ID MC4R_HUMAN Reviewed; 332 AA. AC P32245; B2RAC3; Q16317; Q3MIJ6; DT 01-OCT-1993, integrated into UniProtKB/Swiss-Prot. DT 25-OCT-2004, sequence version 2. DT 11-NOV-2015, entry version 164. DE RecName: Full=Melanocortin receptor 4; DE Short=MC4-R; GN Name=MC4R; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ILE-103. RX PubMed=8392067; RA Gantz I., Miwa H., Konda Y., Shimoto Y., Tashiro T., Waston S.J., RA Delvalle J.; RT "Molecular cloning, expression, and gene localization of a fourth RT melanocortin receptor."; RL J. Biol. Chem. 268:15174-15179(1993). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ILE-103. RX PubMed=7854347; DOI=10.1210/mend.8.10.7854347; RA Mountjoy K.G., Mortrud M.T., Low M.J., Simerly R.B., Cone R.D.; RT "Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine RT and autonomic control circuits in the brain."; RL Mol. Endocrinol. 8:1298-1308(1994). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Kopatz S.A., Aronstam R.S., Sharma S.V.; RT "cDNA clones of human proteins involved in signal transduction RT sequenced by the Guthrie cDNA resource center (www.cdna.org)."; RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Subthalamic nucleus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP INTERACTION WITH MRAP AND MRAP2. RX PubMed=19329486; DOI=10.1073/pnas.0809918106; RA Chan L.F., Webb T.R., Chung T.T., Meimaridou E., Cooray S.N., RA Guasti L., Chapple J.P., Egertova M., Elphick M.R., Cheetham M.E., RA Metherell L.A., Clark A.J.; RT "MRAP and MRAP2 are bidirectional regulators of the melanocortin RT receptor family."; RL Proc. Natl. Acad. Sci. U.S.A. 106:6146-6151(2009). RN [8] RP INTERACTION WITH MGRN1. RX PubMed=19737927; DOI=10.1074/jbc.M109.028100; RA Perez-Oliva A.B., Olivares C., Jimenez-Cervantes C., RA Garcia-Borron J.C.; RT "Mahogunin ring finger-1 (MGRN1) E3 ubiquitin ligase inhibits RT signaling from melanocortin receptor by competition with Galphas."; RL J. Biol. Chem. 284:31714-31725(2009). RN [9] RP INTERCHAIN DISULFIDE BOND, AND SUBUNIT. RX PubMed=23088915; DOI=10.1016/j.bbamem.2012.10.011; RA Chapman K.L., Findlay J.B.; RT "The melanocortin 4 receptor: oligomer formation, interaction sites RT and functional significance."; RL Biochim. Biophys. Acta 1828:535-542(2013). RN [10] RP VARIANTS OBESITY ARG-30; VAL-37; LEU-78; TRP-165; SER-252 AND THR-317, RP AND VARIANTS MET-112 AND LEU-251. RX PubMed=10199800; DOI=10.1210/jc.84.4.1483; RA Hinney A., Schmidt A., Nottebom K., Heibult O., Becker I., Ziegler A., RA Gerber G., Sina M., Gorg T., Mayer H., Siegfried W., Fichter M., RA Remschmidt H., Hebebrand J.; RT "Several mutations in the melanocortin-4 receptor gene including a RT nonsense and a frameshift mutation associated with dominantly RT inherited obesity in humans."; RL J. Clin. Endocrinol. Metab. 84:1483-1486(1999). RN [11] RP VARIANT OBESITY SER-274. RX PubMed=11443223; DOI=10.1210/jcem.86.7.7809; RA Mergen M., Mergen H., Ozata M., Oner R., Oner C.; RT "A novel melanocortin 4 receptor (MC4R) gene mutation associated with RT morbid obesity."; RL J. Clin. Endocrinol. Metab. 86:3448-3448(2001). RN [12] RP VARIANTS OBESITY MET-50; CYS-58; SER-102 AND VAL-170, AND VARIANTS RP ILE-103 AND LEU-251. RX PubMed=11487744; DOI=10.1067/mpd.2001.116284; RA Dubern B., Clement K., Pelloux V., Froguel P., Girardet J.-P., RA Guy-Grand B., Tounian P.; RT "Mutational analysis of melanocortin-4 receptor, agouti-related RT protein, and alpha-melanocyte-stimulating hormone genes in severely RT obese children."; RL J. Pediatr. 139:204-209(2001). RN [13] RP VARIANTS OBESITY SER-62; ASP-97; PRO-106; LYS-125; GLN-165; THR-175; RP ILE-253; TYR-271 AND SER-316, AND CHARACTERIZATION OF VARIANTS OBESITY RP SER-62; ASP-97; PRO-106; LYS-125; GLN-165; THR-175; ILE-253; TYR-271 RP AND SER-316. RX PubMed=12588803; DOI=10.1093/hmg/ddg057; RA Yeo G.S.H., Lank E.J., Farooqi I.S., Keogh J., Challis B.G., RA O'Rahilly S.; RT "Mutations in the human melanocortin-4 receptor gene associated with RT severe familial obesity disrupts receptor function through multiple RT molecular mechanisms."; RL Hum. Mol. Genet. 