp72) mRNA.
 SEQ ID NO:8 showed about 59% nucleic acid identity spanning from
 nucleotide 589 to 828 of clone .
 Example 7
 The following experiment was performed in order to confirm the D. immitis
 origin of the isolated DiTG cDNA nucleic acid molecule nDiTG.sub.707, and
 in order to identify he genomic restriction fragments corresponding to
 nDiTG.sub.707. A Southern blot containing about 10 .mu.g of EcoRI and XhoI
 restricted D. immitis genomic DNA was hybridized under stringent
 conditions with nDiTG.sub.707 DNA labeled with a chemiluminescent label
 (ECL labeling kit, available from Amersham, Arlington Heights, Ill.). The
 probe detected a single band of about 11.7 kilobase pairs (kb) in the
 genomic DNA digested with XhoI, where as in EcoRI digested genomic DNA,
 the probe detected three bands at about 9.5, 1.07 and 0.43 kb,
 respectively.
 Example 8
 This Example describes the isolation and characterization of
 transglutaminase nucleic acid molecules of the present invention from a D.
 immitis L.sub.4 cDNA library.
 D. immitis transglutaminase nucleic acid molecules were cloned from a cDNA
 library by nucleic acid screening using D. immitis transglutaminase
 nucleic acid molecules of the present invention as probes. Specifically, a
 6 day D. immitis larval cDNA library was constructed from 140,420 L.sub.4
 as follows. D. immitis 6 day, L.sub.4 larvae were cultured in NCTC
 135:IMDM media and 20% Seru-MaX.TM. for 48 hours. Larvae were settled by
 gravity at 37.degree. C. culture media were removed and larvae were
 disrupted in 4 M guanidinium thiocyanate, 1.5% sarkosyl, 0.5 M
 2-mercaptoethanol. Total RNA (290 .mu.g) was recovered by the acid
 guanidinium-thiocyanate-phenol-chloroform procedure (Chomczynski, et al.,
 1987, Anal. Biochem. 162, pp. 156-159). Poly A.sup.+ mRNA (6.954 .mu.g)
 was isolated with oligo(dT) cellulose using the RiboSep Mini MRNA
 Isolation Kit (available from Collaborative Research, Inc., Bedford,
 Mass.). The ZAP-cDNA.RTM. Synthesis Kit (available from Stratagene, La
 Jolla, Calif.) was used to synthesize cDNA, which was then ligated into
 the Uni-ZAP XR vector (Stratagene), packaged and amplified to produce the
 L.sub.4 CDNA library. The nucleic acid molecule, nDiTG.sub.707,
 (represented herein by the sequences SEQ ID NO:5 and SEQ ID NO:7) was
 labeled with a chemiluminescent label as described in Example 7, and used
 as a DNA probe to screen the L.sub.4 cDNA expression library. A clone
 containing a D. immitis transglutaminase nucleic acid molecule referred to
 herein as nDiTG.sub.1472 was plaque-purified from the expression library
 using standard methods, and then sequenced. The following nucleotide
 primers were used to sequence this clone: a) two pBluescript.TM. vector
 primers consisting of a sense T.sub.3 X primer (denoted herein as SEQ ID
 NO:17) having the nucleic acid sequence 5' AATTAACCCTCACTAAAGGG 3'; and an
 antisense T.sub.7 X primer (denoted herein as SEQ ID NO:18) having the
 nucleotide sequence, 5' GTAATACGACTCACTATAGGGC 3'; and b) three internal
 primers including a sense primer having the nucleic acid sequence 5'
 GAAAACCGTTATCAGTATGATCT 3' (denoted herein as SEQ ID NO:19), and two
 antisense primers having the nucleic acid sequences 5'
 CTGTGGAATGATTTAAATATTTATCC 3' (denoted herein as SEQ ID NO:20) and 5'
 GTCCATTTTTGCAATAACAACACC 3' (denoted herein as SEQ ID NO:21),
 respectively. The resulting nucleic acid sequences of the two
 complementary DNA strands of nDiTG.sub.1472 are referred to herein as SEQ
 ID NO:10 and SEQ ID NO:12. The sense primer represented by SEQ ID NO:19
 spans nucleotides about nucleotide 359 to about nucleotide 381 of SEQ ID
 NO:10; the antisense primer represented by SEQ ID NO:20 spans about
 nucleotide 1171 to about nucleotide 1192 of SEQ ID NO:10; and the
 antisense primer SEQ ID NO:21 spans from about nucleotide 878 to about
 nucleotide 901 of SEQ ID NO:10.
 Translation of SEQ ID NO:10 yields a protein of about 368 amino acids,
 denoted as PDiTG.sub.368, the amino acid sequence of which is presented in
 SEQ ID NO:11. The nucleic acid molecule encoding PDiTG.sub.368 is referred
 to herein as nDiTG.sub.1107, the nucleic acid sequence of which is
 represented in SEQ ID NO:13 (the coding strand) and SEQ ID NO:14 (the
 complementary strand) assuming that the first codon spans from about
 nucleotide 2 through about nucleotide 5, and a putative stop codon spans
 from about nucleotide 1106 to about nucleotide 1108 (the stop codon
 included in nDiTG.sub.1107). The amino acid sequence of D. immitis
 PDiTG.sub.368 (i.e., SEQ ID NO:11) predicts that PDiTG.sub.368 has an
 estimated molecular weight of about 42.6 kD and an estimated pI of 5.71.
 The amino acid sequence of PDiTG.sub.368 (i.e., SEQ ID NO:11) was analyzed
 using the PC/GENE.TM. program to identify sites and signatures. A number
 of interesting sites were detected. They include: i) a thioredoxin family
 active site detected from residues 268 to 274; ii) an endoplasmic
 reticulum (ER) targeting sequence from residues 365 to 368 (KEEL);
 proteins that permanently reside in the lumen of ER seem to be
 distinguished from newly synthesized secretory proteins by the presence of
 the C-terminal sequence Lys-Asp-Glu-Leu (KDEL), see Munro et al., ibid.
 Cell 48, 899-907; Pelham, ibid.; and iii) a tachykinin family signature
 from residues 186 to 202 (tachykinins are a group of biologically active
 peptides that excite neurons, evoke behavioral responses, are potent
 vasodilators, and contract many smooth muscles; see, Maggio, 1988, Annual
 Review of Neurosciences 11, 13-28).
 A homology search of a non-redundant protein sequence database was
 performed on SEQ ID NO:11 using the BLAST network through the NCBI, as
 described above. The search showed significant homology to PDI, and
 PDI-related proteins of eukaryotic origins, spanning from about amino acid
 1 through about amino acid 368 of SEQ ID NO:11. The highest scoring match
 of the homology search at the amino acid level was to GenBank.TM.
 accession number D16234 (from amino acid residues 130 to 505), a human
 phospholipase C-alpha clone. This match revealed about 47% identity
 spanning amino acid residues about 3 to about 368 of SEQ ID NO:11. The
 nucleic acid coding region represented in SEQ ID NO:13, from about
 nucleotide 717 to about nucleotide 1032, was similar to that of human
 epithelial cell mRNA for ER-60 protease (GenBank.TM. accession number
 D83485), being about 63% identical to nucleotides 1143 through 1458 of the
 ER-60 protease sequence.
 Example 9
 This Example describes the identification of D. immitis poly(A).sup.+ RNA
 transcripts corresponding to nDiTG.sub.707.
 A Northern blot was performed as follows: D. immitis adult female and male
 total RNA (8 .mu.g) and adult female and male poly(A).sup.+ RNA (0.5
 .mu.g) were electrophoresed on a 1% formaldehyde gel and transferred to a
 N+ nylon membrane (available from Amersham). The RNA was cross-linked to
 the membrane using the Stratalinker (available from Stratagene). The
 Northern blot was then hybridized with peroxidase-labeled nDiTG.sub.707
 cDNA using the ECL direct nucleic acid labeling and detection system
 (available from Amersham) as per the manufacturer's instructions. In each
 of the four samples, the nDiTG.sub.707 cDNA probe hybridized to a single
 band of approximately 2613 nucleotides as calculated by MacVector's
 mobility program.
 Example 10
 This Example describes the PCR amplification and subsequent isolation of a
 5 nematode transglutaminase nucleic acid molecule from D. immitis cDNA
 using the nematode 22 nucleotide splice leader sequence as the primer.
 Nematode transglutaminase nucleic acid molecules were PCR amplified from D.
 immitis female adult cDNA using a primer corresponding to the sequence of
 a nematode splice leader (SL). Most, but not all nematode messenger RNAs
 have the SL sequence at their 5' ends, and the presence of the 5' SL
 sequence is indicative of an apparent full length cDNA. See, for example
 Blaxter and Liu, 1996, Int. J. Parasitol. 26, 1025-1033, which is
 incorporated herein by reference. The two primers used in the PCR
 amplification reaction were a sense primer representing the SL sequence,
 having the nucleotide sequence 5' GGTTTAATTACCCAAGTTTGAG 3' (herein
 denoted as SEQ ID NO:22) and an antisense primer having the sequence 5'
 TCCCTCCTTGAAGTCCGCATCTGTAAATTTCAT 3' (herein denoted as SEQ ID NO:23; SEQ
 ID NO:23 represents nucleotides from about, nucleotide 673 to about
 nuclceotide 705 of SEQ ID NO:9) PCR amplification of adult female cDNA
 using these primers resulted in the production of an 143 bp nucleic acid
 molecule (herein denoted as nDiTG.sub.143).
 Nucleic acid molecule nDiTG.sub.143 was gel purified, cloned into TA
 cloning vector (available from Invitrogen, Carlsbad, Calif.) and sequenced
 using an automated DNA sequencer. Sequence analysis of the nDiTG.sub.143
 coding strand (herein denoted as SEQ ID NO:27) and the complementary
 strand (herein denoted as SEQ ID NO:29 demonstrated that nDiTG.sub.143 had
 the SL sequence at its 5' end. Translation of SEQ ID NO:27 yields a
 protein of about 40 amino acids, herein denoted as PDiTG.sub.40, the amino
 acid sequence of which is presented in SEQ ID NO:28. The nucleic acid
 molecule encoding PDiTG.sub.40 is referred to herein as nDiTG.sub.120, the
 nucleic acid sequence of which is represented in SEQ ID NO:30 (the coding
 strand) and SEQ ID NO:31 (the complementary strand). The amino acid
 sequence of D. immitis PDiTG.sub.40 (i.e., SEQ ID NO:28) predicts that
 PDiTG.sub.40 has an estimated molecular weight of about 4.5 kD and an
 estimated pI of about 4.6. PC/GENE.TM. sequence analysis of SEQ ID NO:27
 predicts a translation product having an N-terminal hydrophobic signal
 sequence spanning from about amino acid residue 1 through about amino acid
 residue 25 of SEQ ID NO:28, and having a predicted cleavage site between
 about amino acid residue 25 and about amino acid residue 26. The nucleic
 acid sequence of the predicted mature protein product of PDiTG.sub.40
 (after cleavage at the predicted cleavage site) is an approximately 15
 amino acid protein herein denoted as PDiTG.sub.15 (the amino acid sequence
 of which is represented by SEQ ID NO:52), encoded by a nucleic acid
 molecule spanning from about nucleotide 99 to about nucleotide 143 of SEQ
 ID NO:27 (the coding and complementary sequences of which are herein
 designated as SEQ ID NO:51, and SEQ ID NO:53, respectively).
 Example 11
 This Example describes the amplification and subsequent isolation of a
 nematode transglutaminase nucleic acid molecule of the present invention
 from D. immitis female adult cDNA using primers designed for protein
 expression in the pTrcHisB vector (available from Invitrogen).
 Nematode transglutaminase nucleic acid molecules were PCR amplified from D.
 immitis female adult cDNA using the following two primers in the PCR
 amplification reaction: a sense primer (DiTG-XhoI) with the sequence, 5'
 CCGAGCTCGAGAATGAAATTTACAGATGCGGAC 3' (herein denoted as SEQ ID NO:24, XhoI
 site in bold; nucleic acid residues 13 through 33 of this primer represent
 sequence from about position 1 to about position 21 of SEQ ID NO:5, while
 the remainder of the primer was designed to include the restriction
 endonuclease cleavage site) and an antisense primer (DiTG- HindIII) 5'
 CAGCCAAGCTTCTTACAATTCTTCCTTCTTCTTCGGTTTTCC 3' (herein denoted as SEQ ID
 NO:25; HindIII site in bold) for PCR amplification. PCR amplification of
 D. immitis adult female cDNA using these primers resulted in the
 production of a 1407 bp nucleic acid molecule (herein denoted as
 nDiTG.sub.1407,).
 The nucleic acid molecule designated nDiTG.sub.1407, was gel purified,
 cloned into a TA cloning vector (available from Invitrogen) and sequenced
 using an automated DNA. sequencer. The nucleic acid sequence of the coding
 strand of nDiTG.sub.1407 is herein denoted as SEQ ID NO:32, and the
 complementary strand is herein denoted as SEQ ID NO:34. Translation of SEQ
 ID NO:32 yields a protein of about 468 amino acids, herein denoted as
 PDiTG.sub.468, the amino acid sequence of which is presented in SEQ ID
 NO:33. The amino acid sequence of D. immitis PDiTG.sub.468 (i.e., SEQ ID
 NO:33) predicts that PDiTG.sub.468 has an estimated molecular weight of
 about 54.3 kD and an estimated pI of about 5.6.
 The sequence of nDiTG.sub.1407 overlaps with that of nDiTG.sub.143 and
 nDiTG.sub.1472, allowing for the construction of a composite
 transglutaminase sequence representing a full-length nematode
 transglutaminase gene. The nucleic acid molecule represented by this
 sequence (herein denoted as nDiTG.sub.1881,) includes both the nematode
 splice leader sequence at the 5' end of the molecule, and the
 poly(A).sup.+ sequence at the 3' end of the molecule. The nucleic acid
 sequence of the coding and complementary strands of nDiTG.sub.1881 are
 herein represented by SEQ ID NO:46 and SEQ ID NO:48, respectively.
 Translation of nDiTG.sub.1881 yields an approximately 497 amino acid
 protein herein denoted as PDiTG.sub.497, the amino acid sequence of which
 is presented in SEQ ID NO:47. The nucleic acid molecule encoding
 PDiTG.sub.497 is referred to herein as nDiTG.sub.1494, the nucleic acid
 sequence of which is represented in SEQ ID NO:49 (the coding strand) and
 SEQ ID NO:50 (the complementary strand).
 Sequence analysis of SEQ ID NO:27 (the origin of the sequence of the 5' end
 of nDiTG.sub.1881, i.e., SEQ ID NO:46) predicts a translation product
 having an N-terminal hydrophobic signal sequence spanning from about amino
 acid residue 1 through about amino acid residue 25 of SEQ ID NO:46, and
 having a predicted cleavage site between about amino acid residue 25 and
 about amino acid residue 26. The nucleic acid sequence of the predicted
 mature protein product of nDiTG.sub.1881 (after cleavage at the predicted
 cleavage site) is an approximately 472 amino acid protein herein denoted
 as PDiTG.sub.472 (the amino acid sequence of which is represented by SEQ
 ID NO:55), encoded by a nucleic acid molecule spanning from about
 nucleotide 99 to about nucleotide 1514 of SEQ ID NO:46 (the coding and
 complementary sequences of which are herein designated as SEQ ID NO:54,
 and SEQ ID NO:56, respectively).
 Example 12
 This Example discloses the production of a recombinant molecule and a
 recombinant cell of the present invention.
 Recombinant molecule pTrc-nDiTG.sub.1407, containing a D. immitis
 transglutaminase nucleic acid molecule represented by nucleotides from
 about 1 through about 1407 of SEQ ID NO:32 operatively linked to trc
 transcription control sequences and to a fusion sequence encoding a
 poly-histidine segment comprising 6 histidine residues, was produced in
 the following manner. An about 1407 base nucleic acid molecule including
 nucleotides spanning from about nucleotides 1 through 1407 of SEQ ID NO:32
 was PCR amplified from nDiTG.sub.1407 using the primers DiTG-XhoI sense
 primer 5' CCGAGCTCGAGAATGAAATTTACAGATGCGGAC 3' (herein denoted as SEQ ID
 NO:24; XhoI site in bold) and DiTG-HindIII antisense primer
 5'CAGCCAAGCTTCTTACAATTCTTCCTTCTTCTTCGGTTTTCC 3' (herein denoted as SEQ ID
 NO:25; KpnI site in bold). Recombinant molecule PHis-DiTG.sub.1407 was
 produced by digesting the nDiTG.sub.1407 -containing PCR product with XhoI
 and HindIII restriction endonucleases, gel purifying the resulting
 fragment and directionally subcloning it into the expression vector
 pTrcHisB (available from Invitrogen) that had been cleaved with XhoI and
 HindIII and gel purified.
 Recombinant molecule pTrc-nDiTG.sub.1407 was transformed into E. coli to
 form recombinant cell E. coli:pTrc-nDiTG.sub.1407, using standard
 techniques as disclosed, for example, in Sambrook et al., ibid.
 Example 13
 This Example describes the production of a nematode transglutaminase
 protein of the present invention in a prokaryotic cell as well as studies
 to characterize that protein.
 Recombinant cell E. coli:pTrc-nDiTG.sub.1407 was cultured in shake-flasks
 containing an enriched bacterial growth medium containing 0.1 mg/ml
 ampicillin at about 37.degree. C. When the cells reached an OD.sub.600 of
 about 0.5, expression of D. immitis pTrc-nDiTG.sub.407 was induced by
 addition of about 0.5 mM isopropyl-.beta.-D-thiogalactoside (IPTG), and
 the cells were cultured for about 3 hr. at about 37.degree. C. Protein
 production was monitored by SDS-PAGE of recombinant cell lysates, followed
 by Coomassie blue staining, using standard techniques. Recombinant cell E.
 coli:pTrc-nDiTG.sub.1407 produced a fusion protein, herein denoted as
 PHIS-PDiTG.sub.468, that migrated with an apparent molcular weight of
 about 60 kD.
 Immunoblot analysis of recombinant cell E. coli:pTrc-nDiTG.sub.1407 lysates
 indicated that the about 60 kD protein was able to bind to a T.sub.7
 Tag.RTM. monoclonal antibody (available from Novagen, Inc., Madison, Wis.)
 directed against the fusion portion of the recombinant PHIS-PDiTG.sub.468
 fusion protein.
 The PHIS-PDiTG.sub.468 histidine fusion protein was separated from E. coli
 proteins by cobalt chelation chromatography with an imidazole gradient
 elution. Immunoblot analysis of the E. coli:pTrc-nDiTG.sub.1407 lysates,
 column eluate and column void volume indicated that the approximately 60
 kD PHIS-PDiTG.sub.468 protein isolated using cobalt column chromatography
 was able to selectively bind to a T.sub.7 Tag.RTM. monoclonal antibody.
 The fusion peptide expressed in pTrcHisB contributes approximately 4 kD of
 vector-encoded amino acid sequence to the recombinant protein; and thus
 nDiTG.sub.b 1407 encodes a protein of approximately 55kD.
 Example 14
 This Example discloses the purification of a nematode transglutaminase
 fusion protein of the present invention from total cell lysates. Also
 described is the production of anti-DiTG antibodies of the present
 invention.
 Nematode transglutaminase fusion protein PHIS-PDiTG.sub.468 was separated
 from E. coli proteins by Talon.TM. Metal Affinity Resin Chromatography
 (available from CLONTECH Laboratories, Inc., Palo Alto, Calif.) according
 to the manufacturer's instructions. The nematode transglutaminase fusion
 protein was eluted using an imidazole gradient, pooled and dialyzed
 against 1.times.PBS to produce cobalt column-purified PHIg-PDiTG.sub.468.
 The dialyzed protein was concentrated using a 10K molecular weight cut off
 Centrifugal Ultra-free.RTM. concentrator (available from Millipore
 Corporation, Bedford, Mass.). The protein content of the fusion protein
 was determined using a MicroBCA.TM. Protein Assay (available from Pierce,
 Rockford, Ill.). The purified protein was tested for its purity by SDS
 PAGE and immunoblot analysis as described in Example 3.
 Anti-PHIS-PDiTG.sub.468 (anti-DiTG) antisera was produced as follows: A
 rabbit was immunized subcutaneously, first with approximately 75 .mu.g of
 the purified PHIS-PDiTG.sub.468 (see above) protein with complete Freund's
 Adjuvant (available from Sigma, St. Louis, Mo.), and then with three
 subsequent immunizations of the same dose of PHIS-PDiTG.sub.468 mixed in
 Incomplete Freund's Adjuvant. Bleeding and immunization were performed at
 alternate weeks. Sera were separated and stored at -70.degree. C. until
 use.
