Reviewed, UniProtKB/Swiss-Prot Q969F8 (KISSR_HUMAN)

Names and origin

Protein names

Recommended name:
    KiSS-1 receptor
      Short name=KiSS-1R
Alternative name(s):
    Kisspeptins receptor
    Metastin receptor
    G-protein coupled receptor 54
    Hypogonadotropin-1
      Short name=hOT7T175

Gene names

Name:	KISS1R
Synonyms:	AXOR12, GPR54, OT7T175

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	398 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Receptor for metastin (kisspeptin-54 or kp-54), a C-terminally amidated peptide of KiSS1. KiSS1 is a metastasis suppressor protein that suppresses metastases in malignant melanomas and in some breast carcinomas without affecting tumorigenicity. The metastasis suppressor properties may be mediated in part by cell cycle arrest and induction of apoptosis in malignant cells. The receptor is essential for normal gonadotropin-released hormone physiology and for puberty. The hypothalamic KiSS1/KISS1R system is a pivotal factor in central regulation of the gonadotropic axis at puberty and in adulthood. The receptor is also probably involved in the regulation and fine-tuning of trophoblast invasion generated by the trophoblast itself. Analysis of the transduction pathways activated by the receptor identifies coupling to phospholipase C and intracellular calcium release through pertussis toxin-insensitive G(q) proteins. Ref.4 Ref.10 Ref.14
Subcellular location	Cell membrane; Multi-pass membrane protein.
Tissue specificity	Most highly expressed in the pancreas, placenta and spinal cord, with lower-level of expression in peripheral blood leukocytes, kidney, lung, fetal liver, stomach, small intestine, testes, spleen, thymus, adrenal glands and lymph nodes. In the adult brain, expressed in the superior frontal gyrus, putamen, caudate nucleus, cingulate gyrus, nucleus accumbens, hippocampus, pons and amygdala, as well as the hypothalamus and pituitary. Expression levels are higher in early (7-9 weeks) than term placentas. Expression levels were increased in both early placentas and molar pregnancies and were reduced in choriocarcinoma cells. Expressed at higher levels in first trimester trophoblasts than at term of gestation. Also found in the extravillous trophoblast suggesting endocrine/paracrine activation mechanism. Ref.4 Ref.14 Ref.1 Ref.2 Ref.3 Ref.9
Induction	Expressed at higher levels in first trimester trophoblasts than at term of gestation.
Involvement in disease	Defects in KISS1R are a cause of idiopathic hypogonadotropic hypogonadism (IHH) [MIM:146110]. IHH is defined as a deficiency of the pituitary secretion of follicle-stimulating hormone and luteinizing hormone, which results in the impairment of pubertal maturation and of reproductive function. Ref.5 Ref.11 Ref.16 Ref.17 Defects in KISS1R are a cause of central precocious puberty [MIM:176400]. Precocious puberty is defined as the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. Central precocious puberty refers to a gonadotropin-dependent type which results from premature activation of the hypothalamic-pituitary-gonadal axis. Ref.18
Sequence similarities	Belongs to the G-protein coupled receptor 1 family.

Ontologies

Keywords
Cellular component	Cell membrane Membrane
Coding sequence diversity	Polymorphism
Disease	Disease mutation Hypogonadotropic hypogonadism
Domain	Transmembrane
Molecular function	G-protein coupled receptor Receptor Transducer
PTM	Disulfide bond Glycoprotein
Gene Ontology (GO)
Biological process	G-protein coupled receptor protein signaling pathway Ref.3 Non-traceable author statement. Source: UniProtKB behavior Ref.3 Non-traceable author statement. Source: UniProtKB
Cellular component	integral to membrane Ref.3 Inferred from direct assay. Source: UniProtKB plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	neuropeptide receptor activity Ref.3 Inferred from direct assay. Source: UniProtKB protein binding Ref.3 Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 398	398	KiSS-1 receptor		PRO_0000069695
Regions
	Topological domain	1 – 46	46	Extracellular Potential
	Transmembrane	47 – 67	21	1 Potential
	Topological domain	68 – 78	11	Cytoplasmic Potential
	Transmembrane	79 – 101	23	2 Potential
	Topological domain	102 – 120	19	Extracellular Potential
	Transmembrane	121 – 138	18	3 Potential
	Topological domain	139 – 157	19	Cytoplasmic Potential
	Transmembrane	158 – 178	21	4 Potential
	Topological domain	179 – 202	24	Extracellular Potential
	Transmembrane	203 – 223	21	5 Potential
	Topological domain	224 – 263	40	Cytoplasmic Potential
	Transmembrane	264 – 284	21	6 Potential
	Topological domain	285 – 305	21	Extracellular Potential
	Transmembrane	306 – 328	23	7 Potential
	Topological domain	329 – 398	70	Cytoplasmic Potential
Amino acid modifications
	Glycosylation	10	1	N-linked (GlcNAc...) Potential
	Glycosylation	18	1	N-linked (GlcNAc...) Potential
	Glycosylation	28	1	N-linked (GlcNAc...) Potential
	Disulfide bond	115 ↔ 191		By similarity
Natural variations
	Natural variant	102	1	L → P in IHH; absence of inositol phosphate accumulation under kisspeptin challenge; normal affinity for kisspeptin. Ref.17		VAR_043906
	Natural variant	148	1	L → S in IHH; 65% reduction of inositol phosphate production. dbSNP rs28939719. Ref.5		VAR_021392
	Natural variant	223	1	C → R in IHH; exhibit profoundly impaired signaling. Ref.16		VAR_021393
	Natural variant	297	1	R → L in IHH; mild reduction in ligand-stimulated activity across the ligand dose range. Ref.16		VAR_021394
	Natural variant	364	1	L → H: dbSNP rs350132. Ref.4 Ref.1 Ref.2 Ref.5 Ref.16		VAR_021395
	Natural variant	386	1	R → P in central precocious puberty; reduced rate of decline in inositol phosphate accumulation after kisspeptin stimulation; prolonged phosphorylation of ERK. Ref.18		VAR_043907

