Nucleic acids encoding the G-protein coupled receptor HNFDS78

Details Nucleic acids encoding the G-protein coupled receptor HNFDS78 Nucleic acids encoding the G-protein coupled receptor HNFDS78

1996-07-22

2001-09-11

Kunz, Gary L. (Department: 1647)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Recombinant dna technique included in method of making a...

C435S325000, C435S320100, C435S252300, C536S023100, C536S023500

Reexamination Certificate

active

06287801

ABSTRACT:

This invention relates, in part, to newly identified polynucleotides and polypeptides; variants and derivatives of the polynucleotides and polypeptides; processes for making the polynucleotides and the polypeptides, and their variants and derivatives; agonists and antagonists of the polypeptides; and uses of the polynucleotides, polypeptides, variants, derivatives, agonists and antagonists. In particular, in these and in other regards, the invention relates to polynucleotides and polypeptides of human G-protein coupled receptor, hereinafter referred to as “G-Protein Coupled Receptor HNFDS78”.
BACKGROUND OF THE INVENTION
This invention relates to newly identified polynucleotides, polypeptides encoded by such polynucleotides, the use of such polynucleotides and polypeptides, as well as the production of such polynucleotides and polypeptides. More particularly, the polypeptides of the present invention are human 7-transmembrane receptors (G-protein coupled receptors). The invention also relates to inhibiting the action of such polypeptides.
It is well established that many medically significant biological processes are mediated by proteins participating in signal transduction pathways that involve G-proteins and/or second messengers, e.g., cAMP (Lefkowitz,
Nature
, 351:353-354 (1991)). Herein these proteins are referred to as proteins participating in pathways with G-proteins or PPG proteins. Some examples of these proteins include the GPC receptors, such as those for adrenergic agents and dopamine (Kobilka, et al.,
PNAS
, 84:46-50 (1987); Kobilka, et al.,
Science
, 238:650-656 (1987); Bunzow, et al.,
Nature
, 336:783-787 (1988)), G-proteins themselves, effector proteins, e.g., phospholipase C, adenyl cyclase, and phosphodiesterase, and actuator proteins, e.g., protein kinase A and protein kinase C (Simon, et al.,
Science
, 252:802-8 (1991)).
For example, in one form of signal transduction, the effect of hormone binding is activation of an enzyme, adenylate cyclase, inside the cell. Enzyme activation by hormones is dependent on the presence of the nucleotide GTP, and GTP also influences hormone binding. A G-protein connects the hormone receptors to adenylate cyclase. G-protein was shown to exchange GTP for bound GDP when activated by hormone receptors. The GTP-carrying form then binds to an activated adenylate cyclase. Hydrolysis of GTP to GDP, catalyzed by the G-protein itself, returns the G-protein to its basal, inactive form. Thus, the G-protein serves a dual role, as an intermediate that relays the signal from receptor to effector, and as a clock that controls the duration of the signal.
The membrane protein gene superfamily of G-protein coupled receptors has been characterized as having seven putative transmembrane domains. The domains are believed to represent transmembrane &agr;-helices connected by extracellular or cytoplasmic loops. G-protein coupled receptors include a wide range of biologically active receptors, such as hormone, viral, growth factor and neuroreceptors.
G-protein coupled receptors have been characterized as including these seven conserved hydrophobic stretches of about 20 to 30 amino acids, connecting at least eight divergent hydrophilic loops. The G-protein family of coupled receptors includes dopamine receptors which bind to neuroleptic drugs used for treating psychotic and neurological disorders. Other examples of members of this family include calcitonin, adrenergic, endothelin, cAMP, adenosine, muscarinic, acetylcholine, serotonin, histamine, thrombin, kinin, follicle stimulating hormone, opsins, endothelial differentiation gene-1 receptor, rhodopsins, odorant, cytomegalovirus receptors, etc.