 The immunoglobulin G (IgG) fraction (anti-DiTG IgG) from anti-DiTG antisera
 was collected by 50% ammonium sulfate precipitation. Ammonium ions were
 removed by extensive dialysis in 0.1 M PBS, pH 7.2. The IgG content was
 determined by measuring absorbance at OD.sub.280 and comparing absorbance
 with that of a blank PBS control. The anti-DiTG IgG had a titer of
 1:124,000 as determined by ELISA.
 Example 15
 This Example describes the PCR amplification and subsequent isolation and
 characterization of transglutaminase nucleic acid molecules from other
 related filarial Nematode transglutaminase nucleic acid molecules from
 Brugia malayi and Onchocerca volvulus were identified using standard PCR
 technology and methods as follows. In brief, nematode transglutaminase
 nucleic acid molecules were PCR amplified from B. malayi female adult cDNA
 using two primers, a sense primer representing the SL sequence, having the
 nucleotide sequence, 5' GGTTTAATTACCCAAGTTTGAG 3' (herein denoted as SEQ
 ID NO:22) and an antisense primer 5' GCTGATGGACCTGCCTGTCCACGC 3' (herein
 denoted as SEQ ID NO:26). PCR amplification of B. malayi adult female cDNA
 using these primers resulted in the production of a 440-bp nucleic acid
 molecule (herein denoted as nBmTG.sub.440). Nematode transglutaminase
 nucleic acid molecules were also amplified from B. malayi femlae adult
 cDNA using primers corresponding to internal sequences in the cDNA
 sequence of nDiTG.sub.1472 (SEQ ID NO:10). The two primers used were: i) a
 sense primer spanning from about nucleotide 359 to about nucleotide 371 of
 SEQ ID NO:10, and having the nucleotide sequence 5'
 GAAAACCGTTATCAGTATGATCT 3' (SEQ ID NO:19); and ii) an antisense primer
 spanning from about nucleotides 878 to 901 of SEQ ID NO:10, and having the
 nucleotide sequence 5' GTCCATTTTTGCAATAACAACACC 3' (SEQ ID NO:21). PCR
 amplification of adult female cDNA using these primers resulted in the
 production of a 537 bp nucleic acid molecule (herein denoted as
 nBmTG.sub.537 ; this nucleic acid molecule was previously identified in
 U.S. patent application Ser. No. 08/781,420 as nBmTG.sub.542).
 Transglutaminase nucleic acid molecules were also PCR amplified from an O.
 volvulus larval cDNA library using two primers that represent internal
 sequences of nDiTG.sub.1472 : a sense primer spanning from about
 nucleotide 359 to about nucleotide 371 of SEQ ID NO:10, and having the
 nucleotide sequence 5' GAAAACCGTTATCAGTATGATCT 3' (SEQ ID NO:19), and an
 antisense primer spanning from about nucleotide 878 to about nucleotide
 901 of SEQ ID NO:10, and having the nucleotide sequence
 GTCCATTTTGCAATAACAACACC 3' (SEQ ID NO:21). PCR amplification of adult
 female cDNA using these primers resulted in the production of a 537 bp
 nucleic acid molecule (herein denoted as nOvTG.sub.537 ; this nucleic acid
 molecule was, previously identified in U.S. patent application Ser. No.
 08/781,420 as nOvTG.sub.542).
 Nucleic acid molecules nBmTG.sub.440 (the sequences of the coding and
 complementary strands herein denoted as SEQ ID NO:35 and SEQ ID NO:37,
 respectively), nBmTG.sub.537 (the sequences of the coding and
 complementary strands herein denoted as SEQ ID NO:42 and SEQ ID NO:44,
 respectively), and nOvTG.sub.537 (the sequences of the coding and
 complementary strands herein denoted as SEQ ID NO:43 and SEQ ID NO:45,
 respectively) were gel purified, cloned into TA cloning vector and
 sequenced using an automated DNA sequencer. Sequence analysis of
 nBmTG.sub.440 coding and noncoding strands (represented by SEQ ID NO:35
 and SEQ ID NO:37, respectively) showed that nBmTG.sub.440 included the SL
 sequence at its 5' end. Furthermore, the entire sequences of nOvTG.sub.537
 and nBmTG.sub.537 were, respectively, 98.9% and 87.7% identical in the
 region spanning from about nucleotide 359 to about nucleotide 901 of
 nDiTG.sub.1472 (SEQ ID NO:10).
 Translation of SEQ ID NO:35 yields a protein of about 139 amino acids,
 herein denoted as PBmTG.sub.139, the amino acid sequence of which is
 presented in SEQ ID NO:36. The nucleic acid molecule encoding
 PBmTG.sub.139 is herein referred to as nBmTG.sub.417, the nucleic acid
 sequence of which is represented in SEQ ID NO:38 (the coding strand) and
 SEQ ID NO:39 (the complementary strand). The amino acid sequence of D.
 immitis PBmTG.sub.139 (i.e., SEQ ID NO:36) predicts that PBmTG.sub.139 has
 an estimated molecular weight of about 14.1 kD and an estimated pI of
 about 5.1. PC/GENE.TM. sequence analysis of SEQ ID NO:35 predicts a
 translation product having an N-terminal hydrophobic signal sequence
 spanning from about amino acid residue 1 through about amino acid residue
 26 of SEQ ID NO:36, and having a predicted cleavage site between about
 amino acid residue 26 and about amino acid residue 27. The nucleic acid
 sequence of the predicted mature protein product of nBmTG.sub.417 (after
 cleavage at the predicted cleavage site) is an approximately 113 amino
 acid protein herein denoted as PBmTG.sub.539 (the amino acid sequence of
 which is represented by SEQ ID NO:58), encoded by a nucleic acid molecule
 spanning from about nucleotide 102 to about nucleotide 440 of SEQ ID NO:35
 (the coding and complementary sequences of which are herein designated as
 SEQ ID NO:57, and SEQ ID NO:59, respectively).
 Translation of SEQ ID NO:42 yields a protein of about 179 amino acids,
 herein denoted as PBmTG.sub.179, the amino acid sequence of which is
 presented in SEQ ID NO:43. The amino acid sequence of D. immitis
 PBmTG.sub.179 predicts that PBmTG.sub.179 has an estimated molecular
 weight of about 20.8 kD and an estimated pI of about 4.6. Translation of
 SEQ ID NO:43 yields a protein of about 179 amino acids, herein denoted as
 POvTG.sub.179, the amino acid sequence of which is presented in SEQ ID NO:
 48. The amino acid sequence of D. immitis POvTG.sub.179 (i.e., SEQ ID
 NO:44) predicts that POvTG.sub.179 has an estimated molecular weight of
 about 20.8 kD and an estimated pI of about 4.6.
 Example 16
 This Example demonstrates that proteins of the present invention possess
 transglutaminase activity. The transglutaminase activity of
 column-purified nematode transglutaminase (PIS-PDiTG.sub.468) was
 determined in a microtiter plate assay essentially as previously herein
 described. In brief, microtiter wells were coated with 1% dimethylcasein,
 (available from Sigma) at room temperature overnight; uncoated sites were
 blocked with 1% (w/v) nonfat dry milk. The following reaction mixtures
 were contained in a total volume of 200 .mu.l: 100 mM Tris/HCl pH 8.5, 10
 mM CaCl.sub.2 (except where otherwise indicated), 10 mM dithiothreitol, 1
 mM amine donor substrate 5(biotinamido) pentylamine (BPT), (available from
 Sigma), and PHIS-PDiTG.sub.468. Reactions were performed at 55.degree. C.
 (or as herein indicated) for 2 hours and transglutaminase-catalyzed
 conjugation of BPT into dimethylcasein was determined by
 streptavidin-peroxidase and orthophenyldiamine as a reporter system. The
 enzyme activity (expressed as mU) of extracts was determined relative to
 the activity of purified guinea pig liver transglutaminase (available from
 Sigma) tested in the same microtiter plate. Several biochemial factors
 required for transglutaminase activity of PHIS-PDiTG.sub.468 were also
 investigated. The results of these assays are given in Tables 7-12.
 TABLE 7
 Effect of enzyme concentration on PHIS-PDiTG.sub.468 activity
 Concentration of PHIS-PDiTG.sub.468 Activity
 (.mu.g/ml) (mU .+-. SEM)
 5.0 14.4 .+-. 0.6
 10.0 42.1 .+-. 4.4
 15.0 74.4 .+-. 7.1
 TABLE 8
 Effect of Ca.sup.2+ on transglutaminase activity of PHIS-PDiTG.sub.468 (15
 .mu.g/ml)
 Concentration of Ca.sup.2+ Activity
 (mM) (mU .+-. SEM)
 0.0 2.1 .+-. 1.0
 0.5 65.7 .+-. 0.3
 2.0 110.6 .+-. 1.0
 4.0 125.8 .+-. 0.0
 8.0 125.8 .+-. 0.0
 TABLE 8
 Effect of Ca.sup.2+ on transglutaminase activity of PHIS-PDiTG.sub.468 (15
 .mu.g/ml)
 Concentration of Ca.sup.2+ Activity
 (mM) (mU .+-. SEM)
 0.0 2.1 .+-. 1.0
 0.5 65.7 .+-. 0.3
 2.0 110.6 .+-. 1.0
 4.0 125.8 .+-. 0.0
 8.0 125.8 .+-. 0.0
 TABLE 8
 Effect of Ca.sup.2+ on transglutaminase activity of PHIS-PDiTG.sub.468 (15
 .mu.g/ml)
 Concentration of Ca.sup.2+ Activity
 (mM) (mU .+-. SEM)
 0.0 2.1 .+-. 1.0
 0.5 65.7 .+-. 0.3
 2.0 110.6 .+-. 1.0
 4.0 125.8 .+-. 0.0
 8.0 125.8 .+-. 0.0
 TABLE 11
 Effect of dithiothreitol (DTT) on transglutaminase activity of
 PHIS-PDiTG.sub.468 (15 .mu.g/ml)
 Activity
 Concentration of DTT (mU .+-. SEM)
 (.mu.g/ml) +DTT -DTT
 10.0 55.0 .+-. 8.0 98.6 .+-. 2.0
 15.0 83.0 .+-. 6.6 149.0 .+-. 5.7
 20.0 123.0 .+-. 3.0 161.0 .+-. 3.0
 TABLE 11
 Effect of dithiothreitol (DTT) on transglutaminase activity of
 PHIS-PDiTG.sub.468 (15 .mu.g/ml)
 Activity
 Concentration of DTT (mU .+-. SEM)
 (.mu.g/ml) +DTT -DTT
 10.0 55.0 .+-. 8.0 98.6 .+-. 2.0
 15.0 83.0 .+-. 6.6 149.0 .+-. 5.7
 20.0 123.0 .+-. 3.0 161.0 .+-. 3.0
 As can be seen from the results presented above, PHIS-PDiTG.sub.468 was
 able to cross-link BPT to dimethylcasein and the rate of cross-linking
 activity was concentration dependent (Table 7). Furthermore, the
 transglutaminase activity of PHIS-PDiTG.sub.468 was Ca.sup.2+ -dependent
 (Table 8) and was inhibited by EDTA (Table 9) and EGTA (data not shown).
 Interestingly, the PHIS-PDiTG.sub.468 was found to be highly thermostable
 with optimum activity observed at 55.degree. C. (Table 10). Dithiothreitol
 (DTT, available from Sigma) was not absolutely essential for
 transglutaminase activity. In fact, PHIS-PDiTG.sub.468 was more active in
 the absence of DTT (Table 11). The known inhibitors of transglutaminase
 such as monodansylcadaverine, putrescine, cystamine and iodoacetamide
 inhibited the transglutaminase activity of PHIS-PDiTG.sub.468 (Table 12).
 Example 17
 This Example demonstrates the transglutaminase activity for bovine protein
 disulfide isomerase (PDI).
 Sequence analysis of nDiTG.sub.407 showed significant homology between the
 protein encoded by nDiTG and known PDIs. Therefore, bovine PDI was tested
 to see if it has transglutaminase activity. Transglutaminase activity of
 PDI (Bovine PDI, available from Sigma) was determined in a microtiter
 plate assay as described above. The results of the assays are given in
 Tables 13, 14 and 15.
 TABLE 13
 Transglutaminase activity of bovine protein disulfide isomerase (PDI)
 Concentration of PDI Transglutaminase activity
 (.mu.g/ml) (mU .+-. SEM)
 2.5 57.4 .+-. 3.0
 5.0 93.1 .+-. 7.3
 10.0 119.9 .+-. 7.1
 15.0 173.0 .+-. 4.5
 TABLE 14
 Effect of EDTA (10 mM) on transglutaminase activity of
 bovine protein disulfide isomerase (PDI)
 Concentration of PDI Transglutaminase activity
 (.mu.g/ml) (mU .+-. SEM)
 2.5 1.5 .+-. 0.1
 5.0 0.0 .+-. 0.0
 10.0 0.0 .+-. 0.0
 15.0 0.0 .+-. 0.0
 TABLE 14
 Effect of EDTA (10 mM) on transglutaminase activity of
 bovine protein disulfide isomerase (PDI)
 Concentration of PDI Transglutaminase activity
 (.mu.g/ml) (mU .+-. SEM)
 2.5 1.5 .+-. 0.1
 5.0 0.0 .+-. 0.0
 10.0 0.0 .+-. 0.0
 15.0 0.0 .+-. 0.0
 The data presented in these Tables demonstrate that, surprisingly, bovine
 PDI was able to cross-link BPT to dimethylcasein and that the rate of
 cross-linking activity was concentration dependent (Table 13). The
 transglutaminase activity of bovine PDI was Ca.sup.2+ -dependent and was
 inhibited EDTA (Tables 14). Like PHIS-PDiTG.sub.468, boyine PDI had
 optimum transglutaminase activity at 55.degree. C. (Table 15).
 Example 18
 This Example discloses a novel protein disulfide isomerase (PDI) activity
 of a nemateode transglutaminase protein of the present invention.
 The protein disulfide isomerase activity of PHIS-PDiTG.sub.468 was
 determined essentially as described by Lambert and Freedman (Biochem. J
 213:235, 1983). Briefly, known amounts of purified bovine liver PDI and
 PHIS-PDiTG.sub.468 were incubated for 2 min. at 30.degree. C. in 0.1 ml of
 sodium-phosphate buffer (50 mM, pH 7.5) containing 10 .mu.M DTT and 2.5 mM
 EDTA. 10 .mu.l of "scrambled" RNase (5 mg/ml stock, available from Sigma)
 was then to the above mixture and the incubation was continued for an
 additional 10 min. 10 .mu.l samples were drawn from each reaction mixture,
 and added immediately to 3 ml of pre-chilled TKM buffer (50 mM Tris HCl/25
 mM KCl/5 MM MgCl.sub.2, pH 7.5) and assayed for RNase activity at
 30.degree. C. in the presence of 0.25 mg yeast RNA (Sigma) by measuring
 the increase in A.sub.260 for 2 min. in a Beckman DU-600
 spectrophotometer. The results of these assays are presented in Tables 16
 and 17.
 TABLE 16
 PDI activity of PHIS-PDiTG.sub.468 and purified PDI from bovine liver
 Protein concentration PDI activity* (Mean .+-. SD)
 (.mu.g/ml) PDI PHIS-PDiTG.sub.468
 0.5 10.90 .+-. 1.1 2.84 .+-. 0.3
 1.0 9.84 .+-. 0.9 22.84 .+-. 0.9
 2.5 27.36 .+-. 2.8 34.36 .+-. 3.5
 5.0 39.70 .+-. 0.4 33.60 .+-. 5.2
 10.0 58.20 .+-. 7.3 43.50 .+-. 1.2
 *The PDI activity was determined as described (Lambert, N. and Freedman,
 R.B., 1983, Biochem. J 213, pp. 235-243), and was expressed as the change
 in A.sub.260 relative to A.sub.280 min..sup.-1 [.DELTA.A min.sup.-1 ],
 measured using a Beckman DU-600 dual wavelength spectrophotometer.
 TABLE 16
 PDI activity of PHIS-PDiTG.sub.468 and purified PDI from bovine liver
 Protein concentration PDI activity* (Mean .+-. SD)
 (.mu.g/ml) PDI PHIS-PDiTG.sub.468
 0.5 10.90 .+-. 1.1 2.84 .+-. 0.3
 1.0 9.84 .+-. 0.9 22.84 .+-. 0.9
 2.5 27.36 .+-. 2.8 34.36 .+-. 3.5
 5.0 39.70 .+-. 0.4 33.60 .+-. 5.2
 10.0 58.20 .+-. 7.3 43.50 .+-. 1.2
 *The PDI activity was determined as described (Lambert, N. and Freedman,
 R.B., 1983, Biochem. J 213, pp. 235-243), and was expressed as the change
 in A.sub.260 relative to A.sub.280 min..sup.-1 [.DELTA.A min.sup.-1 ],
 measured using a Beckman DU-600 dual wavelength spectrophotometer.
 PHIS-PDiTG.sub.468 was capable of reactivating "scrambled" RNase, and this
 effect was time- and dose-dependent (Table 16). However, the PDI activity
 of PHIS-PDiTG.sub.468 was not inhibited by transglutaminase inhibitors
 (Table 17).
 Example 19
 This Example describes ultra-structural studies of molting inhibition of D.
 immitis L.sub.3 by the transglutaminase pseudo substrate
 monodansylcadaverine (MDC).
 As herein described, MDC at a final concentration of 100 .mu.M completely
 inhibits the molting of D. immitis L.sub.3 to L.sub.4. The ultra
 structural events in larval molting inhibition were studied by culturing
 D. immitis larvae in the presence of MDC and observing the effects on
 development. Larvae cultured in the presence of MDC were collected every
 24 hr. for 6 days, fixed using standard procedures and embedded in resin.
 Ultra-microtome sections of larvae were prepared and then examined by
 electron microscopy. The L.sub.3 cuticle in untreated controls started
 separating from the new L.sub.4 cuticle after 24 hr. in culture and molted
 by 72 hr. In contrast, the MDC treated L.sub.3 failed to show any
 separation between the L.sub.3 and L.sub.4 cuticles. In addition, the
 L.sub.4 cuticle and the accompanying hypodermis were much thinner in MDC
 treated worms than in controls. Finally, the MDC treated larvae failed to
 molt even on day 6 whereas most of the larvae in control cultures had
 molted to L.sub.4 by day six.
 Example 20
 This Example describes the identification of native D. immitis
 transglutaminase protein by immunoblot analysis.
 Rabbit anti-DiTG IgG was used to identify a native D. immitis
 transglutaminase protein in D. immitis extracts as follows. The material
 in crude extracts from D. immitis larvae, adult male and female worms, and
 excretory-secretory (E-S) products from larvae and adults were separated
 by separating 5 .mu.g protein per lane on a 10-well, 4-20% gradient
 Tris-glycine SDS-PAGE gel at 200 volts for 1 hour. The separated proteins
 were then transferred to a nitrocellulose membrane by standard methods.
 After transfer, the membrane was blocked in 5% (w/v) nonfat dry milk for 1
 hr. at 37.degree. C. The membrane was incubated with rabbit anti-DiTG IgG
 at a dilution of 1:2500 in Tris buffered saline. After 1 hr. incubation at
 room temperature, the blot was washed and antibody binding resolved using
 a peroxidase-labeled goat anti-rabbit IgG secondary antibody (available
 from Kirkegaard and Perry Laboratories) and the substrate NBT/BCIP
 (available from Sigma). Rabbit anti-DiTG IgG recognized a 56 kD native D.
 immitis protein in D. immitis adult male, female and larval extracts. In
 addition, a 57 kD D. immitis protein was identified in the larval E-S
 products, but not in the adult E-S.
 Example 21
 This Example describes immunoblot analysis of bovine protein disulfide
 isomerase using rabbit anti-DiTG IgG as the primary antibody.
 Antibodies raised against PHIS-PDiTG.sub.468 were analyzed for
 cross-reactivity with bovine PDI as follows. Bovine PDI (100 ng) was
 separated by SDS-PAGE and transferred to a nitrocellulose filter
 essentially as previously described. The nitrocellulose filter containing
 bovine PDI was probed with rabbit anti-DiTG. Rabbit anti-DiTG failed to
 react with bovine PDI.
 Example 22
 This Example describes the immuno-localization of native antigen encoded by
 nDiTG.sub.1407 by light microscopy.