Sequences

	Sequence		Length	Mass (Da)
	Q969F8-1 [UniParc]. Last modified February 6, 2007. Version 2. Checksum: ECAE2208848F5B06	FASTA	398	42,586
	10 20 30 40 50 60 MHTVATSGPN ASWGAPANAS GCPGCGANAS DGPVPSPRAV DAWLVPLFFA ALMLLGLVGN 70 80 90 100 110 120 SLVIYVICRH KPMRTVTNFY IANLAATDVT FLLCCVPFTA LLYPLPGWVL GDFMCKFVNY 130 140 150 160 170 180 IQQVSVQATC ATLTAMSVDR WYVTVFPLRA LHRRTPRLAL AVSLSIWVGS AAVSAPVLAL 190 200 210 220 230 240 HRLSPGPRAY CSEAFPSRAL ERAFALYNLL ALYLLPLLAT CACYAAMLRH LGRVAVRPAP 250 260 270 280 290 300 ADSALQGQVL AERAGAVRAK VSRLVAAVVL LFAACWGPIQ LFLVLQALGP AGSWHPRSYA 310 320 330 340 350 360 AYALKTWAHC MSYSNSALNP LLYAFLGSHF RQAFRRVCPC APRRPRRPRR PGPSDPAAPH 370 380 390 AELLRLGSHP APARAQKPGS SGLAARGLCV LGEDNAPL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor." Ohtaki T., Shintani Y., Honda S., Matsumoto H., Hori A., Kanehashi K., Terao Y., Kumano S., Takatsu Y., Masuda Y., Ishibashi Y., Watanabe T., Asada M., Yamada T., Suenaga M., Kitada C., Usuki S., Kurokawa T. , Onda H., Nishimura O., Fujino M. Nature 411:613-617(2001) [PubMed: 11385580] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT HIS-364, TISSUE SPECIFICITY.
[2]	"FMRFamide-related neuropeptides are agonists of the orphan G-protein-coupled receptor GPR54." Clements M.K., McDonald T.P., Wang R., Xie G., O'Dowd B.F., George S.R., Austin C.P., Liu Q. Biochem. Biophys. Res. Commun. 284:1189-1193(2001) [PubMed: 11414709] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT HIS-364, TISSUE SPECIFICITY.
[3]	"AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1." Muir A.I., Chamberlain L., Elshourbagy N.A., Michalovich D., Moore D.J., Calamari A., Szekeres P.G., Sarau H.M., Chambers J.K., Murdock P., Steplewski K., Shabon U., Miller J.E., Middleton S.E., Darker J.G., Larminie C.G.C., Wilson S., Bergsma D.J. , Emson P., Faull R., Philpott K.L., Harrison D.C. J. Biol. Chem. 276:28969-28975(2001) [PubMed: 11387329] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY. Tissue: Brain.
[4]	"The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54." Kotani M., Detheux M., Vandenbogaerde A., Communi D., Vanderwinden J.-M., Le Poul E., Brezillon S., Tyldesley R., Suarez-Huerta N., Vandeput F., Blanpain C., Schiffmann S.N., Vassart G., Parmentier M. J. Biol. Chem. 276:34631-34636(2001) [PubMed: 11457843] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT HIS-364, POSSIBLE FUNCTION, TISSUE SPECIFICITY. Tissue: Hypothalamus.
[5]	"The GPR54 gene as a regulator of puberty." Seminara S.B., Messager S., Chatzidaki E.E., Thresher R.R., Acierno J.S. Jr., Shagoury J.K., Bo-Abbas Y., Kuohung W., Schwinof K.M., Hendrick A.G., Zahn D., Dixon J., Kaiser U.B., Slaugenhaupt S.A., Gusella J.F., O'Rahilly S., Carlton M.B.L., Crowley W.F. Jr., Aparicio S.A.J.R., Colledge W.H. N. Engl. J. Med. 349:1614-1627(2003) [PubMed: 14573733] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT IHH SER-148, VARIANT HIS-364.
[6]	"The DNA sequence and biology of human chromosome 19." Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., Carrano A.V. , Caoile C., Chan Y.M., Christensen M., Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., Rubin E.M., Lucas S.M. Nature 428:529-535(2004) [PubMed: 15057824] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"GPR54 and puberty." Colledge W.H. Trends Endocrinol. Metab. 15:448-453(2004) [PubMed: 15519892] [Abstract] Cited for: REVIEW.
[8]	"Metastin suppresses the motility and growth of CHO cells transfected with its receptor." Hori A., Honda S., Asada M., Ohtaki T., Oda K., Watanabe T., Shintani Y., Yamada T., Suenaga M., Kitada C., Onda H., Kurokawa T., Nishimura O., Fujino M. Biochem. Biophys. Res. Commun. 286:958-963(2001) [PubMed: 11527393] [Abstract] Cited for: INVOLVEMENT IN CELL MOBILITY AND GROWTH INHIBITION.