Most G-protein coupled receptors have single conserved cysteine residues in each of the first two extracellular loops which form disulfide bonds that are believed to stabilize functional protein structure. The 7 transmembrane regions are designated as TM1, TM2, TM3, TM4, TM5, TM6, and TM7. TM3 has been implicated in signal transduction.
Phosphorylation and lipidation (palmitylation or farnesylation) of cysteine residues can influence signal transduction of some G-protein coupled receptors. Most G-protein coupled receptors contain potential phosphorylation sites within the third cytoplasmic loop and/or the carboxy terminus. For several G-protein coupled receptors, such as the &bgr;-adrenoreceptor, phosphorylation by protein kinase A and/or specific receptor kinases mediates receptor desensitization.
For some receptors, the ligand binding sites of G-protein coupled receptors are believed to comprise a hydrophilic socket formed by several G-protein coupled receptors transmembrane domains, which socket is surrounded by hydrophobic residues of the G-protein coupled receptors. The hydrophilic side of each G-protein coupled receptor transmembrane helix is postulated to face inward and form the polar ligand binding site. TM3 has been implicated in several G-protein coupled receptors as having a ligand binding site, such as including the TM3 aspartate residue. Additionally, TM5 serines, a TM6 asparagine and TM6 or TM7 phenylalanines or tyrosines are also implicated in ligand binding.
G-protein coupled receptors can be intracellularly coupled by heterotrimeric G-proteins to various intracellular enzymes, ion channels and transporters (see, Johnson et al.,
Endoc. Rev
., 10:317-331 (1989)). Different G-protein &agr;-subunits preferentially stimulate particular effectors to modulate various biological functions in a cell. Phosphorylation of cytoplasmic residues of G-protein coupled receptors have been identified as an important mechanism for the regulation of G-protein coupling of some G-protein coupled receptors. G-protein coupled receptors are found in numerous sites within a mammalian host.
Clearly, there is a need for factors that are receptors for chemokines and their roles in dysfunction and disease. There is a need, therefore, for identification and characterization of such factors that are chemokine receptors, and which can play a role in preventing, ameliorating or correcting dysfunctions or diseases.
The polypeptides of the present invention have conserved 7 transmembrane domain residues, and have amino acid sequence homology to known chemokine receptors, such as, for example, CC CKR1 (Ben-Baruch, et al.,
J. Biol. Chem
. 270:22123 1995), CC CKR3 (Combadiere, C.,
P.M.J. Biol. Chem
. 270:16491 (1995)), CC CKR4 (Power, et al.,
J. Biol. Chem
. 270:19495 (1995)) and CC CKR5 (Deng, et al.,
Nature
381:20 (1996); Dragic, et al.,
Nature
381:20 (1996)).
SUMMARY OF THE INVENTION
Toward these ends, and others, it is an object of the present invention to provide polypeptides, inter alia, that have been identified as novel G-Protein Coupled Receptor HNFDS78 by homology between the amino acid sequence set out in FIG.
1
and known amino acid sequences of other proteins, such as, for example, CC CKR1, CC CKR3, CC CKR4 and CC CKR5.
It is a further object of the invention, moreover, to provide polynucleotides that encode G-Protein Coupled Receptor HNFDS78, particularly polynucleotides that encode the polypeptide herein designated G-Protein Coupled Receptor HNFDS78.
In a particularly preferred embodiment of this aspect of the invention, the polynucleotide comprises the region encoding human G-Protein Coupled Receptor HNFDS78 in the sequence set out in FIG.
1
.
In accordance with this aspect of the present invention there is provided an isolated nucleic acid molecule encoding a mature polypeptide expressed by the human cDNA contained in ATCC Deposit No. 98099.
In accordance with this aspect of the invention there are provided isolated nucleic acid molecules encoding human G-Protein Coupled Receptor HNFDS78, including mRNAs, cDNAs, genomic DNAs and, in further embodiments of this aspect of the invention, biologically, diagnostically, clinically or therapeutically useful variants, analogs or derivatives thereof, or fragments thereof, including fragments of the variants, analogs and derivatives.
Among the particularly preferred embodiments of this aspect of the invention

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