 Adult male and female D. immitis worms were fixed in 4% paraformaldehyde
 (available from Sigma) in 0.1 M phosphate buffer, pH 7.2 overnight at
 4.degree. C. Fixed worms were cut into 1-cm pieces, dehydrated and
 embedded in paraffin. Thin sections (about 7 microns) of the worm were
 then prepared using a microtome. The sections on glass slides were
 de-paraffinized and dehydrated using graded series of alcohol. The
 sections were then rehydrated in PBS, and treated for 1 hr. in 0.7% of 30%
 H.sub.2 O.sub.2 in PBS containing 10% ethanol in order to block endogenous
 peroxidases. For immuno-localization, the slides were blocked in PBS
 containing 10% fetal calf serum (available from Sigma) and 3% bovine serum
 albumin (available from Sigma) (PBS/FCS/BSA) for 1 hr. at room
 temperature. The slides were then flooded with a 1:1000 dilution of
 anti-DiTG IgG in PBS/BSA, and incubated overnight at 4.degree. C. The
 slides were then rinsed thoroughly with PBS and the antibody binding
 resolved using a peroxidase-labeled goat anti-rabbit IgG secondary
 antibody, and the substrate 3',3'-diaminobenzidine tetrahydrochloride
 (SigmaFast.TM. tablets, available from Sigma). After color development,
 the slides were dehydrated in graded series of alcohol and cleared in
 xylene. The slides were then covered with cover slips and observed under a
 Nikon MicroPhot-FXA.TM. microscope (available from Nikon Corporation,
 Japan). Using anti-DiTG IgG antibody, the native antigen corresponding to
 nematode transglutaminase was localized mainly in the contents and the
 walls of the male reproductive system. In the females, reaction products
 were seen in the gut epithelium and in the channels in the hypodermis. In
 addition, labeling was seen in the afibrillar muscle cells in males and in
 some areas of uterine walls in females.
 Example 23
 This Example demonstrates that D. immitis-infected cats, D.
 immitis-infected dogs and immune dogs generate antibodies that recognize a
 nematode transglutaminase protein of the present invention.
 Recombinant antigen PHIS-PDiTG.sub.468 (100 .mu.l/well; 1.0 .mu.g/ml in
 0.06 M carbonate buffer, pH 9.6) was incubated in Immulon.RTM. 2
 microtiter plates (Dynatech Laboratories, Alexandria, Va.) overnight at
 4.degree. C. Plates were blocked with 0.01 M PBS (pH 7.4) with 0.05% Tween
 20 (available from Sigma) and 5% fetal calf serum (PBS/T/FCS) for 1 hr. at
 37.degree. C. Sera from infected and immune animals, diluted 1:25 in
 PBS/T/FCS, were added to the first row of the ELISA plates and two-fold
 dilution was carried out. After 1 hr. incubation at 37.degree. C., the
 plates were washed with PBS/T and a peroxidase-conjugated anti-dog IgG
 antibody (1:5000) (available from Sigma) was added to detect binding of
 the primary antibody. After 1 hr. incubation, the plates were washed and
 substrate was added (o-phenyldiamine, available from Amresco.RTM., Solon,
 Ohio) with H.sub.2 O.sub.2. The enzyme reaction was stopped after 5 min.
 at room temperature with 4M H.sub.2 SO.sub.4. Optical density (OD) was
 compared with a PBS blank at 490 nm using a SpectraMax.TM. 250 ELISA
 reader (available from Molecular Devices, Sunnyvale, Calif.).
 Immune dogs (n=4) (immune dogs are defined as described in PCT Publication
 No. WO 94/15593, published Jul. 21, 1994, by Grieve et al.), D., infected
 dog (n=8), and infected cats (n=6) had detectable levels of IgG antibodies
 to PHIS-PDiTG.sub.468. In infected dogs and cats, the mean antibody levels
 were significantly higher at days 140-160 days post infection than
 antibody levels earlier in the infection. Specific antibody response to
 PHIS-PDiTG.sub.468 coincided with the onset of maturity of developing
 worms in the host.
 While various embodiments of the present invention have been described in
 detail, it is apparent that modifications and adaptions of those
 embodiments will occur to those skilled in the art. It is to be expressly
 understood, however, that such modifications and adaptations are within
 the scope of the present invention, as set forth in the following claims.
 SEQUENCE LISTING
 (1) GENERAL INFORMATION:
 (iii) NUMBER OF SEQUENCES: 59
 (2) INFORMATION FOR SEQ ID NO: 1:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 20 amino acids
 (B) TYPE: amino acid
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (ix) FEATURE:
 (A) NAME/KEY: Xaa = Unknown
 (B) LOCATION: 18
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1
 Asp Gly Asp Val Met Lys Phe Thr Asp Ala Asp Phe Lys Glu Gly Ile
 1 5 10 15
 Lys Xaa Tyr Asp
 20
 (2) INFORMATION FOR SEQ ID NO: 2:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 29 amino acids
 (B) TYPE: amino acid
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2
 Asp Gly Asp Val Met Lys Phe Thr Asp Ala Asp Phe Lys Glu Gly Ile
 1 5 10 15
 Lys Pro Tyr Asp Val Leu Leu Val Lys Phe Tyr Ala Pro
 20 25
 (2) INFORMATION FOR SEQ ID NO: 3:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 14 amino acids
 (B) TYPE: amino acid
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3
 Tyr Gln Tyr Asp Leu Leu Pro Met Phe Val Val Tyr Gly Lys
 1 5 10
 (2) INFORMATION FOR SEQ ID NO: 4:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 19 amino acids
 (B) TYPE: amino acid
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4
 Met Asp Ala Thr Ala Asn Asp Val Pro Pro Pro Phe Gln Val Gln Gly
 1 5 10 15
 Phe Pro Thr
 (2) INFORMATION FOR SEQ ID NO: 5:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 707 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (ix) FEATURE:
 (A) NAME/KEY: CDS
 (B) LOCATION: 1...705
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5
 ATG AAA TTT ACA GAT GCG GAC TTC AAG GAG GGA ATT AAA CCA TAT GAT 48
 Met Lys Phe Thr Asp Ala Asp Phe Lys Glu Gly Ile Lys Pro Tyr Asp
 1 5 10 15
 GTA TTA CTT GTG AAA TTT TAT GCA CCA TGG TGC GGA CAC TGC AAA AAG 96
 Val Leu Leu Val Lys Phe Tyr Ala Pro Trp Cys Gly His Cys Lys Lys
 20 25 30
 ATA GCA CCA GAA TTT GAA AAA GCA GCA ACC AAA CTT TTA CAG AAT GAT 144
 Ile Ala Pro Glu Phe Glu Lys Ala Ala Thr Lys Leu Leu Gln Asn Asp
 35 40 45
 CCG CCT ATT CAT TTA GCA GAG GTT GAC TGT ACG GAG GAG AAG AAA ACT 192
 Pro Pro Ile His Leu Ala Glu Val Asp Cys Thr Glu Glu Lys Lys Thr
 50 55 60
 TGC GAT GAA TAC GGT GTT AGT GGC TTC CCG ACT TTG AAA ATT TTC CGT 240
 Cys Asp Glu Tyr Gly Val Ser Gly Phe Pro Thr Leu Lys Ile Phe Arg
 65 70 75 80
 AAG GGA GAA CTA GCA CAG GAT TAT GAT GGT CCG AGA GTA GCA GAA GGT 288
 Lys Gly Glu Leu Ala Gln Asp Tyr Asp Gly Pro Arg Val Ala Glu Gly
 85 90 95
 ATT GTG AAA TAT ATG CGT GGA CAG GCA GGT CCA TCA GCT ACA GAA ATT 336
 Ile Val Lys Tyr Met Arg Gly Gln Ala Gly Pro Ser Ala Thr Glu Ile
 100 105 110
 AAT ACA CAA CAA GAA TTC GAA AAA ATG TTG CAA GCC GAT GAC GTT ACT 384
 Asn Thr Gln Gln Glu Phe Glu Lys Met Leu Gln Ala Asp Asp Val Thr
 115 120 125
 ATT TGT GGA TTT TTC GAA GAG AAC AGC AAG TTA AAA GAC TCA TTC TTA 432
 Ile Cys Gly Phe Phe Glu Glu Asn Ser Lys Leu Lys Asp Ser Phe Leu
 130 135 140
 AAA GTT GCG GAT ACA GAA AGA GAT CGT TTT AAG TTT GTG TGG ACA TCA 480
 Lys Val Ala Asp Thr Glu Arg Asp Arg Phe Lys Phe Val Trp Thr Ser
 145 150 155 160
 AAT AAA CAA ATT CTG GAA TCA AGG GGA TAC AAT GAT GAT ATC GTC GCA 528
 Asn Lys Gln Ile Leu Glu Ser Arg Gly Tyr Asn Asp Asp Ile Val Ala
 165 170 175
 TAT CAA CCG AAG AAA TTT CAT AAT AAA TTT GAA CCA AAT GAA TTC AAG 576
 Tyr Gln Pro Lys Lys Phe His Asn Lys Phe Glu Pro Asn Glu Phe Lys
 180 185 190
 TAT GAT GGA AAT TAC GAC ACA GAC AAG ATT AAA GAA TTT CTC CTA CAC 624
 Tyr Asp Gly Asn Tyr Asp Thr Asp Lys Ile Lys Glu Phe Leu Leu His
 195 200 205
 GAA ACA AAT GGG CTT GTT GGT ATA CGA ACG GCC GAA AAC CGT TAT CAG 672
 Glu Thr Asn Gly Leu Val Gly Ile Arg Thr Ala Glu Asn Arg Tyr Gln
 210 215 220
 TAT GAT CTA CTT CCG ATG TTC GTC GTC TAT GGC AA 707
 Tyr Asp Leu Leu Pro Met Phe Val Val Tyr Gly
 225 230 235
 (2) INFORMATION FOR SEQ ID NO: 6:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 235 amino acids
 (B) TYPE: amino acid
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6
 Met Lys Phe Thr Asp Ala Asp Phe Lys Glu Gly Ile Lys Pro Tyr Asp
 1 5 10 15
 Val Leu Leu Val Lys Phe Tyr Ala Pro Trp Cys Gly His Cys Lys Lys
 20 25 30
 Ile Ala Pro Glu Phe Glu Lys Ala Ala Thr Lys Leu Leu Gln Asn Asp
 35 40 45
 Pro Pro Ile His Leu Ala Glu Val Asp Cys Thr Glu Glu Lys Lys Thr
 50 55 60
 Cys Asp Glu Tyr Gly Val Ser Gly Phe Pro Thr Leu Lys Ile Phe Arg
 65 70 75 80
 Lys Gly Glu Leu Ala Gln Asp Tyr Asp Gly Pro Arg Val Ala Glu Gly
 85 90 95
 Ile Val Lys Tyr Met Arg Gly Gln Ala Gly Pro Ser Ala Thr Glu Ile
 100 105 110
 Asn Thr Gln Gln Glu Phe Glu Lys Met Leu Gln Ala Asp Asp Val Thr
 115 120 125
 Ile Cys Gly Phe Phe Glu Glu Asn Ser Lys Leu Lys Asp Ser Phe Leu
 130 135 140
 Lys Val Ala Asp Thr Glu Arg Asp Arg Phe Lys Phe Val Trp Thr Ser
 145 150 155 160
 Asn Lys Gln Ile Leu Glu Ser Arg Gly Tyr Asn Asp Asp Ile Val Ala
 165 170 175
 Tyr Gln Pro Lys Lys Phe His Asn Lys Phe Glu Pro Asn Glu Phe Lys
 180 185 190
 Tyr Asp Gly Asn Tyr Asp Thr Asp Lys Ile Lys Glu Phe Leu Leu His
 195 200 205
 Glu Thr Asn Gly Leu Val Gly Ile Arg Thr Ala Glu Asn Arg Tyr Gln
 210 215 220
 Tyr Asp Leu Leu Pro Met Phe Val Val Tyr Gly
 225 230 235
 (2) INFORMATION FOR SEQ ID NO: 7:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 707 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7
 TTGCCATAGA CGACGAACAT CGGAAGTAGA TCATACTGAT AACGGTTTTC GGCCGTTCGT 60
 ATACCAACAA GCCCATTTGT TTCGTGTAGG AGAAATTCTT TAATCTTGTC TGTGTCGTAA 120
 TTTCCATCAT ACTTGAATTC ATTTGGTTCA AATTTATTAT GAAATTTCTT CGGTTGATAT 180
 GCGACGATAT CATCATTGTA TCCCCTTGAT TCCAGAATTT GTTTATTTGA TGTCCACACA 240
 AACTTAAAAC GATCTCTTTC TGTATCCGCA ACTTTTAAGA ATGAGTCTTT TAACTTGCTG 300
 TTCTCTTCGA AAAATCCACA AATAGTAACG TCATCGGCTT GCAACATTTT TTCGAATTCT 360
 TGTTGTGTAT TAATTTCTGT AGCTGATGGA CCTGCCTGTC CACGCATATA TTTCACAATA 420
 CCTTCTGCTA CTCTCGGACC ATCATAATCC TGTGCTAGTT CTCCCTTACG GAAAATTTTC 480
 AAAGTCGGGA AGCCACTAAC ACCGTATTCA TCGCAAGTTT TCTTCTCCTC CGTACAGTCA 540
 ACCTCTGCTA AATGAATAGG CGGATCATTC TGTAAAAGTT TGGTTGCTGC TTTTTCAAAT 600
 TCTGGTGCTA TCTTTTTGCA GTGTCCGCAC CATGGTGCAT AAAATTTCAC AAGTAATACA 660
 TCATATGGTT TAATTCCCTC CTTGAAGTCC GCATCTGTAA ATTTCAT 707
 (2) INFORMATION FOR SEQ ID NO: 8:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 705 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8
 ATGAAATTTA CAGATGCGGA CTTCAAGGAG GGAATTAAAC CATATGATGT ATTACTTGTG 60
 AAATTTTATG CACCATGGTG CGGACACTGC AAAAAGATAG CACCAGAATT TGAAAAAGCA 120
 GCAACCAAAC TTTTACAGAA TGATCCGCCT ATTCATTTAG CAGAGGTTGA CTGTACGGAG 180
 GAGAAGAAAA CTTGCGATGA ATACGGTGTT AGTGGCTTCC CGACTTTGAA AATTTTCCGT 240
 AAGGGAGAAC TAGCACAGGA TTATGATGGT CCGAGAGTAG CAGAAGGTAT TGTGAAATAT 300
 ATGCGTGGAC AGGCAGGTCC ATCAGCTACA GAAATTAATA CACAACAAGA ATTCGAAAAA 360
 ATGTTGCAAG CCGATGACGT TACTATTTGT GGATTTTTCG AAGAGAACAG CAAGTTAAAA 420
 GACTCATTCT TAAAAGTTGC GGATACAGAA AGAGATCGTT TTAAGTTTGT GTGGACATCA 480
 AATAAACAAA TTCTGGAATC AAGGGGATAC AATGATGATA TCGTCGCATA TCAACCGAAG 540
 AAATTTCATA ATAAATTTGA ACCAAATGAA TTCAAGTATG ATGGAAATTA CGACACAGAC 600
 AAGATTAAAG AATTTCTCCT ACACGAAACA AATGGGCTTG TTGGTATACG AACGGCCGAA 660
 AACCGTTATC AGTATGATCT ACTTCCGATG TTCGTCGTCT ATGGC 705
 (2) INFORMATION FOR SEQ ID NO: 9:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 705 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9
 GCCATAGACG ACGAACATCG GAAGTAGATC ATACTGATAA CGGTTTTCGG CCGTTCGTAT 60
 ACCAACAAGC CCATTTGTTT CGTGTAGGAG AAATTCTTTA ATCTTGTCTG TGTCGTAATT 120
 TCCATCATAC TTGAATTCAT TTGGTTCAAA TTTATTATGA AATTTCTTCG GTTGATATGC 180
 GACGATATCA TCATTGTATC CCCTTGATTC CAGAATTTGT TTATTTGATG TCCACACAAA 240
 CTTAAAACGA TCTCTTTCTG TATCCGCAAC TTTTAAGAAT GAGTCTTTTA ACTTGCTGTT 300
 CTCTTCGAAA AATCCACAAA TAGTAACGTC ATCGGCTTGC AACATTTTTT CGAATTCTTG 360
 TTGTGTATTA ATTTCTGTAG CTGATGGACC TGCCTGTCCA CGCATATATT TCACAATACC 420
 TTCTGCTACT CTCGGACCAT CATAATCCTG TGCTAGTTCT CCCTTACGGA AAATTTTCAA 480
 AGTCGGGAAG CCACTAACAC CGTATTCATC GCAAGTTTTC TTCTCCTCCG TACAGTCAAC 540
 CTCTGCTAAA TGAATAGGCG GATCATTCTG TAAAAGTTTG GTTGCTGCTT TTTCAAATTC 600
 TGGTGCTATC TTTTTGCAGT GTCCGCACCA TGGTGCATAA AATTTCACAA GTAATACATC 660
 ATATGGTTTA ATTCCCTCCT TGAAGTCCGC ATCTGTAAAT TTCAT 705
 (2) INFORMATION FOR SEQ ID NO: 10:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 1472 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (ix) FEATURE:
 (A) NAME/KEY: CDS
 (B) LOCATION: 2..1105
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10
 T ATG CGT GGA CAG GCA GGT CCA TCA GCT ACA GAA ATT AAT ACA CAA CAA 49
 Met Arg Gly Gln Ala Gly Pro Ser Ala Thr Glu Ile Asn Thr Gln Gln
 1 5 10 15
 GAA TTC GAA AAA ATG TTG CAA GCC GAT GAC GTT ACT ATT TGT GGA TTT 97
 Glu Phe Glu Lys Met Leu Gln Ala Asp Asp Val Thr Ile Cys Gly Phe