[9]	"Transcriptional expression of genes involved in cell invasion and migration by normal and tumoral trophoblast cells." Janneau J.-L., Maldonado-Estrada J., Tachdjian G., Miran I., Motte N., Saulnier P., Sabourin J.-C., Cote J.-F., Simon B., Frydman R., Chaouat G., Bellet D. J. Clin. Endocrinol. Metab. 87:5336-5339(2002) [PubMed: 12414911] [Abstract] Cited for: TISSUE SPECIFICITY, POSSIBLE INVOLVEMENT IN INVASION/MIGRATION OF TROPHOBLAST CELLS.
[10]	"Metastin receptor is overexpressed in papillary thyroid cancer and activates MAP kinase in thyroid cancer cells." Ringel M.D., Hardy E., Bernet V.J., Burch H.B., Schuppert F., Burman K.D., Saji M. J. Clin. Endocrinol. Metab. 87:2399-2399(2002) [PubMed: 11994395] [Abstract] Cited for: ROLE IN THYROID CANCER.
[11]	"Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54." de Roux N., Genin E., Carel J.-C., Matsuda F., Chaussain J.-L., Milgrom E. Proc. Natl. Acad. Sci. U.S.A. 100:10972-10976(2003) [PubMed: 12944565] [Abstract] Cited for: INVOLVEMENT IN IHH.
[12]	"Quantitative reverse transcriptase polymerase chain reaction analysis for KiSS-1 and orphan G-protein-coupled receptor (hOT7T175) gene expression in hepatocellular carcinoma." Ikeguchi M., Hirooka Y., Kaibara N. J. Cancer Res. Clin. Oncol. 129:531-535(2003) [PubMed: 12898236] [Abstract] Cited for: POSSIBLE INVOLVEMENT IN HEPATOCELLULAR CARCINOMA.
[13]	"Clinical significance of the loss of KiSS-1 and orphan G-protein-coupled receptor (hOT7T175) gene expression in esophageal squamous cell carcinoma." Ikeguchi M., Yamaguchi K., Kaibara N. Clin. Cancer Res. 10:1379-1383(2004) [PubMed: 14977840] [Abstract] Cited for: POSSIBLE INVOLVEMENT IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA.
[14]	"Kisspeptin-10, a KiSS-1/metastin-derived decapeptide, is a physiological invasion inhibitor of primary human trophoblasts." Bilban M., Ghaffari-Tabrizi N., Hintermann E., Bauer S., Molzer S., Zoratti C., Malli R., Sharabi A., Hiden U., Graier W., Knoefler M., Andreae F., Wagner O., Quaranta V., Desoye G. J. Cell Sci. 117:1319-1328(2004) [PubMed: 15020672] [Abstract] Cited for: TISSUE SPECIFICITY, ROLE IN THROPHOBLAST MIGRATION AND INVASION.
[15]	"Activation of GPR54 promotes cell cycle arrest and apoptosis of human tumor cells through a specific transcriptional program not shared by other G(q)-coupled receptors." Becker J.A.J., Mirjolet J.-F., Bernard J., Burgeon E., Simons M.-J., Vassart G., Parmentier M., Libert F. Biochem. Biophys. Res. Commun. 326:677-686(2005) [PubMed: 15596153] [Abstract] Cited for: CHARACTERIZATION OF METASTASIS SUPPRESSOR PROPERTIES.
[16]	"Two novel missense mutations in G protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism." Semple R.K., Achermann J.C., Ellery J., Farooqi I.S., Karet F.E., Stanhope R.G., O'rahilly S., Aparicio S.A. J. Clin. Endocrinol. Metab. 90:1849-1855(2005) [PubMed: 15598687] [Abstract] Cited for: VARIANTS IHH ARG-223 AND LEU-297, VARIANT HIS-364, CHARACTERIZATION OF VARIANTS IHH ARG-223 AND LEU-297.
[17]	"Neuroendocrine phenotype analysis in five patients with isolated hypogonadotropic hypogonadism due to a L102P inactivating mutation of GPR54." Tenenbaum-Rakover Y., Commenges-Ducos M., Iovane A., Aumas C., Admoni O., de Roux N. J. Clin. Endocrinol. Metab. 92:1137-1144(2007) [PubMed: 17164310] [Abstract] Cited for: VARIANT IHH PRO-102.
[18]	"A GPR54-activating mutation in a patient with central precocious puberty." Teles M.G., Bianco S.D.C., Brito V.N., Trarbach E.B., Kuohung W., Xu S., Seminara S.B., Mendonca B.B., Kaiser U.B., Latronico A.C. N. Engl. J. Med. 358:709-715(2008) [PubMed: 18272894] [Abstract] Cited for: VARIANT CENTRAL PRECOCIOUS PUBERTY PRO-386, CHARACTERIZATION OF VARIANT CENTRAL PRECOCIOUS PUBERTY PRO-386.
+	Additional computationally mapped references.