 20 25 30
 TTC GAA GAG AAC AGC AAG TTA AAA GAC TCA TTC TTA AAA GTT GCG GAT 145
 Phe Glu Glu Asn Ser Lys Leu Lys Asp Ser Phe Leu Lys Val Ala Asp
 35 40 45
 ACA GAA AGA GAT CGT TTT AAG TTT GTG TGG ACA TCA AAT AAA CAA ATT 193
 Thr Glu Arg Asp Arg Phe Lys Phe Val Trp Thr Ser Asn Lys Gln Ile
 50 55 60
 CTG GAA TCA AGG GGA TAC AAT GAT GAT ATC GTC GCA TAT CAA CCG AAG 241
 Leu Glu Ser Arg Gly Tyr Asn Asp Asp Ile Val Ala Tyr Gln Pro Lys
 65 70 75 80
 AAA TTT CAT AAT AAA TTT GAA CCA AAT GAA TTC AAG TAT GAT GGA AAT 289
 Lys Phe His Asn Lys Phe Glu Pro Asn Glu Phe Lys Tyr Asp Gly Asn
 85 90 95
 TAC GAC ACA GAC AAG ATT AAA GAA TTT CTC CTA CAC GAA ACA AAT GGG 337
 Tyr Asp Thr Asp Lys Ile Lys Glu Phe Leu Leu His Glu Thr Asn Gly
 100 105 110
 CTT GTT GGT ATA CGA ACG GCC GAA AAC CGT TAT CAG TAT GAT CTA CTT 385
 Leu Val Gly Ile Arg Thr Ala Glu Asn Arg Tyr Gln Tyr Asp Leu Leu
 115 120 125
 CCG ATG TTT GTT GTG TAT GGC AAG GTT GAC TAT GAA TTG GAT CCA AAA 433
 Pro Met Phe Val Val Tyr Gly Lys Val Asp Tyr Glu Leu Asp Pro Lys
 130 135 140
 GGT TCC AAC TAT TGG CGA AAT CGT GTT CTT ATG GTT GCA AAA GAT TAC 481
 Gly Ser Asn Tyr Trp Arg Asn Arg Val Leu Met Val Ala Lys Asp Tyr
 145 150 155 160
 AAA AGG AAA GCA AAT TTT GCT ATG AGT AAC AAA GAA GAC TTC TCT TTT 529
 Lys Arg Lys Ala Asn Phe Ala Met Ser Asn Lys Glu Asp Phe Ser Phe
 165 170 175
 GAT CTT GAT GAA TTT GGC TTA GCT AAT CGT AAA GAT ACC AAG CCG CTT 577
 Asp Leu Asp Glu Phe Gly Leu Ala Asn Arg Lys Asp Thr Lys Pro Leu
 180 185 190
 GTT GCA GCA CGT AGC AAA AAA GGC AAA TTC TTT ATG AAA GAA GAA TTC 625
 Val Ala Ala Arg Ser Lys Lys Gly Lys Phe Phe Met Lys Glu Glu Phe
 195 200 205
 AGT TTT AGC GTG GAA AAT TTG AAA AAA TTT GTC GAA GAT GTT ATT GGT 673
 Ser Phe Ser Val Glu Asn Leu Lys Lys Phe Val Glu Asp Val Ile Gly
 210 215 220
 GAT AGA TTA GAA CCG TAT ATG AAG AGC GAA GAA GCA CCT GAA GAT CAG 721
 Asp Arg Leu Glu Pro Tyr Met Lys Ser Glu Glu Ala Pro Glu Asp Gln
 225 230 235 240
 GGT GAT GTT AAG GTC GTT GTT GCT AAG ACA TTC CAA GAA ATG ATC ATG 769
 Gly Asp Val Lys Val Val Val Ala Lys Thr Phe Gln Glu Met Ile Met
 245 250 255
 AAT GTG GAA AAG GAT GTT TTA ATC GAA TTT TAT GCT CCA TGG TGT GGC 817
 Asn Val Glu Lys Asp Val Leu Ile Glu Phe Tyr Ala Pro Trp Cys Gly
 260 265 270
 CAC TGC AAA GCA CTC GCA CCG AAA TAT GAT GAA TTA GGC CAG AAA TTA 865
 His Cys Lys Ala Leu Ala Pro Lys Tyr Asp Glu Leu Gly Gln Lys Leu
 275 280 285
 TCC GGT GAA CCA GGT GTT GTT ATT GCA AAA ATG GAC GCA ACA GCG AAT 913
 Ser Gly Glu Pro Gly Val Val Ile Ala Lys Met Asp Ala Thr Ala Asn
 290 295 300
 GAT GTC CCA CCA CCA TTC CAA GTA CAA GGA TTT CCA ACT CTT TAC TGG 961
 Asp Val Pro Pro Pro Phe Gln Val Gln Gly Phe Pro Thr Leu Tyr Trp
 305 310 315 320
 GTA CCG AAG AAT AAA AAA GAC AAA CCA GAG CCA TAC TCT GGT GGT CGA 1009
 Val Pro Lys Asn Lys Lys Asp Lys Pro Glu Pro Tyr Ser Gly Gly Arg
 325 330 335
 GAA GTG GAT GAT TTT ATT AAA TAC ATC GCG AAG CAT GCA ACG GAA GAA 1057
 Glu Val Asp Asp Phe Ile Lys Tyr Ile Ala Lys His Ala Thr Glu Glu
 340 345 350
 CTG AAG GGA TAC AAG AGA GAT GGA AAA CCG AAG AAG AAG GAA GAA TTG 1105
 Leu Lys Gly Tyr Lys Arg Asp Gly Lys Pro Lys Lys Lys Glu Glu Leu
 355 360 365
 TAAAGGGTAA TAATGATGAA TTTTTAATTT GATGTGAACC CAAACAACCT CAGTTGCTTA 1165
 TTGGTGGATA AATATTTAAA TCATTCCACA GAGCTGTGAT ATGAATTTTC AAATATGTTT 1225
 TTTTTTGGTT TATTTTGATA AATTCATATT TTAAGTTGTT ATTTTTTAGT GCCTTAGGCT 1285
 GTTTCATCAG TTGCCTTAGG CTATTTTGTC AGTTCGGAAT GTTTATTCCG TTAGCTTAGG 1345
 CTTTTTTTTG TTTACCTTAT GTTACTGTTG TTATTGTATT ACTATTTTGC CCTTGTTTTT 1405
 TAAATTTTAA ATAAATTTTT TTTGGAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA 1465
 AAAAAAA 1472
 (2) INFORMATION FOR SEQ ID NO: 11:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 368 amino acids
 (B) TYPE: amino acid
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11
 Met Arg Gly Gln Ala Gly Pro Ser Ala Thr Glu Ile Asn Thr Gln Gln
 1 5 10 15
 Glu Phe Glu Lys Met Leu Gln Ala Asp Asp Val Thr Ile Cys Gly Phe
 20 25 30
 Phe Glu Glu Asn Ser Lys Leu Lys Asp Ser Phe Leu Lys Val Ala Asp
 35 40 45
 Thr Glu Arg Asp Arg Phe Lys Phe Val Trp Thr Ser Asn Lys Gln Ile
 50 55 60
 Leu Glu Ser Arg Gly Tyr Asn Asp Asp Ile Val Ala Tyr Gln Pro Lys
 65 70 75 80
 Lys Phe His Asn Lys Phe Glu Pro Asn Glu Phe Lys Tyr Asp Gly Asn
 85 90 95
 Tyr Asp Thr Asp Lys Ile Lys Glu Phe Leu Leu His Glu Thr Asn Gly
 100 105 110
 Leu Val Gly Ile Arg Thr Ala Glu Asn Arg Tyr Gln Tyr Asp Leu Leu
 115 120 125
 Pro Met Phe Val Val Tyr Gly Lys Val Asp Tyr Glu Leu Asp Pro Lys
 130 135 140
 Gly Ser Asn Tyr Trp Arg Asn Arg Val Leu Met Val Ala Lys Asp Tyr
 145 150 155 160
 Lys Arg Lys Ala Asn Phe Ala Met Ser Asn Lys Glu Asp Phe Ser Phe
 165 170 175
 Asp Leu Asp Glu Phe Gly Leu Ala Asn Arg Lys Asp Thr Lys Pro Leu
 180 185 190
 Val Ala Ala Arg Ser Lys Lys Gly Lys Phe Phe Met Lys Glu Glu Phe
 195 200 205
 Ser Phe Ser Val Glu Asn Leu Lys Lys Phe Val Glu Asp Val Ile Gly
 210 215 220
 Asp Arg Leu Glu Pro Tyr Met Lys Ser Glu Glu Ala Pro Glu Asp Gln
 225 230 235 240
 Gly Asp Val Lys Val Val Val Ala Lys Thr Phe Gln Glu Met Ile Met
 245 250 255
 Asn Val Glu Lys Asp Val Leu Ile Glu Phe Tyr Ala Pro Trp Cys Gly
 260 265 270
 His Cys Lys Ala Leu Ala Pro Lys Tyr Asp Glu Leu Gly Gln Lys Leu
 275 280 285
 Ser Gly Glu Pro Gly Val Val Ile Ala Lys Met Asp Ala Thr Ala Asn
 290 295 300
 Asp Val Pro Pro Pro Phe Gln Val Gln Gly Phe Pro Thr Leu Tyr Trp
 305 310 315 320
 Val Pro Lys Asn Lys Lys Asp Lys Pro Glu Pro Tyr Ser Gly Gly Arg
 325 330 335
 Glu Val Asp Asp Phe Ile Lys Tyr Ile Ala Lys His Ala Thr Glu Glu
 340 345 350
 Leu Lys Gly Tyr Lys Arg Asp Gly Lys Pro Lys Lys Lys Glu Glu Leu
 355 360 365
 (2) INFORMATION FOR SEQ ID NO: 12:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 1472 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12
 TTTTTTTTTT TTTTTTTTTT TTTTTTTTTT TTTTTTTTTT TTCCAAAAAA AATTTATTTA 60
 AAATTTAAAA AACAAGGGCA AAATAGTAAT ACAATAACAA CAGTAACATA AGGTAAACAA 120
 AAAAAAGCCT AAGCTAACGG AATAAACATT CCGAACTGAC AAAATAGCCT AAGGCAACTG 180
 ATGAAACAGC CTAAGGCACT AAAAAATAAC AACTTAAAAT ATGAATTTAT CAAAATAAAC 240
 CAAAAAAAAA CATATTTGAA AATTCATATC ACAGCTCTGT GGAATGATTT AAATATTTAT 300
 CCACCAATAA GCAACTGAGG TTGTTTGGGT TCACATCAAA TTAAAAATTC ATCATTATTA 360
 CCCTTTACAA TTCTTCCTTC TTCTTCGGTT TTCCATCTCT CTTGTATCCC TTCAGTTCTT 420
 CCGTTGCATG CTTCGCGATG TATTTAATAA AATCATCCAC TTCTCGACCA CCAGAGTATG 480
 GCTCTGGTTT GTCTTTTTTA TTCTTCGGTA CCCAGTAAAG AGTTGGAAAT CCTTGTACTT 540
 GGAATGGTGG TGGGACATCA TTCGCTGTTG CGTCCATTTT TGCAATAACA AAACCTGGTT 600
 CACCGGATAA TTTCTGGCCT AATTCATCAT ATTTCGGTGC GAGTGCTTTG CAGTGGCCAC 660
 ACCATGGAGC ATAAAATTCG ATTAAAACAT CCTTTTCCAC ATTCATGATC ATTTCTTGGA 720
 ATGTCTTAGC AACAACGACC TTAACATCAC CCTGATCTTC AGGTGCTTCT TCGCTCTTCA 780
 TATACGGTTC TAATCTATCA CCAATAACAT CTTCGACAAA TTTTTTCAAA TTTTCCACGC 840
 TAAAACTGAA TTCTTCTTTC ATAAAGAATT TGCCTTTTTT GCTACGTGCT GCAACAAGCG 900
 GCTTGGTATC TTTACGATTA GCTAAGCCAA ATTCATCAAG ATCAAAAGAG AAGTCTTCTT 960
 TGTTACTCAT AGCAAAATTT GCTTTCCTTT TGTAATCTTT TGCAACCATA AGAACACGAT 1020
 TTCGCCAATA GTTGGAACCT TTTGGATCCA ATTCATAGTC AACCTTGCCA TACACAACAA 1080
 ACATCGGAAG TAGATCATAC TGATAACGGT TTTCGGCCGT TCGTATACCA ACAAGCCCAT 1140
 TTGTTTCGTG TAGGAGAAAT TCTTTAATCT TGTCTGTGTC GTAATTTCCA TCATACTTGA 1200
 ATTCATTTGG TTCAAATTTA TTATGAAATT TCTTCGGTTG ATATGCGACG ATATCATCAT 1260
 TGTATCCCCT TGATTCCAGA ATTTGTTTAT TTGATGTCCA CACAAACTTA AAACGATCTC 1320
 TTTCTGTATC CGCAACTTTT AAGAATGAGT CTTTTAACTT GCTGTTCTCT TCGAAAAATC 1380
 CACAAATAGT AACGTCATCG GCTTGCAACA TTTTTTCGAA TTCTTGTTGT GTATTAATTT 1440
 CTGTAGCTGA TGGACCTGCC TGTCCACGCA TA 1472
 (2) INFORMATION FOR SEQ ID NO: 13:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 1107 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13
 ATGCGTGGAC AGGCAGGTCC ATCAGCTACA GAAATTAATA CACAACAAGA ATTCGAAAAA 60
 ATGTTGCAAG CCGATGACGT TACTATTTGT GGATTTTTCG AAGAGAACAG CAAGTTAAAA 120
 GACTCATTCT TAAAAGTTGC GGATACAGAA AGAGATCGTT TTAAGTTTGT GTGGACATCA 180
 AATAAACAAA TTCTGGAATC AAGGGGATAC AATGATGATA TCGTCGCATA TCAACCGAAG 240
 AAATTTCATA ATAAATTTGA ACCAAATGAA TTCAAGTATG ATGGAAATTA CGACACAGAC 300
 AAGATTAAAG AATTTCTCCT ACACGAAACA AATGGGCTTG TTGGTATACG AACGGCCGAA 360
 AACCGTTATC AGTATGATCT ACTTCCGATG TTTGTTGTGT ATGGCAAGGT TGACTATGAA 420
 TTGGATCCAA AAGGTTCCAA CTATTGGCGA AATCGTGTTC TTATGGTTGC AAAAGATTAC 480
 AAAAGGAAAG CAAATTTTGC TATGAGTAAC AAAGAAGACT TCTCTTTTGA TCTTGATGAA 540
 TTTGGCTTAG CTAATCGTAA AGATACCAAG CCGCTTGTTG CAGCACGTAG CAAAAAAGGC 600
 AAATTCTTTA TGAAAGAAGA ATTCAGTTTT AGCGTGGAAA ATTTGAAAAA ATTTGTCGAA 660
 GATGTTATTG GTGATAGATT AGAACCGTAT ATGAAGAGCG AAGAAGCACC TGAAGATCAG 720
 GGTGATGTTA AGGTCGTTGT TGCTAAGACA TTCCAAGAAA TGATCATGAA TGTGGAAAAG 780
 GATGTTTTAA TCGAATTTTA TGCTCCATGG TGTGGCCACT GCAAAGCACT CGCACCGAAA 840
 TATGATGAAT TAGGCCAGAA ATTATCCGGT GAACCAGGTG TTGTTATTGC AAAAATGGAC 900
 GCAACAGCGA ATGATGTCCC ACCACCATTC CAAGTACAAG GATTTCCAAC TCTTTACTGG 960
 GTACCGAAGA ATAAAAAAGA CAAACCAGAG CCATACTCTG GTGGTCGAGA AGTGGATGAT 1020
 TTTATTAAAT ACATCGCGAA GCATGCAACG GAAGAACTGA AGGGATACAA GAGAGATGGA 1080
 AAACCGAAGA AGAAGGAAGA ATTGTAA 1107
 (2) INFORMATION FOR SEQ ID NO: 14:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 1107 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14
 TTACAATTCT TCCTTCTTCT TCGGTTTTCC ATCTCTCTTG TATCCCTTCA GTTCTTCCGT 60
 TGCATGCTTC GCGATGTATT TAATAAAATC ATCCACTTCT CGACCACCAG AGTATGGCTC 120
 TGGTTTGTCT TTTTTATTCT TCGGTACCCA GTAAAGAGTT GGAAATCCTT GTACTTGGAA 180
 TGGTGGTGGG ACATCATTCG CTGTTGCGTC CATTTTTGCA ATAACAACAC CTGGTTCACC 240
 GGATAATTTC TGGCCTAATT CATCATATTT CGGTGCGAGT GCTTTGCAGT GGCCACACCA 300
 TGGAGCATAA AATTCGATTA AAACATCCTT TTCCACATTC ATGATCATTT CTTGGAATGT 360
 CTTAGCAACA ACGACCTTAA CATCACCCTG ATCTTCAGGT GCTTCTTCGC TCTTCATATA 420
 CGGTTCTAAT CTATCACCAA TAACATCTTC GACAAATTTT TTCAAATTTT CCACGCTAAA 480
 ACTGAATTCT TCTTTCATAA AGAATTTGCC TTTTTTGCTA CGTGCTGCAA CAAGCGGCTT 540
 GGTATCTTTA CGATTAGCTA AGCCAAATTC ATCAAGATCA AAAGAGAAGT CTTCTTTGTT 600
 ACTCATAGCA AAATTTGCTT TCCTTTTGTA ATCTTTTGCA ACCATAAGAA CACGATTTCG 660
 CCAATAGTTG GAACCTTTTG GATCCAATTC ATAGTCAACC TTGCCATACA CAACAAACAT 720
 CGGAAGTAGA TCATACTGAT AACGGTTTTC GGCCGTTCGT ATACCAACAA GCCCATTTGT 780
 TTCGTGTAGG AGAAATTCTT TAATCTTGTC TGTGTCGTAA TTTCCATCAT ACTTGAATTC 840
 ATTTGGTTCA AATTTATTAT GAAATTTCTT CGGTTGATAT GCGACGATAT CATCATTGTA 900
 TCCCCTTGAT TCCAGAATTT GTTTATTTGA TGTCCACACA AACTTAAAAC GATCTCTTTC 960
 TGTATCCGCA ACTTTTAAGA ATGAGTCTTT TAACTTGCTG TTCTCTTCGA AAAATCCACA 1020
 AATAGTAACG TCATCGGCTT GCAACATTTT TTCGAATTCT TGTTGTGTAT TAATTTCTGT 1080
 AGCTGATGGA CCTGCCTGTC CACGCAT 1107
 (2) INFORMATION FOR SEQ ID NO: 15:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 32
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: primer
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15
 ATGAARTTYA CNGAYGCNGA YTTYAARGAR GG 32
 (2) INFORMATION FOR SEQ ID NO: 16:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 20 bases
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: primer
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16
 TTNCCRTANA CNACRAACAT 20
 (2) INFORMATION FOR SEQ ID NO: 17:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 20 bases
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: primer
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17
 AATTAACCCT CACTAAAGGG 20
 (2) INFORMATION FOR SEQ ID NO: 18:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 22 bases
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: primer
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18
 GTAATACGAC TCACTATAGG GC 22
 (2) INFORMATION FOR SEQ ID NO: 19:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 23 bases
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: primer
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19
 GAAAACCGTT ATCAGTATGA TCT 23
 (2) INFORMATION FOR SEQ ID NO: 20:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 26 bases
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: primer
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20
 CTGTGGAATG ATTTAAATAT TTATCC 26
 (2) INFORMATION FOR SEQ ID NO: 21:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 24 bases
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: primer
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21
 GTCCATTTTT GCAATAACAA CACC 24
 (2) INFORMATION FOR SEQ ID NO: 22:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 22 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: primer
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22
 GGTTTAATTA CCCAAGTTTG AG 22
 (2) INFORMATION FOR SEQ ID NO: 23:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 33 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: primer
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23
 TCCCTCCTTG AAGTCCGCAT CTGTAAATTT CAT 33
 (2) INFORMATION FOR SEQ ID NO: 24:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 33 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: primer
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24
 CCGAGCTCGA GAATGAAATT TACAGATGCG GAC 33
 (2) INFORMATION FOR SEQ ID NO: 25:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 42 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: primer
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25
 CAGCCAAGCT TCTTACAATT CTTCCTTCTT CTTCGGTTTT CC 42
 (2) INFORMATION FOR SEQ ID NO: 26:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 24 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: primer
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26
 GCTGATGGAC CTGCCTGTCC ACGC 24
 (2) INFORMATION FOR SEQ ID NO: 27:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 143 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (ix) FEATURE:
 (A) NAME/KEY: CDS
 (B) LOCATION: 24..143
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27
 GGTTTAATTA CCCAAGTTTG AGG ATG ACA CTG GTG AGG TTG TTT 44
 Met Thr Leu Val Arg Leu Phe
 1 5
 GAT GCT TCG ATT TTT AAA TTA TTC TTG TTT CTG ATA TTG CCA 86
 Asp Ala Ser Ile Phe Lys Leu Phe Leu Phe Leu Ile Leu Pro
 10 15 20
 TTA ACG AAT GCC GAT GGC GAT GTG ATG AAA TTT ACA GAT GCG 128
 Leu Thr Asn Ala Asp Gly Asp Val Met Lys Phe Thr Asp Ala
 25 30 35
 GAC TTC AAG GAG GGA 143
 Asp Phe Lys Glu Gly
 40
 (2) INFORMATION FOR SEQ ID NO: 28:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 40 amino acids
 (B) TYPE: amino acid
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28
 Met Thr Leu Val Arg Leu Phe Asp Ala Ser Ile Phe Lys Leu
 1 5 10
 Phe Leu Phe Leu Ile Leu Pro Leu Thr Asn Ala Asp Gly Asp
 15 20 25
 Val Met Lys Phe Thr Asp Ala Asp Phe Lys Glu Gly
 30 35 40
 (2) INFORMATION FOR SEQ ID NO: 29:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 143 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29
 TCCCTCCTTG AAGTCCGCAT CTGTAAATTT CATCACATCG CCATCGGCAT 50
 TCGTTAATGG CAATATCAGA AACAAGAATA ATTTAAAAAT CGAAGCATCA 100
 AACAACCTCA CCAGTGTCAT CCTCAAACTT GGGTAATTAA ACC 143
 (2) INFORMATION FOR SEQ ID NO: 30:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 120 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30
 ATGACACTGG TGAGGTTGTT TGATGCTTCG ATTTTTAAAT TATTCTTGTT 50
 TCTGATATTG CCATTAACGA ATGCCGATGG CGATGTGATG AAATTTACAG 100
 ATGCGGACTT CAAGGAGGGA 120
 (2) INFORMATION FOR SEQ ID NO: 31:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 120 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31
 TCCCTCCTTG AAGTCCGCAT CTGTAAATTT CATCACATCG CCATCGGCAT 50
 TCGTTAATGG CAATATCAGA AACAAGAATA ATTTAAAAAT CGAAGCATCA 100
 AACAACCTCA CCAGTGTCAT 120
 (2) INFORMATION FOR SEQ ID NO: 32:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 1407 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (ix) FEATURE:
 (A) NAME/KEY: CDS
 (B) LOCATION: 1..1404
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32
 ATG AAA TTT ACA GAT GCG GAC TTC AAG GAG GGA ATT AAA CCA 42
 Met Lys Phe Thr Asp Ala Asp Phe Lys Glu Gly Ile Lys Pro
 1 5 10
 TAT GAT GTA TTA CTT GTG AAA TTT TAT GCA CCA TGG TGC GGA 84
 Tyr Asp Val Leu Leu Val Lys Phe Tyr Ala Pro Trp Cys Gly
 15 20 25
 CAC TGC AAA AAG ATA GCA CCA GAA TTT GAA AAA GCA GCA ACC 126
 His Cys Lys Lys Ile Ala Pro Glu Phe Glu Lys Ala Ala Thr
 30 35 40
 AAA CTT TTA CAG AAT GAT CCG CCT ATT CAT TTA GCA GAG GTT 168
 Lys Leu Leu Gln Asn Asp Pro Pro Ile His Leu Ala Glu Val
 45 50 55
 GAC TGT ACG GAG GAG AAG AAA ACT TGC GAT GAA TAC GGT GTT 210
 Asp Cys Thr Glu Glu Lys Lys Thr Cys Asp Glu Tyr Gly Val
 60 65 70
 AGT GGC TTC CCG ACT TTG AAA ATT TTC CGT AAG GGA GAA CTA 252
 Ser Gly Phe Pro Thr Leu Lys Ile Phe Arg Lys Gly Glu Leu
 75 80
 GCA CAG GAT TAT GAT GGT CCG AGA GTA GCA GAA GGT ATT GTG 294
 Ala Gln Asp Tyr Asp Gly Pro Arg Val Ala Glu Gly Ile Val
 85 90 95
 AAA TAT ATG CGT GGA CAG GCA GGT CCA TCA GCT ACA GAA ATT 336
 Lys Tyr Met Arg Gly Gln Ala Gly Pro Ser Ala Thr Glu Ile
 100 105 110
 AAT ACA CAA CAA GAA TTC GAA AAA ATG TTG CAA GCC GAT GAC 378
 Asn Thr Gln Gln Glu Phe Glu Lys Met Leu Gln Ala Asp Asp
 115 120 125
 GTT ACT ATT TGT GGA TTT TTC GAA GAG AAC AGC AAG TTA AAA 420
 Val Thr Ile Cys Gly Phe Phe Glu Glu Asn Ser Lys Leu Lys
 130 135 140
 GAC TCA TTC TTA AAA GTT GCG GAT ACA GAA AGA GAT CGT TTT 462
 Asp Ser Phe Leu Lys Val Ala Asp Thr Glu Arg Asp Arg Phe
 145 150
 AAG TTT GTG TGG ACA TCA AAT AAA CAA ATT CTG GAA TCA AGG 504
 Lys Phe Val Trp Thr Ser Asn Lys Gln Ile Leu Glu Ser Arg
 155 160 165
 GGA TAC AAT GAT GAT ATC GTC GCA TAT CAA CCG AAG AAA TTT 546
 Gly Tyr Asn Asp Asp Ile Val Ala Tyr Gln Pro Lys Lys Phe
 170 175 180
 CAT AAT AAA TTT GAA CCA AAT GAA TTC AAG TAT GAT GGA AAT 588
 His Asn Lys Phe Glu Pro Asn Glu Phe Lys Tyr Asp Gly Asn
 185 190 195
 TAC GAC ACA GAC AAG ATT AAA GAA TTT CTC CTA CAC GAA ACA 630
 Tyr Asp Thr Asp Lys Ile Lys Glu Phe Leu Leu His Glu Thr
 200 205 210
 AAT GGG CTT GTT GGT ATA CGA ACG GCC GAA AAC CGT TAT CAG 672
 Asn Gly Leu Val Gly Ile Arg Thr Ala Glu Asn Arg Tyr Gln
 215 220
 TAT GAT CTA CTT CCG ATG TTC GTC GTC TAT GGC AAG GTT GAC 714
 Tyr Asp Leu Leu Pro Met Phe Val Val Tyr Gly Lys Val Asp
 225 230 235
 TAT GAA TTG GAT CCA AAA GGT TCC AAC TAT TGG CGA AAT CGT 756
 Tyr Glu Leu Asp Pro Lys Gly Ser Asn Tyr Trp Arg Asn Arg
 240 245 250
 GTT CTT ATG GTT GCA AAA GAT TAC AAA AGG AAA GCA AAT TTT 798
 Val Leu Met Val Ala Lys Asp Tyr Lys Arg Lys Ala Asn Phe
 255 260 265
 GCT ATG AGT AAC AAA GAA GAC TTC TCT TTT GAT CTT GAT GAA 840
 Ala Met Ser Asn Lys Glu Asp Phe Ser Phe Asp Leu Asp Glu
 270 275 280
 TTT GGC TTA GCT AAT CGT AAA GAT ACC AAG CCG CTT GTT GCA 882
 Phe Gly Leu Ala Asn Arg Lys Asp Thr Lys Pro Leu Val Ala
 285 290
 GCA CGT AGC AAA AAA GGC AAA TTC TTT ATG AAA GAA GAA TTC 924
 Ala Arg Ser Lys Lys Gly Lys Phe Phe Met Lys Glu Glu Phe
 295 300 305
 AGT TTT AGC GTG GAA AAT TTG AAA AAA TTT GTC GAA GAT GTT 966
 Ser Phe Ser Val Glu Asn Leu Lys Lys Phe Val Glu Asp Val
 310 315 320
 ATT GGT GAT AGA TTA GAA CCG TAT ATG AAG AGC GAA GAA GCA 1008
 Ile Gly Asp Arg Leu Glu Pro Tyr Met Lys Ser Glu Glu Ala
 325 330 335
 CCT GAA GAT CAG GGT GAT GTT AAG GTC GTT GTT GCT AAG ACA 1050
 Pro Glu Asp Gln Gly Asp Val Lys Val Val Val Ala Lys Thr
 340 345 350
 TTC CAA GAA ATG ATC ATG AAT GTG GAA AAG GAT GTT TTA ATC 1092
 Phe Gln Glu Met Ile Met Asn Val Glu Lys Asp Val Leu Ile
 355 360
 GAA TTT TAT GCT CCA TGG TGT GGC CAC TGC AAA GCA CTC GCA 1134
 Glu Phe Tyr Ala Pro Trp Cys Gly His Cys Lys Ala Leu Ala
 365 370 375
 CCG AAA TAT GAT GAA TTA GGC CAG AAA TTA TCC GGT GAA CCA 1176
 Pro Lys Tyr Asp Glu Leu Gly Gln Lys Leu Ser Gly Glu Pro
 380 385 390
 GGT GTT GTT ATT GCA AAA ATG GAC GCA ACA GCG AAT GAT GTC 1218
 Gly Val Val Ile Ala Lys Met Asp Ala Thr Ala Asn Asp Val
 395 400 405
 CCA CCA CCA TTC CAA GTA CAA GGA TTT CCA ACT CTT TAC TGG 1260
 Pro Pro Pro Phe Gln Val Gln Gly Phe Pro Thr Leu Tyr Trp
 410 415 420
 GTA CCG AAG AAT AAA AAA GAC AAA CCA GAG CCA TAC TCT GGT 1302
 Val Pro Lys Asn Lys Lys Asp Lys Pro Glu Pro Tyr Ser Gly
 425 430
 GGT CGA GAA GTG GAT GAT TTT ATT AAA TAC ATC GCG AAG CAT 1344
 Gly Arg Glu Val Asp Asp Phe Ile Lys Tyr Ile Ala Lys His
 435 440 445
 GCA ACG GAA GAA CTG AAG GGA TAC AAG AGA GAT GGA AAA CCG 1386
 Ala Thr Glu Glu Leu Lys Gly Tyr Lys Arg Asp Gly Lys Pro
 450 455 460
 AAG AAG AAG GAA GAA TTG TAA 1407
 Lys Lys Lys Glu Glu Leu
 465
 (2) INFORMATION FOR SEQ ID NO: 33:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 468 amino acids
 (B) TYPE: amino acid
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33
 Met Lys Phe Thr Asp Ala Asp Phe Lys Glu Gly Ile Lys Pro
 1 5 10
 Tyr Asp Val Leu Leu Val Lys Phe Tyr Ala Pro Trp Cys Gly
 15 20 25
 His Cys Lys Lys Ile Ala Pro Glu Phe Glu Lys Ala Ala Thr
 30 35 40
 Lys Leu Leu Gln Asn Asp Pro Pro Ile His Leu Ala Glu Val
 45 50 55
 Asp Cys Thr Glu Glu Lys Lys Thr Cys Asp Glu Tyr Gly Val
 60 65 70
 Ser Gly Phe Pro Thr Leu Lys Ile Phe Arg Lys Gly Glu Leu
 75 80
 Ala Gln Asp Tyr Asp Gly Pro Arg Val Ala Glu Gly Ile Val
 85 90 95
 Lys Tyr Met Arg Gly Gln Ala Gly Pro Ser Ala Thr Glu Ile
 100 105 110
 Asn Thr Gln Gln Glu Phe Glu Lys Met Leu Gln Ala Asp Asp
 115 120 125
 Val Thr Ile Cys Gly Phe Phe Glu Glu Asn Ser Lys Leu Lys
 130 135 140
 Asp Ser Phe Leu Lys Val Ala Asp Thr Glu Arg Asp Arg Phe
 145 150
 Lys Phe Val Trp Thr Ser Asn Lys Gln Ile Leu Glu Ser Arg
 155 160 165
 Gly Tyr Asn Asp Asp Ile Val Ala Tyr Gln Pro Lys Lys Phe
 170 175 180
 His Asn Lys Phe Glu Pro Asn Glu Phe Lys Tyr Asp Gly Asn
 185 190 195
 Tyr Asp Thr Asp Lys Ile Lys Glu Phe Leu Leu His Glu Thr
 200 205 210
 Asn Gly Leu Val Gly Ile Arg Thr Ala Glu Asn Arg Tyr Gln
 215 220
 Tyr Asp Leu Leu Pro Met Phe Val Val Tyr Gly Lys Val Asp
 225 230 235
 Tyr Glu Leu Asp Pro Lys Gly Ser Asn Tyr Trp Arg Asn Arg
 240 245 250
 Val Leu Met Val Ala Lys Asp Tyr Lys Arg Lys Ala Asn Phe
 255 260 265
 Ala Met Ser Asn Lys Glu Asp Phe Ser Phe Asp Leu Asp Glu
 270 275 280
 Phe Gly Leu Ala Asn Arg Lys Asp Thr Lys Pro Leu Val Ala
 285 290
 Ala Arg Ser Lys Lys Gly Lys Phe Phe Met Lys Glu Glu Phe
 295 300 305
 Ser Phe Ser Val Glu Asn Leu Lys Lys Phe Val Glu Asp Val
 310 315 320
 Ile Gly Asp Arg Leu Glu Pro Tyr Met Lys Ser Glu Glu Ala
 325 330 335
 Pro Glu Asp Gln Gly Asp Val Lys Val Val Val Ala Lys Thr
 340 345 350
 Phe Gln Glu Met Ile Met Asn Val Glu Lys Asp Val Leu Ile
 355 360
 Glu Phe Tyr Ala Pro Trp Cys Gly His Cys Lys Ala Leu Ala
 365 370 375
 Pro Lys Tyr Asp Glu Leu Gly Gln Lys Leu Ser Gly Glu Pro
 380 385 390
 Gly Val Val Ile Ala Lys Met Asp Ala Thr Ala Asn Asp Val
 395 400 405
 Pro Pro Pro Phe Gln Val Gln Gly Phe Pro Thr Leu Tyr Trp
 410 415 420
 Val Pro Lys Asn Lys Lys Asp Lys Pro Glu Pro Tyr Ser Gly
 425 430
 Gly Arg Glu Val Asp Asp Phe Ile Lys Tyr Ile Ala Lys His
 435 440 445
 Ala Thr Glu Glu Leu Lys Gly Tyr Lys Arg Asp Gly Lys Pro
 450 455 460
 Lys Lys Lys Glu Glu Leu
 465
 (2) INFORMATION FOR SEQ ID NO: 34:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 1407 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34
 TTACAATTCT TCCTTCTTCT TCGGTTTTCC ATCTCTCTTG TATCCCTTCA 50
 GTTCTTCCGT TGCATGCTTC GCGATGTATT TAATAAAATC ATCCACTTCT 100
 CGACCACCAG AGTATGGCTC TGGTTTGTCT TTTTTATTCT TCGGTACCCA 150
 GTAAAGAGTT GGAAATCCTT GTACTTGGAA TGGTGGTGGG ACATCATTCG 200
 CTGTTGCGTC CATTTTTGCA ATAACAACAC CTGGTTCACC GGATAATTTC 250
 TGGCCTAATT CATCATATTT CGGTGCGAGT GCTTTGCAGT GGCCACACCA 300
 TGGAGCATAA AATTCGATTA AAACATCCTT TTCCACATTC ATGATCATTT 350
 CTTGGAATGT CTTAGCAACA ACGACCTTAA CATCACCCTG ATCTTCAGGT 400
 GCTTCTTCGC TCTTCATATA CGGTTCTAAT CTATCACCAA TAACATCTTC 450
 GACAAATTTT TTCAAATTTT CCACGCTAAA ACTGAATTCT TCTTTCATAA 500
 AGAATTTGCC TTTTTTGCTA CGTGCTGCAA CAAGCGGCTT GGTATCTTTA 550
 CGATTAGCTA AGCCAAATTC ATCAAGATCA AAAGAGAAGT CTTCTTTGTT 600
 ACTCATAGCA AAATTTGCTT TCCTTTTGTA ATCTTTTGCA ACCATAAGAA 650
 CACGATTTCG CCAATAGTTG GAACCTTTTG GATCCAATTC ATAGTCAACC 700
 TTGCCATAGA CGACGAACAT CGGAAGTAGA TCATACTGAT AACGGTTTTC 750
 GGCCGTTCGT ATACCAACAA GCCCATTTGT TTCGTGTAGG AGAAATTCTT 800
 TAATCTTGTC TGTGTCGTAA TTTCCATCAT ACTTGAATTC ATTTGGTTCA 850
 AATTTATTAT GAAATTTCTT CGGTTGATAT GCGACGATAT CATCATTGTA 900
 TCCCCTTGAT TCCAGAATTT GTTTATTTGA TGTCCACACA AACTTAAAAC 950
 GATCTCTTTC TGTATCCGCA ACTTTTAAGA ATGAGTCTTT TAACTTGCTG 1000
 TTCTCTTCGA AAAATCCACA AATAGTAACG TCATCGGCTT GCAACATTTT 1050
 TTCGAATTCT TGTTGTGTAT TAATTTCTGT AGCTGATGGA CCTGCCTGTC 1100
 CACGCATATA TTTCACAATA CCTTCTGCTA CTCTCGGACC ATCATAATCC 1150
 TGTGCTAGTT CTCCCTTACG GAAAATTTTC AAAGTCGGGA AGCCACTAAC 1200
 ACCGTATTCA TCGCAAGTTT TCTTCTCCTC CGTACAGTCA ACCTCTGCTA 1250
 AATGAATAGG CGGATCATTC TGTAAAAGTT TGGTTGCTGC TTTTTCAAAT 1300
 TCTGGTGCTA TCTTTTTGCA GTGTCCGCAC CATGGTGCAT AAAATTTCAC 1350
 AAGTAATACA TCATATGGTT TAATTCCCTC CTTGAAGTCC GCATCTGTAA 1400
 ATTTCAT 1407
 (2) INFORMATION FOR SEQ ID NO: 35:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 440 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (ix) FEATURE:
 (A) NAME/KEY: CDS
 (B) LOCATION: 24..440
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35
 GGTTTAATTA CCCAAGTTTG AGG ATG GCG CAG TTG AGG CTG TTT 44
 Met Ala Gln Leu Arg Leu Phe
 1 5
 AAT CAT GCT TCG GTT TTG AAT TTA TTC TTA TTA CTG GTA TTG 86
 Asn His Ala Ser Val Leu Asn Leu Phe Leu Leu Leu Val Leu
 10 15 20
 CCG GTA GCA AAT GGC GAT GGT GAT GTG ATG AAA TTC ACA GAT 128
 Pro Val Ala Asn Gly Asp Gly Asp Val Met Lys Phe Thr Asp
 25 30 35
 GCT GAT TTT AAG GAA GGA ATC AAA TCA TAT GAT GTA TTA CTT 170
 Ala Asp Phe Lys Glu Gly Ile Lys Ser Tyr Asp Val Leu Leu
 40 45
 GTG AAA TTT TAT GCA CCA TGG TGT GGG CAC TGC AAG AAA CTG 212
 Val Lys Phe Tyr Ala Pro Trp Cys Gly His Cys Lys Lys Leu
 50 55 60
 GCC CCA GAA TTT GAG AAG GCA GCA ACA AAA CTT TTA CAA AAT 254
 Ala Pro Glu Phe Glu Lys Ala Ala Thr Lys Leu Leu Gln Asn
 65 70 75