Web resources

Protein Spotlight

Tintin's blight - Issue 58 of May 2005

GeneReviews

Cross-references

Sequence databases
EMBLGenBankDDBJ	AB051065 mRNA. Translation: BAB55446.1. AF343725 mRNA. Translation: AAK83235.1. AJ309020 mRNA. Translation: CAC40817.1. AY029541 mRNA. Translation: AAK33126.1. AY253981 mRNA. Translation: AAP82929.1. AY253982 mRNA. Translation: AAP82930.1. AC005379 Genomic DNA. No translation available.
IPI	IPI00099988.
RefSeq	NP_115940.2.
UniGene	Hs.208229
3D structure databases
ModBase	Search...
Protein family/group databases
GPCRDB	Search...
Proteomic databases
PRIDE	Q969F8.
Genome annotation databases
Ensembl	ENSG00000116014. Homo sapiens. [Contig view]
GeneID	84634.
KEGG	hsa:84634.
Organism-specific databases
GeneCards	GC19P000870.
HGNC	HGNC:4510. KISS1R.
MIM	146110. phenotype. 176400. phenotype. 604161. gene.
Orphanet	432. Hypogonadism, hypogonadotropic, congenital, normosmic.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	Q969F8.
HOVERGEN	Q969F8.
OMA	Q969F8. VIFVICR.
Gene expression databases
ArrayExpress	Q969F8.
Bgee	Q969F8.
CleanEx	HS_KISS1R.
GermOnline	ENSG00000116014. Homo sapiens.
Family and domain databases
InterPro	IPR000276. 7TM_GPCR_Rhodpsn. IPR017452. GPCR_Rhodpsn_supfam. IPR008103. KiSS_1_rcpt. [Graphical view]
PANTHER	PTHR19264:SF173. KiSS_1_rcpt. 1 hit.
Pfam	PF00001. 7tm_1. 1 hit. [Graphical view]
PRINTS	PR00237. GPCRRHODOPSN. PR01728. KISS1RECEPTR.
PROSITE	PS00237. G_PROTEIN_RECEP_F1_1. False negative. PS50262. G_PROTEIN_RECEP_F1_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	74561.
SOURCE	Search...

Entry information

Entry name

KISSR_HUMAN

Accession

Primary (citable) accession number: Q969F8
Secondary accession number(s): Q96QG0

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 1, 2005
Last sequence update:	February 6, 2007
Last modified:	June 16, 2009
This is version 63 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)