 GAT CCA CCT ATT CAT TTA GCA GAT GTC GAT TGC ACA GAG GAA 296
 Asp Pro Pro Ile His Leu Ala Asp Val Asp Cys Thr Glu Glu
 80 85 90
 AAG AAA ATT TGC GAT GAA TTC AGT GTT AGT GGT TTT CCG ACT 338
 Lys Lys Ile Cys Asp Glu Phe Ser Val Ser Gly Phe Pro Thr
 95 100 105
 TTA AAA ATT TTC CGT AAG GGT GAA CTG GCT CAG GAT TAT GAT 380
 Leu Lys Ile Phe Arg Lys Gly Glu Leu Ala Gln Asp Tyr Asp
 110 115
 GGC CCA CGA GTT GCA GAA GGT ATT GTT AAA TAT ATG CGT GGA 422
 Gly Pro Arg Val Ala Glu Gly Ile Val Lys Tyr Met Arg Gly
 120 125 130
 CAG GCA GGT CCA TCA GCT 440
 Gln Ala Gly Pro Ser Ala
 135
 (2) INFORMATION FOR SEQ ID NO: 36:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 139 amino acids
 (B) TYPE: amino acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36
 Met Ala Gln Leu Arg Leu Phe Asn His Ala Ser Val Leu Asn
 1 5 10
 Leu Phe Leu Leu Leu Val Leu Pro Val Ala Asn Gly Asp Gly
 15 20 25
 Asp Val Met Lys Phe Thr Asp Ala Asp Phe Lys Glu Gly Ile
 30 35 40
 Lys Ser Tyr Asp Val Leu Leu Val Lys Phe Tyr Ala Pro Trp
 45 50 55
 Cys Gly His Cys Lys Lys Leu Ala Pro Glu Phe Glu Lys Ala
 60 65 70
 Ala Thr Lys Leu Leu Gln Asn Asp Pro Pro Ile His Leu Ala
 75 80
 Asp Val Asp Cys Thr Glu Glu Lys Lys Ile Cys Asp Glu Phe
 85 90 95
 Ser Val Ser Gly Phe Pro Thr Leu Lys Ile Phe Arg Lys Gly
 100 105 110
 Glu Leu Ala Gln Asp Tyr Asp Gly Pro Arg Val Ala Glu Gly
 115 120 125
 Ile Val Lys Tyr Met Arg Gly Gln Ala Gly Pro Ser Ala
 130 135
 (2) INFORMATION FOR SEQ ID NO: 37:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 440 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37
 AGCTGATGGA CCTGCCTGTC CACGCATATA TTTAACAATA CCTTCTGCAA 50
 CTCGTGGGCC ATCATAATCC TGAGCCAGTT CACCCTTACG GAAAATTTTT 100
 AAAGTCGGAA AACCACTAAC ACTGAATTCA TCGCAAATTT TCTTTTCCTC 150
 TGTGCAATCG ACATCTGCTA AATGAATAGG TGGATCATTT TGTAAAAGTT 200
 TTGTTGCTGC CTTCTCAAAT TCTGGGGCCA GTTTCTTGCA GTGCCCACAC 250
 CATGGTGCAT AAAATTTCAC AAGTAATACA TCATATGATT TGATTCCTTC 300
 CTTAAAATCA GCATCTGTGA ATTTCATCAC ATCACCATCG CCATTTGCTA 350
 CCGGCAATAC CAGTAATAAG AATAAATTCA AAACCGAAGC ATGATTAAAC 400
 AGCCTCAACT GCGCCATCCT CAAACTTGGG TAATTAAACC 440
 (2) INFORMATION FOR SEQ ID NO: 38:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 417 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38
 ATGGCGCAGT TGAGGCTGTT TAATCATGCT TCGGTTTTGA ATTTATTCTT 50
 ATTACTGGTA TTGCCGGTAG CAAATGGCGA TGGTGATGTG ATGAAATTCA 100
 CAGATGCTGA TTTTAAGGAA GGAATCAAAT CATATGATGT ATTACTTGTG 150
 AAATTTTATG CACCATGGTG TGGGCACTGC AAGAAACTGG CCCCAGAATT 200
 TGAGAAGGCA GCAACAAAAC TTTTACAAAA TGATCCACCT ATTCATTTAG 250
 CAGATGTCGA TTGCACAGAG GAAAAGAAAA TTTGCGATGA ATTCAGTGTT 300
 AGTGGTTTTC CGACTTTAAA AATTTTCCGT AAGGGTGAAC TGGCTCAGGA 350
 TTATGATGGC CCACGAGTTG CAGAAGGTAT TGTTAAATAT ATGCGTGGAC 400
 AGGCAGGTCC ATCAGCT 417
 (2) INFORMATION FOR SEQ ID NO: 39:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 417 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39
 AGCTGATGGA CCTGCCTGTC CACGCATATA TTTAACAATA CCTTCTGCAA 50
 CTCGTGGGCC ATCATAATCC TGAGCCAGTT CACCCTTACG GAAAATTTTT 100
 AAAGTCGGAA AACCACTAAC ACTGAATTCA TCGCAAATTT TCTTTTCCTC 150
 TGTGCAATCG ACATCTGCTA AATGAATAGG TGGATCATTT TGTAAAAGTT 200
 TTGTTGCTGC CTTCTCAAAT TCTGGGGCCA GTTTCTTGCA GTGCCCACAC 250
 CATGGTGCAT AAAATTTCAC AAGTAATACA TCATATGATT TGATTCCTTC 300
 CTTAAAATCA GCATCTGTGA ATTTCATCAC ATCACCATCG CCATTTGCTA 350
 CCGGCAATAC CAGTAATAAG AATAAATTCA AAACCGAAGC ATGATTAAAC 400
 AGCCTCAACT GCGCCAT 417
 (2) INFORMATION FOR SEQ ID NO: 40:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 537 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (ix) FEATURE:
 (A) NAME/KEY: CDS
 (B) LOCATION: 1..537
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40
 GAA AAC CGT TAT CAG TAT GAT CTG CTC CCA ATG TTT GTT GTG 42
 Glu Asn Arg Tyr Gln Tyr Asp Leu Leu Pro Met Phe Val Val
 1 5 10
 TAC AGC AAG ATT GAC TAT GAA TTG GAT CCA AAA GGG TCC AAT 84
 Tyr Ser Lys Ile Asp Tyr Glu Leu Asp Pro Lys Gly Ser Asn
 15 20 25
 TAT TGG AGA AAT CGT GTT CTT ACA GTT GCA AAG GAT TAC AGA 126
 Tyr Trp Arg Asn Arg Val Leu Thr Val Ala Lys Asp Tyr Arg
 30 35 40
 AGA AAA GCA TAT TTT GCT ATA AGT AAT AAG GAC GAT TTC TCA 168
 Arg Lys Ala Tyr Phe Ala Ile Ser Asn Lys Asp Asp Phe Ser
 45 50 55
 TTT GAC CTT GAT GAA TTT GGC TTA GCT GGT CGT AAA GAT ACT 210
 Phe Asp Leu Asp Glu Phe Gly Leu Ala Gly Arg Lys Asp Thr
 60 65 70
 AAA CCG CTT GTT GCA GCT CGT AGT AAG AAA GGC AAA TTC TTC 252
 Lys Pro Leu Val Ala Ala Arg Ser Lys Lys Gly Lys Phe Phe
 75 80
 ATG AAA GAA GAG TTC AGC GTG GAA AAT TTG AGA AAA TTT GTC 294
 Met Lys Glu Glu Phe Ser Val Glu Asn Leu Arg Lys Phe Val
 85 90 95
 GAA GAC GTT ATA AAT GAT AGA TTA GAA CCA CAT ATG AAA AGC 336
 Glu Asp Val Ile Asn Asp Arg Leu Glu Pro His Met Lys Ser
 100 105 110
 GAG GAA CCA CCG GAA GAA CAG GGC GAT GTT AAG GTT GTT GTT 378
 Glu Glu Pro Pro Glu Glu Gln Gly Asp Val Lys Val Val Val
 115 120 125
 GCT AAA ACA TTC CAA GAG ATG GTT GTT GAT GTG GAA AAG GAT 420
 Ala Lys Thr Phe Gln Glu Met Val Val Asp Val Glu Lys Asp
 130 135 140
 GTC CTG ATC GAA TTC TAT GCT CCA TGG TGT GGA CAT TGC AAG 462
 Val Leu Ile Glu Phe Tyr Ala Pro Trp Cys Gly His Cys Lys
 145 150
 GCA CTA GCA CCT AAA TAT GAT GAA TTA GGC CAG AAA TTA TCC 504
 Ala Leu Ala Pro Lys Tyr Asp Glu Leu Gly Gln Lys Leu Ser
 155 160 165
 GGC GAA CCA GGT GTT GTT ATT GCA AAA ATG GAC 537
 Gly Glu Pro Gly Val Val Ile Ala Lys Met Asp
 170 175
 (2) INFORMATION FOR SEQ ID NO: 41:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 179 amino acids
 (B) TYPE: amino acid
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:41
 Glu Asn Arg Tyr Gln Tyr Asp Leu Leu Pro Met Phe Val Val
 1 5 10
 Tyr Ser Lys Ile Asp Tyr Glu Leu Asp Pro Lys Gly Ser Asn
 15 20 25
 Tyr Trp Arg Asn Arg Val Leu Thr Val Ala Lys Asp Tyr Arg
 30 35 40
 Arg Lys Ala Tyr Phe Ala Ile Ser Asn Lys Asp Asp Phe Ser
 45 50 55
 Phe Asp Leu Asp Glu Phe Gly Leu Ala Gly Arg Lys Asp Thr
 60 65 70
 Lys Pro Leu Val Ala Ala Arg Ser Lys Lys Gly Lys Phe Phe
 75 80
 Met Lys Glu Glu Phe Ser Val Glu Asn Leu Arg Lys Phe Val
 85 90 95
 Glu Asp Val Ile Asn Asp Arg Leu Glu Pro His Met Lys Ser
 100 105 110
 Glu Glu Pro Pro Glu Glu Gln Gly Asp Val Lys Val Val Val
 115 120 125
 Ala Lys Thr Phe Gln Glu Met Val Val Asp Val Glu Lys Asp
 130 135 140
 Val Leu Ile Glu Phe Tyr Ala Pro Trp Cys Gly His Cys Lys
 145 150
 Ala Leu Ala Pro Lys Tyr Asp Glu Leu Gly Gln Lys Leu Ser
 155 160 165
 Gly Glu Pro Gly Val Val Ile Ala Lys Met Asp
 170 175
 (2) INFORMATION FOR SEQ ID NO: 42:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 537 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42
 GTCCATTTTT GCAATAACAA CACCTGGTTC ACCGGATAAT TTCTGGCCTA 50
 ATTCATCATA TTTCGGTGCG AGTGCTTTGC AGTGGCCACA CCATGGAGCA 100
 TAAAATTCGA TTAAAACATC CTTTTCCACA TTCATGATCA TTTCTTGGAA 150
 TGTCTTAGCA ACAACGACCT TAGCATCACC CTGATCTTCA GGTGCTTCTT 200
 CGCTCTTCAT ATACGGTTCT AATCTATCAC CAATAACATC TTCGACAAAT 250
 TTTTCCAAAT TTTCCACGCT GAATTCTTCT TTCATAAAGA ATTTGCCTTT 300
 TTTGCTACGT GCTGCAACAA GCGGCTTGGT ATCTTTACGA TTAGCTAAGC 350
 CAAATTCATC AAGATCAAAA GAGAAGTCTT CTTTGTTACT CATAGCAAAA 400
 TTTGCTTTCC TTTTGTAATC TTTTGCAACC ATAAGAACAC GATTTCGCCA 450
 ATAGTTGGAA CCTTTTGGAT CCAATTCATA GTCAACCTTG CCATACACAA 500
 CAAACATCGG AAGTAGATCA TACTGATAAC GGTTTTC 537
 (2) INFORMATION FOR SEQ ID NO: 43:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 537 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (ix) FEATURE:
 (A) NAME/KEY: CDS
 (B) LOCATION: 1..537
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43
 GAA AAC CGT TAT CAG TAT GAT CTA CTT CCG ATG TTT GTT GTG 42
 Glu Asn Arg Tyr Gln Tyr Asp Leu Leu Pro Met Phe Val Val
 1 5 10
 TAT GGC AAG GTT GAC TAT GAA TTG GAT CCA AAA GGT TCC AAC 84
 Tyr Gly Lys Val Asp Tyr Glu Leu Asp Pro Lys Gly Ser Asn
 15 20 25
 TAT TGG CGA AAT CGT GTT CTT ATG GTT GCA AAA GAT TAC AAA 126
 Tyr Trp Arg Asn Arg Val Leu Met Val Ala Lys Asp Tyr Lys
 30 35 40
 AGG AAA GCA AAT TTT GCT ATG AGT AAC AAA GAA GAC TTC TCT 168
 Arg Lys Ala Asn Phe Ala Met Ser Asn Lys Glu Asp Phe Ser
 45 50 55
 TTT GAT CTT GAT GAA TTT GGC TTA GCT AAT CGT AAA GAT ACC 210
 Phe Asp Leu Asp Glu Phe Gly Leu Ala Asn Arg Lys Asp Thr
 60 65 70
 AAG CCG CTT GTT GCA GCA CGT AGC AAA AAA GGC AAA TTC TTT 252
 Lys Pro Leu Val Ala Ala Arg Ser Lys Lys Gly Lys Phe Phe
 75 80
 ATG AAA GAA GAA TTC AGC GTG GAA AAT TTG GAA AAA TTT GTC 294
 Met Lys Glu Glu Phe Ser Val Glu Asn Leu Glu Lys Phe Val
 85 90 95
 GAA GAT GTT ATT GGT GAT AGA TTA GAA CCG TAT ATG AAG AGC 336
 Glu Asp Val Ile Gly Asp Arg Leu Glu Pro Tyr Met Lys Ser
 100 105 110
 GAA GAA GCA CCT GAA GAT CAG GGT GAT GCT AAG GTC GTT GTT 378
 Glu Glu Ala Pro Glu Asp Gln Gly Asp Ala Lys Val Val Val
 115 120 125
 GCT AAG ACA TTC CAA GAA ATG ATC ATG AAT GTG GAA AAG GAT 420
 Ala Lys Thr Phe Gln Glu Met Ile Met Asn Val Glu Lys Asp
 130 135 140
 GTT TTA ATC GAA TTT TAT GCT CCA TGG TGT GGC CAC TGC AAA 462
 Val Leu Ile Glu Phe Tyr Ala Pro Trp Cys Gly His Cys Lys
 145 150
 GCA CTC GCA CCG AAA TAT GAT GAA TTA GGC CAG AAA TTA TCC 504
 Ala Leu Ala Pro Lys Tyr Asp Glu Leu Gly Gln Lys Leu Ser
 155 160 165
 GGT GAA CCA GGT GTT GTT ATT GCA AAA ATG GAC 537
 Gly Glu Pro Gly Val Val Ile Ala Lys Met Asp
 170 175
 (2) INFORMATION FOR SEQ ID NO: 44:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 179 amino acids
 (B) TYPE: amino acid
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44
 Glu Asn Arg Tyr Gln Tyr Asp Leu Leu Pro Met Phe Val Val
 1 5 10
 Tyr Gly Lys Val Asp Tyr Glu Leu Asp Pro Lys Gly Ser Asn
 15 20 25
 Tyr Trp Arg Asn Arg Val Leu Met Val Ala Lys Asp Tyr Lys
 30 35 40
 Arg Lys Ala Asn Phe Ala Met Ser Asn Lys Glu Asp Phe Ser
 45 50 55
 Phe Asp Leu Asp Glu Phe Gly Leu Ala Asn Arg Lys Asp Thr
 60 65 70
 Lys Pro Leu Val Ala Ala Arg Ser Lys Lys Gly Lys Phe Phe
 75 80
 Met Lys Glu Glu Phe Ser Val Glu Asn Leu Glu Lys Phe Val
 85 90 95
 Glu Asp Val Ile Gly Asp Arg Leu Glu Pro Tyr Met Lys Ser
 100 105 110
 Glu Glu Ala Pro Glu Asp Gln Gly Asp Ala Lys Val Val Val
 115 120 125
 Ala Lys Thr Phe Gln Glu Met Ile Met Asn Val Glu Lys Asp
 130 135 140
 Val Leu Ile Glu Phe Tyr Ala Pro Trp Cys Gly His Cys Lys
 145 150
 Ala Leu Ala Pro Lys Tyr Asp Glu Leu Gly Gln Lys Leu Ser
 155 160 165
 Gly Glu Pro Gly Val Val Ile Ala Lys Met Asp
 170 175
 (2) INFORMATION FOR SEQ ID NO: 45:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 537 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:45
 GTCCATTTTT GCAATAACAA CACCTGGTTC ACCGGATAAT TTCTGGCCTA 50
 ATTCATCATA TTTCGGTGCG AGTGCTTTGC AGTGGCCACA CCATGGAGCA 100
 TAAAATTCGA TTAAAACATC CTTTTCCACA TTCATGATCA TTTCTTGGAA 150
 TGTCTTAGCA ACAACGACCT TAGCATCACC CTGATCTTCA GGTGCTTCTT 200
 CGCTCTTCAT ATACGGTTCT AATCTATCAC CAATAACATC TTCGACAAAT 250
 TTTTCCAAAT TTTCCACGCT GAATTCTTCT TTCATAAAGA ATTTGCCTTT 300
 TTTGCTACGT GCTGCAACAA GCGGCTTGGT ATCTTTACGA TTAGCTAAGC 350
 CAAATTCATC AAGATCAAAA GAGAAGTCTT CTTTGTTACT CATAGCAAAA 400
 TTTGCTTTCC TTTTGTAATC TTTTGCAACC ATAAGAACAC GATTTCGCCA 450
 ATAGTTGGAA CCTTTTGGAT CCAATTCATA GTCAACCTTG CCATACACAA 500
 CAAACATCGG AAGTAGATCA TACTGATAAC GGTTTTC 537
 (2) INFORMATION FOR SEQ ID NO: 46:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 1881 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (ix) FEATURE:
 (A) NAME/KEY: CDS
 (B) LOCATION: 24..1514
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:46
 GGTTTAATTA CCCAAGTTTG AGG ATG ACA CTG GTG AGG TTG TTT 44
 Met Thr Leu Val Arg Leu Phe
 1 5
 GAT GCT TCG ATT TTT AAA TTA TTC TTG TTT CTG ATA TTG CCA 86
 Asp Ala Ser Ile Phe Lys Leu Phe Leu Phe Leu Ile Leu Pro
 10 15 20
 TTA ACG AAT GCC GAT GGC GAT GTG ATG AAA TTT ACA GAT GCG 128
 Leu Thr Asn Ala Asp Gly Asp Val Met Lys Phe Thr Asp Ala
 25 30 35
 GAC TTC AAG GAG GGA ATT AAA CCA TAT GAT GTA TTA CTT GTG 170
 Asp Phe Lys Glu Gly Ile Lys Pro Tyr Asp Val Leu Leu Val
 40 45
 AAA TTT TAT GCA CCA TGG TGC GGA CAC TGC AAA AAG ATA GCA 212
 Lys Phe Tyr Ala Pro Trp Cys Gly His Cys Lys Lys Ile Ala
 50 55 60
 CCA GAA TTT GAA AAA GCA GCA ACC AAA CTT TTA CAG AAT GAT 254
 Pro Glu Phe Glu Lys Ala Ala Thr Lys Leu Leu Gln Asn Asp
 65 70 75
 CCG CCT ATT CAT TTA GCA GAG GTT GAC TGT ACG GAG GAG AAG 296
 Pro Pro Ile His Leu Ala Glu Val Asp Cys Thr Glu Glu Lys
 80 85 90
 AAA ACT TGC GAT GAA TAC GGT GTT AGT GGC TTC CCG ACT TTG 338
 Lys Thr Cys Asp Glu Tyr Gly Val Ser Gly Phe Pro Thr Leu
 95 100 105
 AAA ATT TTC CGT AAG GGA GAA CTA GCA CAG GAT TAT GAT GGT 380
 Lys Ile Phe Arg Lys Gly Glu Leu Ala Gln Asp Tyr Asp Gly
 110 115
 CCG AGA GTA GCA GAA GGT ATT GTG AAA TAT ATG CGT GGA CAG 422
 Pro Arg Val Ala Glu Gly Ile Val Lys Tyr Met Arg Gly Gln
 120 125 130
 GCA GGT CCA TCA GCT ACA GAA ATT AAT ACA CAA CAA GAA TTC 464
 Ala Gly Pro Ser Ala Thr Glu Ile Asn Thr Gln Gln Glu Phe
 135 140 145
 GAA AAA ATG TTG CAA GCC GAT GAC GTT ACT ATT TGT GGA TTT 506
 Glu Lys Met Leu Gln Ala Asp Asp Val Thr Ile Cys Gly Phe
 150 155 160
 TTC GAA GAG AAC AGC AAG TTA AAA GAC TCA TTC TTA AAA GTT 548
 Phe Glu Glu Asn Ser Lys Leu Lys Asp Ser Phe Leu Lys Val
 165 170 175
 GCG GAT ACA GAA AGA GAT CGT TTT AAG TTT GTG TGG ACA TCA 590
 Ala Asp Thr Glu Arg Asp Arg Phe Lys Phe Val Trp Thr Ser
 180 185
 AAT AAA CAA ATT CTG GAA TCA AGG GGA TAC AAT GAT GAT ATC 632
 Asn Lys Gln Ile Leu Glu Ser Arg Gly Tyr Asn Asp Asp Ile
 190 195 200
 GTC GCA TAT CAA CCG AAG AAA TTT CAT AAT AAA TTT GAA CCA 674
 Val Ala Tyr Gln Pro Lys Lys Phe His Asn Lys Phe Glu Pro
 205 210 215
 AAT GAA TTC AAG TAT GAT GGA AAT TAC GAC ACA GAC AAG ATT 716
 Asn Glu Phe Lys Tyr Asp Gly Asn Tyr Asp Thr Asp Lys Ile
 220 225 230
 AAA GAA TTT CTC CTA CAC GAA ACA AAT GGG CTT GTT GGT ATA 758
 Lys Glu Phe Leu Leu His Glu Thr Asn Gly Leu Val Gly Ile
 235 240 245
 CGA ACG GCC GAA AAC CGT TAT CAG TAT GAT CTA CTT CCG ATG 800
 Arg Thr Ala Glu Asn Arg Tyr Gln Tyr Asp Leu Leu Pro Met
 250 255
 TTC GTC GTC TAT GGC AAG GTT GAC TAT GAA TTG GAT CCA AAA 842
 Phe Val Val Tyr Gly Lys Val Asp Tyr Glu Leu Asp Pro Lys
 260 265 270
 GGT TCC AAC TAT TGG CGA AAT CGT GTT CTT ATG GTT GCA AAA 884
 Gly Ser Asn Tyr Trp Arg Asn Arg Val Leu Met Val Ala Lys
 275 280 285
 GAT TAC AAA AGG AAA GCA AAT TTT GCT ATG AGT AAC AAA GAA 926
 Asp Tyr Lys Arg Lys Ala Asn Phe Ala Met Ser Asn Lys Glu
 290 295 300
 GAC TTC TCT TTT GAT CTT GAT GAA TTT GGC TTA GCT AAT CGT 968
 Asp Phe Ser Phe Asp Leu Asp Glu Phe Gly Leu Ala Asn Arg
 305 310 315
 AAA GAT ACC AAG CCG CTT GTT GCA GCA CGT AGC AAA AAA GGC 1010
 Lys Asp Thr Lys Pro Leu Val Ala Ala Arg Ser Lys Lys Gly
 320 325
 AAA TTC TTT ATG AAA GAA GAA TTC AGT TTT AGC GTG GAA AAT 1052
 Lys Phe Phe Met Lys Glu Glu Phe Ser Phe Ser Val Glu Asn
 330 335 340
 TTG AAA AAA TTT GTC GAA GAT GTT ATT GGT GAT AGA TTA GAA 1094
 Leu Lys Lys Phe Val Glu Asp Val Ile Gly Asp Arg Leu Glu
 345 350 355
 CCG TAT ATG AAG AGC GAA GAA GCA CCT GAA GAT CAG GGT GAT 1136
 Pro Tyr Met Lys Ser Glu Glu Ala Pro Glu Asp Gln Gly Asp
 360 365 370
 GTT AAG GTC GTT GTT GCT AAG ACA TTC CAA GAA ATG ATC ATG 1178
 Val Lys Val Val Val Ala Lys Thr Phe Gln Glu Met Ile Met
 375 380 385
 AAT GTG GAA AAG GAT GTT TTA ATC GAA TTT TAT GCT CCA TGG 1220
 Asn Val Glu Lys Asp Val Leu Ile Glu Phe Tyr Ala Pro Trp
 390 395
 TGT GGC CAC TGC AAA GCA CTC GCA CCG AAA TAT GAT GAA TTA 1262
 Cys Gly His Cys Lys Ala Leu Ala Pro Lys Tyr Asp Glu Leu
 400 405 410
 GGC CAG AAA TTA TCC GGT GAA CCA GGT GTT GTT ATT GCA AAA 1304
 Gly Gln Lys Leu Ser Gly Glu Pro Gly Val Val Ile Ala Lys
 415 420 425
 ATG GAC GCA ACA GCG AAT GAT GTC CCA CCA CCA TTC CAA GTA 1346
 Met Asp Ala Thr Ala Asn Asp Val Pro Pro Pro Phe Gln Val
 430 435 440
 CAA GGA TTT CCA ACT CTT TAC TGG GTA CCG AAG AAT AAA AAA 1388
 Gln Gly Phe Pro Thr Leu Tyr Trp Val Pro Lys Asn Lys Lys
 445 450 455
 GAC AAA CCA GAG CCA TAC TCT GGT GGT CGA GAA GTG GAT GAT 1430
 Asp Lys Pro Glu Pro Tyr Ser Gly Gly Arg Glu Val Asp Asp
 460 465
 TTT ATT AAA TAC ATC GCG AAG CAT GCA ACG GAA GAA CTG AAG 1472
 Phe Ile Lys Tyr Ile Ala Lys His Ala Thr Glu Glu Leu Lys
 470 475 480
 GGA TAC AAG AGA GAT GGA AAA CCG AAG AAG AAG GAA GAA TTG 1514
 Gly Tyr Lys Arg Asp Gly Lys Pro Lys Lys Lys Glu Glu Leu
 485 490 495
 TAAAGGGTAA TAATGATGAA TTTTTAATTT GATGTGAACC CAAACAACCT 1564
 CAGTTGCTTA TTGGTGGATA AATATTTAAA TCATTCCACA GAGCTGTGAT 1614
 ATGAATTTTC AAATATGTTT TTTTTTGGTT TATTTTGATA AATTCATATT 1664
 TTAAGTTGTT ATTTTTTAGT GCCTTAGGCT GTTTCATCAG TTGCCTTAGG 1714
 CTATTTTGTC AGTTCGGAAT GTTTATTCCG TTAGCTTAGG CTTTTTTTTG 1764
 TTTACCTTAT GTTACTGTTG TTATTGTATT ACTATTTTGC CCTTGTTTTT 1814
 TAAATTTTAA ATAAATTTTT TTTGGAAAAA AAAAAAAAAA AAAAAAAAAA 1864
 AAAAAAAAAA AAAAAAA 1881
 (2) INFORMATION FOR SEQ ID NO: 47:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 497 amino acids
 (B) TYPE: amino acid
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:47
 Met Thr Leu Val Arg Leu Phe Asp Ala Ser Ile Phe Lys Leu
 1 5 10
 Phe Leu Phe Leu Ile Leu Pro Leu Thr Asn Ala Asp Gly Asp
 15 20 25
 Val Met Lys Phe Thr Asp Ala Asp Phe Lys Glu Gly Ile Lys
 30 35 40
 Pro Tyr Asp Val Leu Leu Val Lys Phe Tyr Ala Pro Trp Cys
 45 50 55
 Gly His Cys Lys Lys Ile Ala Pro Glu Phe Glu Lys Ala Ala
 60 65 70
 Thr Lys Leu Leu Gln Asn Asp Pro Pro Ile His Leu Ala Glu
 75 80
 Val Asp Cys Thr Glu Glu Lys Lys Thr Cys Asp Glu Tyr Gly
 85 90 95
 Val Ser Gly Phe Pro Thr Leu Lys Ile Phe Arg Lys Gly Glu
 100 105 110
 Leu Ala Gln Asp Tyr Asp Gly Pro Arg Val Ala Glu Gly Ile
 115 120 125
 Val Lys Tyr Met Arg Gly Gln Ala Gly Pro Ser Ala Thr Glu
 130 135 140
 Ile Asn Thr Gln Gln Glu Phe Glu Lys Met Leu Gln Ala Asp
 145 150
 Asp Val Thr Ile Cys Gly Phe Phe Glu Glu Asn Ser Lys Leu
 155 160 165
 Lys Asp Ser Phe Leu Lys Val Ala Asp Thr Glu Arg Asp Arg
 170 175 180
 Phe Lys Phe Val Trp Thr Ser Asn Lys Gln Ile Leu Glu Ser
 185 190 195
 Arg Gly Tyr Asn Asp Asp Ile Val Ala Tyr Gln Pro Lys Lys
 200 205 210
 Phe His Asn Lys Phe Glu Pro Asn Glu Phe Lys Tyr Asp Gly
 215 220
 Asn Tyr Asp Thr Asp Lys Ile Lys Glu Phe Leu Leu His Glu
 225 230 235
 Thr Asn Gly Leu Val Gly Ile Arg Thr Ala Glu Asn Arg Tyr
 240 245 250
 Gln Tyr Asp Leu Leu Pro Met Phe Val Val Tyr Gly Lys Val
 255 260 265
 Asp Tyr Glu Leu Asp Pro Lys Gly Ser Asn Tyr Trp Arg Asn
 270 275 280
 Arg Val Leu Met Val Ala Lys Asp Tyr Lys Arg Lys Ala Asn
 285 290
 Phe Ala Met Ser Asn Lys Glu Asp Phe Ser Phe Asp Leu Asp
 295 300 305
 Glu Phe Gly Leu Ala Asn Arg Lys Asp Thr Lys Pro Leu Val
 310 315 320
 Ala Ala Arg Ser Lys Lys Gly Lys Phe Phe Met Lys Glu Glu
 325 330 335
 Phe Ser Phe Ser Val Glu Asn Leu Lys Lys Phe Val Glu Asp
 340 345 350
 Val Ile Gly Asp Arg Leu Glu Pro Tyr Met Lys Ser Glu Glu
 355 360
 Ala Pro Glu Asp Gln Gly Asp Val Lys Val Val Val Ala Lys
 365 370 375
 Thr Phe Gln Glu Met Ile Met Asn Val Glu Lys Asp Val Leu
 380 385 390
 Ile Glu Phe Tyr Ala Pro Trp Cys Gly His Cys Lys Ala Leu
 395 400 405
 Ala Pro Lys Tyr Asp Glu Leu Gly Gln Lys Leu Ser Gly Glu
 410 415 420
 Pro Gly Val Val Ile Ala Lys Met Asp Ala Thr Ala Asn Asp
 425 430
 Val Pro Pro Pro Phe Gln Val Gln Gly Phe Pro Thr Leu Tyr
 435 440 445
 Trp Val Pro Lys Asn Lys Lys Asp Lys Pro Glu Pro Tyr Ser
 450 455 460
 Gly Gly Arg Glu Val Asp Asp Phe Ile Lys Tyr Ile Ala Lys
 465 470 475
 His Ala Thr Glu Glu Leu Lys Gly Tyr Lys Arg Asp Gly Lys
 480 485 490
 Pro Lys Lys Lys Glu Glu Leu
 495
 (2) INFORMATION FOR SEQ ID NO: 48:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 1881 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:48
 TTTTTTTTTT TTTTTTTTTT TTTTTTTTTT TTTTTTTTTT TTCCAAAAAA 50
 AATTTATTTA AAATTTAAAA AACAAGGGCA AAATAGTAAT ACAATAACAA 100
 CAGTAACATA AGGTAAACAA AAAAAAGCCT AAGCTAACGG AATAAACATT 150
 CCGAACTGAC AAAATAGCCT AAGGCAACTG ATGAAACAGC CTAAGGCACT 200
 AAAAAATAAC AACTTAAAAT ATGAATTTAT CAAAATAAAC CAAAAAAAAA 250
 CATATTTGAA AATTCATATC ACAGCTCTGT GGAATGATTT AAATATTTAT 300
 CCACCAATAA GCAACTGAGG TTGTTTGGGT TCACATCAAA TTAAAAATTC 350
 ATCATTATTA CCCTTTACAA TTCTTCCTTC TTCTTCGGTT TTCCATCTCT 400
 CTTGTATCCC TTCAGTTCTT CCGTTGCATG CTTCGCGATG TATTTAATAA 450
 AATCATCCAC TTCTCGACCA CCAGAGTATG GCTCTGGTTT GTCTTTTTTA 500
 TTCTTCGGTA CCCAGTAAAG AGTTGGAAAT CCTTGTACTT GGAATGGTGG 550
 TGGGACATCA TTCGCTGTTG CGTCCATTTT TGCAATAACA ACACCTGGTT 600
 CACCGGATAA TTTCTGGCCT AATTCATCAT ATTTCGGTGC GAGTGCTTTG 650
 CAGTGGCCAC ACCATGGAGC ATAAAATTCG ATTAAAACAT CCTTTTCCAC 700
 ATTCATGATC ATTTCTTGGA ATGTCTTAGC AACAACGACC TTAACATCAC 750
 CCTGATCTTC AGGTGCTTCT TCGCTCTTCA TATACGGTTC TAATCTATCA 800
 CCAATAACAT CTTCGACAAA TTTTTTCAAA TTTTCCACGC TAAAACTGAA 850
 TTCTTCTTTC ATAAAGAATT TGCCTTTTTT GCTACGTGCT GCAACAAGCG 900
 GCTTGGTATC TTTACGATTA GCTAAGCCAA ATTCATCAAG ATCAAAAGAG 950
 AAGTCTTCTT TGTTACTCAT AGCAAAATTT GCTTTCCTTT TGTAATCTTT 1000
 TGCAACCATA AGAACACGAT TTCGCCAATA GTTGGAACCT TTTGGATCCA 1050
 ATTCATAGTC AACCTTGCCA TAGACGACGA ACATCGGAAG TAGATCATAC 1100
 TGATAACGGT TTTCGGCCGT TCGTATACCA ACAAGCCCAT TTGTTTCGTG 1150
 TAGGAGAAAT TCTTTAATCT TGTCTGTGTC GTAATTTCCA TCATACTTGA 1200
 ATTCATTTGG TTCAAATTTA TTATGAAATT TCTTCGGTTG ATATGCGACG 1250
 ATATCATCAT TGTATCCCCT TGATTCCAGA ATTTGTTTAT TTGATGTCCA 1300
 CACAAACTTA AAACGATCTC TTTCTGTATC CGCAACTTTT AAGAATGAGT 1350
 CTTTTAACTT GCTGTTCTCT TCGAAAAATC CACAAATAGT AACGTCATCG 1400
 GCTTGCAACA TTTTTTCGAA TTCTTGTTGT GTATTAATTT CTGTAGCTGA 1450
 TGGACCTGCC TGTCCACGCA TATATTTCAC AATACCTTCT GCTACTCTCG 1500
 GACCATCATA ATCCTGTGCT AGTTCTCCCT TACGGAAAAT TTTCAAAGTC 1550
 GGGAAGCCAC TAACACCGTA TTCATCGCAA GTTTTCTTCT CCTCCGTACA 1600
 GTCAACCTCT GCTAAATGAA TAGGCGGATC ATTCTGTAAA AGTTTGGTTG 1650
 CTGCTTTTTC AAATTCTGGT GCTATCTTTT TGCAGTGTCC GCACCATGGT 1700
 GCATAAAATT TCACAAGTAA TACATCATAT GGTTTAATTC CCTCCTTGAA 1750
 GTCCGCATCT GTAAATTTCA TCACATCGCC ATCGGCATTC GTTAATGGCA 1800
 ATATCAGAAA CAAGAATAAT TTAAAAATCG AAGCATCAAA CAACCTCACC 1850
 AGTGTCATCC TCAAACTTGG GTAATTAAAC C 1881
 (2) INFORMATION FOR SEQ ID NO: 49:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 1494 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49
 ATGACACTGG TGAGGTTGTT TGATGCTTCG ATTTTTAAAT TATTCTTGTT 50
 TCTGATATTG CCATTAACGA ATGCCGATGG CGATGTGATG AAATTTACAG 100
 ATGCGGACTT CAAGGAGGGA ATTAAACCAT ATGATGTATT ACTTGTGAAA 150
 TTTTATGCAC CATGGTGCGG ACACTGCAAA AAGATAGCAC CAGAATTTGA 200
 AAAAGCAGCA ACCAAACTTT TACAGAATGA TCCGCCTATT CATTTAGCAG 250
 AGGTTGACTG TACGGAGGAG AAGAAAACTT GCGATGAATA CGGTGTTAGT 300
 GGCTTCCCGA CTTTGAAAAT TTTCCGTAAG GGAGAACTAG CACAGGATTA 350
 TGATGGTCCG AGAGTAGCAG AAGGTATTGT GAAATATATG CGTGGACAGG 400
 CAGGTCCATC AGCTACAGAA ATTAATACAC AACAAGAATT CGAAAAAATG 450
 TTGCAAGCCG ATGACGTTAC TATTTGTGGA TTTTTCGAAG AGAACAGCAA 500
 GTTAAAAGAC TCATTCTTAA AAGTTGCGGA TACAGAAAGA GATCGTTTTA 550
 AGTTTGTGTG GACATCAAAT AAACAAATTC TGGAATCAAG GGGATACAAT 600
 GATGATATCG TCGCATATCA ACCGAAGAAA TTTCATAATA AATTTGAACC 650
 AAATGAATTC AAGTATGATG GAAATTACGA CACAGACAAG ATTAAAGAAT 700
 TTCTCCTACA CGAAACAAAT GGGCTTGTTG GTATACGAAC GGCCGAAAAC 750
 CGTTATCAGT ATGATCTACT TCCGATGTTC GTCGTCTATG GCAAGGTTGA 800
 CTATGAATTG GATCCAAAAG GTTCCAACTA TTGGCGAAAT CGTGTTCTTA 850
 TGGTTGCAAA AGATTACAAA AGGAAAGCAA ATTTTGCTAT GAGTAACAAA 900
 GAAGACTTCT CTTTTGATCT TGATGAATTT GGCTTAGCTA ATCGTAAAGA 950
 TACCAAGCCG CTTGTTGCAG CACGTAGCAA AAAAGGCAAA TTCTTTATGA 1000
 AAGAAGAATT CAGTTTTAGC GTGGAAAATT TGAAAAAATT TGTCGAAGAT 1050
 GTTATTGGTG ATAGATTAGA ACCGTATATG AAGAGCGAAG AAGCACCTGA 1100
 AGATCAGGGT GATGTTAAGG TCGTTGTTGC TAAGACATTC CAAGAAATGA 1150
 TCATGAATGT GGAAAAGGAT GTTTTAATCG AATTTTATGC TCCATGGTGT 1200
 GGCCACTGCA AAGCACTCGC ACCGAAATAT GATGAATTAG GCCAGAAATT 1250
 ATCCGGTGAA CCAGGTGTTG TTATTGCAAA AATGGACGCA ACAGCGAATG 1300
 ATGTCCCACC ACCATTCCAA GTACAAGGAT TTCCAACTCT TTACTGGGTA 1350
 CCGAAGAATA AAAAAGACAA ACCAGAGCCA TACTCTGGTG GTCGAGAAGT 1400
 GGATGATTTT ATTAAATACA TCGCGAAGCA TGCAACGGAA GAACTGAAGG 1450
 GATACAAGAG AGATGGAAAA CCGAAGAAGA AGGAAGAATT GTAA 1494
 (2) INFORMATION FOR SEQ ID NO: 50:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 1494 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:50
 TTACAATTCT TCCTTCTTCT TCGGTTTTCC ATCTCTCTTG TATCCCTTCA 50
 GTTCTTCCGT TGCATGCTTC GCGATGTATT TAATAAAATC ATCCACTTCT 100
 CGACCACCAG AGTATGGCTC TGGTTTGTCT TTTTTATTCT TCGGTACCCA 150
 GTAAAGAGTT GGAAATCCTT GTACTTGGAA TGGTGGTGGG ACATCATTCG 200
 CTGTTGCGTC CATTTTTGCA ATAACAACAC CTGGTTCACC GGATAATTTC 250
 TGGCCTAATT CATCATATTT CGGTGCGAGT GCTTTGCAGT GGCCACACCA 300
 TGGAGCATAA AATTCGATTA AAACATCCTT TTCCACATTC ATGATCATTT 350
 CTTGGAATGT CTTAGCAACA ACGACCTTAA CATCACCCTG ATCTTCAGGT 400
 GCTTCTTCGC TCTTCATATA CGGTTCTAAT CTATCACCAA TAACATCTTC 450
 GACAAATTTT TTCAAATTTT CCACGCTAAA ACTGAATTCT TCTTTCATAA 500
 AGAATTTGCC TTTTTTGCTA CGTGCTGCAA CAAGCGGCTT GGTATCTTTA 550
 CGATTAGCTA AGCCAAATTC ATCAAGATCA AAAGAGAAGT CTTCTTTGTT 600
 ACTCATAGCA AAATTTGCTT TCCTTTTGTA ATCTTTTGCA ACCATAAGAA 650
 CACGATTTCG CCAATAGTTG GAACCTTTTG GATCCAATTC ATAGTCAACC 700
 TTGCCATAGA CGACGAACAT CGGAAGTAGA TCATACTGAT AACGGTTTTC 750
 GGCCGTTCGT ATACCAACAA GCCCATTTGT TTCGTGTAGG AGAAATTCTT 800
 TAATCTTGTC TGTGTCGTAA TTTCCATCAT ACTTGAATTC ATTTGGTTCA 850
 AATTTATTAT GAAATTTCTT CGGTTGATAT GCGACGATAT CATCATTGTA 900
 TCCCCTTGAT TCCAGAATTT GTTTATTTGA TGTCCACACA AACTTAAAAC 950
 GATCTCTTTC TGTATCCGCA ACTTTTAAGA ATGAGTCTTT TAACTTGCTG 1000
 TTCTCTTCGA AAAATCCACA AATAGTAACG TCATCGGCTT GCAACATTTT 1050
 TTCGAATTCT TGTTGTGTAT TAATTTCTGT AGCTGATGGA CCTGCCTGTC 1100
 CACGCATATA TTTCACAATA CCTTCTGCTA CTCTCGGACC ATCATAATCC 1150
 TGTGCTAGTT CTCCCTTACG GAAAATTTTC AAAGTCGGGA AGCCACTAAC 1200
 ACCGTATTCA TCGCAAGTTT TCTTCTCCTC CGTACAGTCA ACCTCTGCTA 1250
 AATGAATAGG CGGATCATTC TGTAAAAGTT TGGTTGCTGC TTTTTCAAAT 1300
 TCTGGTGCTA TCTTTTTGCA GTGTCCGCAC CATGGTGCAT AAAATTTCAC 1350
 AAGTAATACA TCATATGGTT TAATTCCCTC CTTGAAGTCC GCATCTGTAA 1400
 ATTTCATCAC ATCGCCATCG GCATTCGTTA ATGGCAATAT CAGAAACAAG 1450
 AATAATTTAA AAATCGAAGC ATCAAACAAC CTCACCAGTG TCAT 1494
 (2) INFORMATION FOR SEQ ID NO: 51:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 45 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (ix) FEATURE:
 (A) NAME/KEY: CDS
 (B) LOCATION: 1..45
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:51
 GAT GGC GAT GTG ATG AAA TTT ACA GAT GCG GAC TTC AAG GAG 42
 Asp Gly Asp Val Met Lys Phe Thr Asp Ala Asp Phe Lys Glu
 1 5 10
 GGA 45
 Gly
 15
 (2) INFORMATION FOR SEQ ID NO: 52:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 15 amino acids
 (B) TYPE: amino acid
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:52
 Asp Gly Asp Val Met Lys Phe Thr Asp Ala Asp Phe Lys Glu
 1 5 10
 Gly
 15
 (2) INFORMATION FOR SEQ ID NO: 53:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 45 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:53
 TCCCTCCTTG AAGTCCGCAT CTGTAAATTT CATCACATCG CCATC 45
 (2) INFORMATION FOR SEQ ID NO: 54:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 1416 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (ix) FEATURE:
 (A) NAME/KEY: CDS
 (B) LOCATION: 1..1416
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:54
 GAT GGC GAT GTG ATG AAA TTT ACA GAT GCG GAC TTC AAG GAG 42
 Asp Gly Asp Val Met Lys Phe Thr Asp Ala Asp Phe Lys Glu
 1 5 10
 GGA ATT AAA CCA TAT GAT GTA TTA CTT GTG AAA TTT TAT GCA 84
 Gly Ile Lys Pro Tyr Asp Val Leu Leu Val Lys Phe Tyr Ala
 15 20 25
 CCA TGG TGC GGA CAC TGC AAA AAG ATA GCA CCA GAA TTT GAA 126
 Pro Trp Cys Gly His Cys Lys Lys Ile Ala Pro Glu Phe Glu
 30 35 40
 AAA GCA GCA ACC AAA CTT TTA CAG AAT GAT CCG CCT ATT CAT 168
 Lys Ala Ala Thr Lys Leu Leu Gln Asn Asp Pro Pro Ile His
 45 50 55
 TTA GCA GAG GTT GAC TGT ACG GAG GAG AAG AAA ACT TGC GAT 210
 Leu Ala Glu Val Asp Cys Thr Glu Glu Lys Lys Thr Cys Asp
 60 65 70
 GAA TAC GGT GTT AGT GGC TTC CCG ACT TTG AAA ATT TTC CGT 252
 Glu Tyr Gly Val Ser Gly Phe Pro Thr Leu Lys Ile Phe Arg
 75 80
 AAG GGA GAA CTA GCA CAG GAT TAT GAT GGT CCG AGA GTA GCA 294
 Lys Gly Glu Leu Ala Gln Asp Tyr Asp Gly Pro Arg Val Ala
 85 90 95
 GAA GGT ATT GTG AAA TAT ATG CGT GGA CAG GCA GGT CCA TCA 336
 Glu Gly Ile Val Lys Tyr Met Arg Gly Gln Ala Gly Pro Ser
 100 105 110
 GCT ACA GAA ATT AAT ACA CAA CAA GAA TTC GAA AAA ATG TTG 378
 Ala Thr Glu Ile Asn Thr Gln Gln Glu Phe Glu Lys Met Leu
 115 120 125
 CAA GCC GAT GAC GTT ACT ATT TGT GGA TTT TTC GAA GAG AAC 420
 Gln Ala Asp Asp Val Thr Ile Cys Gly Phe Phe Glu Glu Asn
 130 135 140
 AGC AAG TTA AAA GAC TCA TTC TTA AAA GTT GCG GAT ACA GAA 462
 Ser Lys Leu Lys Asp Ser Phe Leu Lys Val Ala Asp Thr Glu
 145 150
 AGA GAT CGT TTT AAG TTT GTG TGG ACA TCA AAT AAA CAA ATT 504
 Arg Asp Arg Phe Lys Phe Val Trp Thr Ser Asn Lys Gln Ile
 155 160 165
 CTG GAA TCA AGG GGA TAC AAT GAT GAT ATC GTC GCA TAT CAA 546
 Leu Glu Ser Arg Gly Tyr Asn Asp Asp Ile Val Ala Tyr Gln
 170 175 180
 CCG AAG AAA TTT CAT AAT AAA TTT GAA CCA AAT GAA TTC AAG 588
 Pro Lys Lys Phe His Asn Lys Phe Glu Pro Asn Glu Phe Lys
 185 190 195
 TAT GAT GGA AAT TAC GAC ACA GAC AAG ATT AAA GAA TTT CTC 630
 Tyr Asp Gly Asn Tyr Asp Thr Asp Lys Ile Lys Glu Phe Leu
 200 205 210
 CTA CAC GAA ACA AAT GGG CTT GTT GGT ATA CGA ACG GCC GAA 672
 Leu His Glu Thr Asn Gly Leu Val Gly Ile Arg Thr Ala Glu
 215 220
 AAC CGT TAT CAG TAT GAT CTA CTT CCG ATG TTC GTC GTC TAT 714
 Asn Arg Tyr Gln Tyr Asp Leu Leu Pro Met Phe Val Val Tyr
 225 230 235
 GGC AAG GTT GAC TAT GAA TTG GAT CCA AAA GGT TCC AAC TAT 756
 Gly Lys Val Asp Tyr Glu Leu Asp Pro Lys Gly Ser Asn Tyr
 240 245 250
 TGG CGA AAT CGT GTT CTT ATG GTT GCA AAA GAT TAC AAA AGG 798
 Trp Arg Asn Arg Val Leu Met Val Ala Lys Asp Tyr Lys Arg
 255 260 265
 AAA GCA AAT TTT GCT ATG AGT AAC AAA GAA GAC TTC TCT TTT 840
 Lys Ala Asn Phe Ala Met Ser Asn Lys Glu Asp Phe Ser Phe
 270 275 280
 GAT CTT GAT GAA TTT GGC TTA GCT AAT CGT AAA GAT ACC AAG 882
 Asp Leu Asp Glu Phe Gly Leu Ala Asn Arg Lys Asp Thr Lys
 285 290
 CCG CTT GTT GCA GCA CGT AGC AAA AAA GGC AAA TTC TTT ATG 924
 Pro Leu Val Ala Ala Arg Ser Lys Lys Gly Lys Phe Phe Met
 295 300 305
 AAA GAA GAA TTC AGT TTT AGC GTG GAA AAT TTG AAA AAA TTT 966
 Lys Glu Glu Phe Ser Phe Ser Val Glu Asn Leu Lys Lys Phe
 310 315 320
 GTC GAA GAT GTT ATT GGT GAT AGA TTA GAA CCG TAT ATG AAG 1008
 Val Glu Asp Val Ile Gly Asp Arg Leu Glu Pro Tyr Met Lys
 325 330 335
 AGC GAA GAA GCA CCT GAA GAT CAG GGT GAT GTT AAG GTC GTT 1050
 Ser Glu Glu Ala Pro Glu Asp Gln Gly Asp Val Lys Val Val
 340 345 350
 GTT GCT AAG ACA TTC CAA GAA ATG ATC ATG AAT GTG GAA AAG 1092
 Val Ala Lys Thr Phe Gln Glu Met Ile Met Asn Val Glu Lys
 355 360
 GAT GTT TTA ATC GAA TTT TAT GCT CCA TGG TGT GGC CAC TGC 1134
 Asp Val Leu Ile Glu Phe Tyr Ala Pro Trp Cys Gly His Cys
 365 370 375
 AAA GCA CTC GCA CCG AAA TAT GAT GAA TTA GGC CAG AAA TTA 1176
 Lys Ala Leu Ala Pro Lys Tyr Asp Glu Leu Gly Gln Lys Leu
 380 385 390
 TCC GGT GAA CCA GGT GTT GTT ATT GCA AAA ATG GAC GCA ACA 1218
 Ser Gly Glu Pro Gly Val Val Ile Ala Lys Met Asp Ala Thr
 395 400 405
 GCG AAT GAT GTC CCA CCA CCA TTC CAA GTA CAA GGA TTT CCA 1260
 Ala Asn Asp Val Pro Pro Pro Phe Gln Val Gln Gly Phe Pro
 410 415 420
 ACT CTT TAC TGG GTA CCG AAG AAT AAA AAA GAC AAA CCA GAG 1302
 Thr Leu Tyr Trp Val Pro Lys Asn Lys Lys Asp Lys Pro Glu
 425 430
 CCA TAC TCT GGT GGT CGA GAA GTG GAT GAT TTT ATT AAA TAC 1344
 Pro Tyr Ser Gly Gly Arg Glu Val Asp Asp Phe Ile Lys Tyr
 435 440 445
 ATC GCG AAG CAT GCA ACG GAA GAA CTG AAG GGA TAC AAG AGA 1386
 Ile Ala Lys His Ala Thr Glu Glu Leu Lys Gly Tyr Lys Arg
 450 455 460
 GAT GGA AAA CCG AAG AAG AAG GAA GAA TTG 1416
 Asp Gly Lys Pro Lys Lys Lys Glu Glu Leu
 465 470
 (2) INFORMATION FOR SEQ ID NO: 55:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 472 amino acids
 (B) TYPE: amino acid
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:55
 Asp Gly Asp Val Met Lys Phe Thr Asp Ala Asp Phe Lys Glu
 1 5 10
 Gly Ile Lys Pro Tyr Asp Val Leu Leu Val Lys Phe Tyr Ala
 15 20 25
 Pro Trp Cys Gly His Cys Lys Lys Ile Ala Pro Glu Phe Glu
 30 35 40
 Lys Ala Ala Thr Lys Leu Leu Gln Asn Asp Pro Pro Ile His
 45 50 55
 Leu Ala Glu Val Asp Cys Thr Glu Glu Lys Lys Thr Cys Asp
 60 65 70
 Glu Tyr Gly Val Ser Gly Phe Pro Thr Leu Lys Ile Phe Arg
 75 80
 Lys Gly Glu Leu Ala Gln Asp Tyr Asp Gly Pro Arg Val Ala
 85 90 95
 Glu Gly Ile Val Lys Tyr Met Arg Gly Gln Ala Gly Pro Ser
 100 105 110
 Ala Thr Glu Ile Asn Thr Gln Gln Glu Phe Glu Lys Met Leu
 115 120 125
 Gln Ala Asp Asp Val Thr Ile Cys Gly Phe Phe Glu Glu Asn
 130 135 140
 Ser Lys Leu Lys Asp Ser Phe Leu Lys Val Ala Asp Thr Glu
 145 150
 Arg Asp Arg Phe Lys Phe Val Trp Thr Ser Asn Lys Gln Ile
 155 160 165
 Leu Glu Ser Arg Gly Tyr Asn Asp Asp Ile Val Ala Tyr Gln
 170 175 180
 Pro Lys Lys Phe His Asn Lys Phe Glu Pro Asn Glu Phe Lys
 185 190 195
 Tyr Asp Gly Asn Tyr Asp Thr Asp Lys Ile Lys Glu Phe Leu
 200 205 210
 Leu His Glu Thr Asn Gly Leu Val Gly Ile Arg Thr Ala Glu
 215 220
 Asn Arg Tyr Gln Tyr Asp Leu Leu Pro Met Phe Val Val Tyr
 225 230 235
 Gly Lys Val Asp Tyr Glu Leu Asp Pro Lys Gly Ser Asn Tyr
 240 245 250
 Trp Arg Asn Arg Val Leu Met Val Ala Lys Asp Tyr Lys Arg
 255 260 265
 Lys Ala Asn Phe Ala Met Ser Asn Lys Glu Asp Phe Ser Phe
 270 275 280
 Asp Leu Asp Glu Phe Gly Leu Ala Asn Arg Lys Asp Thr Lys
 285 290
 Pro Leu Val Ala Ala Arg Ser Lys Lys Gly Lys Phe Phe Met
 295 300 305
 Lys Glu Glu Phe Ser Phe Ser Val Glu Asn Leu Lys Lys Phe
 310 315 320
 Val Glu Asp Val Ile Gly Asp Arg Leu Glu Pro Tyr Met Lys
 325 330 335
 Ser Glu Glu Ala Pro Glu Asp Gln Gly Asp Val Lys Val Val
 340 345 350
 Val Ala Lys Thr Phe Gln Glu Met Ile Met Asn Val Glu Lys
 355 360
 Asp Val Leu Ile Glu Phe Tyr Ala Pro Trp Cys Gly His Cys
 365 370 375
 Lys Ala Leu Ala Pro Lys Tyr Asp Glu Leu Gly Gln Lys Leu
 380 385 390
 Ser Gly Glu Pro Gly Val Val Ile Ala Lys Met Asp Ala Thr
 395 400 405
 Ala Asn Asp Val Pro Pro Pro Phe Gln Val Gln Gly Phe Pro
 410 415 420
 Thr Leu Tyr Trp Val Pro Lys Asn Lys Lys Asp Lys Pro Glu
 425 430
 Pro Tyr Ser Gly Gly Arg Glu Val Asp Asp Phe Ile Lys Tyr
 435 440 445
 Ile Ala Lys His Ala Thr Glu Glu Leu Lys Gly Tyr Lys Arg
 450 455 460
 Asp Gly Lys Pro Lys Lys Lys Glu Glu Leu
 465 470
 (2) INFORMATION FOR SEQ ID NO: 56:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 1419 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:56
 TTACAATTCT TCCTTCTTCT TCGGTTTTCC ATCTCTCTTG TATCCCTTCA 50
 GTTCTTCCGT TGCATGCTTC GCGATGTATT TAATAAAATC ATCCACTTCT 100
 CGACCACCAG AGTATGGCTC TGGTTTGTCT TTTTTATTCT TCGGTACCCA 150
 GTAAAGAGTT GGAAATCCTT GTACTTGGAA TGGTGGTGGG ACATCATTCG 200
 CTGTTGCGTC CATTTTTGCA ATAACAACAC CTGGTTCACC GGATAATTTC 250
 TGGCCTAATT CATCATATTT CGGTGCGAGT GCTTTGCAGT GGCCACACCA 300
 TGGAGCATAA AATTCGATTA AAACATCCTT TTCCACATTC ATGATCATTT 350
 CTTGGAATGT CTTAGCAACA ACGACCTTAA CATCACCCTG ATCTTCAGGT 400
 GCTTCTTCGC TCTTCATATA CGGTTCTAAT CTATCACCAA TAACATCTTC 450
 GACAAATTTT TTCAAATTTT CCACGCTAAA ACTGAATTCT TCTTTCATAA 500
 AGAATTTGCC TTTTTTGCTA CGTGCTGCAA CAAGCGGCTT GGTATCTTTA 550
 CGATTAGCTA AGCCAAATTC ATCAAGATCA AAAGAGAAGT CTTCTTTGTT 600
 ACTCATAGCA AAATTTGCTT TCCTTTTGTA ATCTTTTGCA ACCATAAGAA 650
 CACGATTTCG CCAATAGTTG GAACCTTTTG GATCCAATTC ATAGTCAACC 700
 TTGCCATAGA CGACGAACAT CGGAAGTAGA TCATACTGAT AACGGTTTTC 750
 GGCCGTTCGT ATACCAACAA GCCCATTTGT TTCGTGTAGG AGAAATTCTT 800
 TAATCTTGTC TGTGTCGTAA TTTCCATCAT ACTTGAATTC ATTTGGTTCA 850
 AATTTATTAT GAAATTTCTT CGGTTGATAT GCGACGATAT CATCATTGTA 900
 TCCCCTTGAT TCCAGAATTT GTTTATTTGA TGTCCACACA AACTTAAAAC 950
 GATCTCTTTC TGTATCCGCA ACTTTTAAGA ATGAGTCTTT TAACTTGCTG 1000
 TTCTCTTCGA AAAATCCACA AATAGTAACG TCATCGGCTT GCAACATTTT 1050
 TTCGAATTCT TGTTGTGTAT TAATTTCTGT AGCTGATGGA CCTGCCTGTC 1100
 CACGCATATA TTTCACAATA CCTTCTGCTA CTCTCGGACC ATCATAATCC 1150
 TGTGCTAGTT CTCCCTTACG GAAAATTTTC AAAGTCGGGA AGCCACTAAC 1200
 ACCGTATTCA TCGCAAGTTT TCTTCTCCTC CGTACAGTCA ACCTCTGCTA 1250
 AATGAATAGG CGGATCATTC TGTAAAAGTT TGGTTGCTGC TTTTTCAAAT 1300
 TCTGGTGCTA TCTTTTTGCA GTGTCCGCAC CATGGTGCAT AAAATTTCAC 1350
 AAGTAATACA TCATATGGTT TAATTCCCTC CTTGAAGTCC GCATCTGTAA 1400
 ATTTCATCAC ATCGCCATC 1419
 (2) INFORMATION FOR SEQ ID NO: 57:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 339 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (ix) FEATURE:
 (A) NAME/KEY: CDS
 (B) LOCATION: 1..339
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:57
 GAT GGT GAT GTG ATG AAA TTC ACA GAT GCT GAT TTT AAG GAA 42
 Asp Gly Asp Val Met Lys Phe Thr Asp Ala Asp Phe Lys Glu
 1 5 10
 GGA ATC AAA TCA TAT GAT GTA TTA CTT GTG AAA TTT TAT GCA 84
 Gly Ile Lys Ser Tyr Asp Val Leu Leu Val Lys Phe Tyr Ala
 15 20 25
 CCA TGG TGT GGG CAC TGC AAG AAA CTG GCC CCA GAA TTT GAG 126
 Pro Trp Cys Gly His Cys Lys Lys Leu Ala Pro Glu Phe Glu
 30 35 40
 AAG GCA GCA ACA AAA CTT TTA CAA AAT GAT CCA CCT ATT CAT 168
 Lys Ala Ala Thr Lys Leu Leu Gln Asn Asp Pro Pro Ile His
 45 50 55
 TTA GCA GAT GTC GAT TGC ACA GAG GAA AAG AAA ATT TGC GAT 210
 Leu Ala Asp Val Asp Cys Thr Glu Glu Lys Lys Ile Cys Asp
 60 65 70
 GAA TTC AGT GTT AGT GGT TTT CCG ACT TTA AAA ATT TTC CGT 252
 Glu Phe Ser Val Ser Gly Phe Pro Thr Leu Lys Ile Phe Arg
 75 80
 AAG GGT GAA CTG GCT CAG GAT TAT GAT GGC CCA CGA GTT GCA 294
 Lys Gly Glu Leu Ala Gln Asp Tyr Asp Gly Pro Arg Val Ala
 85 90 95
 GAA GGT ATT GTT AAA TAT ATG CGT GGA CAG GCA GGT CCA TCA 336
 Glu Gly Ile Val Lys Tyr Met Arg Gly Gln Ala Gly Pro Ser
 100 105 110
 GCT 339
 Ala
 (2) INFORMATION FOR SEQ ID NO: 58:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 113 amino acids
 (B) TYPE: amino acid
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: protein
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:58
 Asp Gly Asp Val Met Lys Phe Thr Asp Ala Asp Phe Lys Glu
 1 5 10
 Gly Ile Lys Ser Tyr Asp Val Leu Leu Val Lys Phe Tyr Ala
 15 20 25
 Pro Trp Cys Gly His Cys Lys Lys Leu Ala Pro Glu Phe Glu
 30 35 40
 Lys Ala Ala Thr Lys Leu Leu Gln Asn Asp Pro Pro Ile His
 45 50 55
 Leu Ala Asp Val Asp Cys Thr Glu Glu Lys Lys Ile Cys Asp
 60 65 70
 Glu Phe Ser Val Ser Gly Phe Pro Thr Leu Lys Ile Phe Arg
 75 80
 Lys Gly Glu Leu Ala Gln Asp Tyr Asp Gly Pro Arg Val Ala
 85 90 95
 Glu Gly Ile Val Lys Tyr Met Arg Gly Gln Ala Gly Pro Ser
 100 105 110
 Ala
 (2) INFORMATION FOR SEQ ID NO: 59:
 (i) SEQUENCE CHARACTERISTICS:
 (A) LENGTH: 339 nucleotides
 (B) TYPE: nucleic acid
 (C) STRANDEDNESS: single
 (D) TOPOLOGY: linear
 (ii) MOLECULE TYPE: cDNA
 (vi) ORIGINAL SOURCE:
 (A) ORGANISM: not provided
 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:59
 AGCTGATGGA CCTGCCTGTC CACGCATATA TTTAACAATA CCTTCTGCAA 50
 CTCGTGGGCC ATCATAATCC TGAGCCAGTT CACCCTTACG GAAAATTTTT 100
 AAAGTCGGAA AACCACTAAC ACTGAATTCA TCGCAAATTT TCTTTTCCTC 150
 TGTGCAATCG ACATCTGCTA AATGAATAGG TGGATCATTT TGTAAAAGTT 200
 TTGTTGCTGC CTTCTCAAAT TCTGGGGCCA GTTTCTTGCA GTGCCCACAC 250
 CATGGTGCAT AAAATTTCAC AAGTAATACA TCATATGATT TGATTCCTTC 300
 CTTAAAATCA GCATCTGTGA ATTTCATCAC ATCACCATC 339