12:561-574(2003). RN [14] RP VARIANT OBESITY 88-VAL--LEU-92 DEL, AND CHARACTERIZATION OF VARIANT RP OBESITY 88-VAL--LEU-92 DEL. RX PubMed=14671178; DOI=10.1210/jc.2003-030903; RA Donohoue P.A., Tao Y.-X., Collins M., Yeo G.S.H., O'Rahilly S., RA Segaloff D.L.; RT "Deletion of codons 88-92 of the melanocortin-4 receptor gene: a novel RT deleterious mutation in an obese female."; RL J. Clin. Endocrinol. Metab. 88:5841-5845(2003). RN [15] RP VARIANTS OBESITY ALA-11; SER-62; ASP-97; LYS-125; GLN-165; THR-175; RP TYR-271; ARG-271 AND SER-316, VARIANTS ILE-103; MET-112 AND LEU-251, RP CHARACTERIZATION OF VARIANTS OBESITY ALA-11; SER-62; ASP-97; LYS-125; RP GLN-165; THR-175; TYR-271 AND SER-316, CHARACTERIZATION OF VARIANTS RP ILE-103; MET-112 AND LEU-251, AND FUNCTION. RX PubMed=12646665; DOI=10.1056/NEJMoa022050; RA Farooqi I.S., Keogh J.M., Yeo G.S.H., Lank E.J., Cheetham T., RA O'Rahilly S.; RT "Clinical spectrum of obesity and mutations in the melanocortin 4 RT receptor gene."; RL N. Engl. J. Med. 348:1085-1095(2003). RN [16] RP VARIANT OBESITY LEU-127, VARIANTS ILE-103; MET-112; THR-226 AND RP LEU-251, CHARACTERIZATION OF VARIANT OBESITY LEU-127, AND RP CHARACTERIZATION OF VARIANTS MET-112 AND THR-226. RX PubMed=14764818; DOI=10.1210/jc.2003-031182; RA Valli-Jaakola K., Lipsanen-Nyman M., Oksanen L., Hollenberg A.N., RA Kontula K., Bjoerbaek C., Schalin-Jaentti C.; RT "Identification and characterization of melanocortin-4 receptor gene RT mutations in morbidly obese Finnish children and adults."; RL J. Clin. Endocrinol. Metab. 89:940-945(2004). RN [17] RP VARIANTS OBESITY TYR-36; THR-102; GLN-165; THR-175; ASP-181; VAL-219 RP AND PHE-325, VARIANTS ILE-103; MET-112 AND LEU-251, AND RP CHARACTERIZATION OF VARIANTS OBESITY TYR-36; THR-102; GLN-165; RP ASP-181; VAL-219 AND PHE-325. RX PubMed=15486053; DOI=10.1210/jc.2004-0497; RA Larsen L.H., Echwald S.M., Soerensen T.I.A., Andersen T., Wulff B.S., RA Pedersen O.; RT "Prevalence of mutations and functional analyses of melanocortin 4 RT receptor variants identified among 750 men with juvenile-onset RT obesity."; RL J. Clin. Endocrinol. Metab. 90:219-224(2005). CC -!- FUNCTION: Receptor specific to the heptapeptide core common to CC adrenocorticotropic hormone and alpha-, beta-, and gamma-MSH. CC Plays a central role in energy homeostasis and somatic growth. CC This receptor is mediated by G proteins that stimulate adenylate CC cyclase (cAMP). {ECO:0000269|PubMed:12646665}. CC -!- SUBUNIT: Interacts with ATRNL1 (By similarity). Homodimer; CC disulfide-linked, also forms higher order oligomers. Interacts CC with MGRN1, but does not undergo MGRN1-mediated ubiquitination; CC this interaction competes with GNAS-binding and thus inhibits CC agonist-induced cAMP production. Interacts with MRAP and MRAP2; CC these associated factors increase ligand-sensitivity and CC generation of cAMP. {ECO:0000250, ECO:0000269|PubMed:19329486, CC ECO:0000269|PubMed:19737927, ECO:0000269|PubMed:23088915}. CC -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein. CC -!- TISSUE SPECIFICITY: Brain, placental, and gut tissues. CC -!- DISEASE: Obesity (OBESITY) [MIM:601665]: A condition characterized CC by an increase of body weight beyond the limitation of skeletal CC and physical requirements, as the result of excessive accumulation CC of body fat. {ECO:0000269|PubMed:10199800, CC ECO:0000269|PubMed:11443223, ECO:0000269|PubMed:11487744, CC ECO:0000269|PubMed:12588803, ECO:0000269|PubMed:12646665, CC ECO:0000269|PubMed:14671178, ECO:0000269|PubMed:14764818, CC ECO:0000269|PubMed:15486053}. Note=The disease is caused by CC mutations affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family. CC {ECO:0000255|PROSITE-ProRule:PRU00521}. CC -!- WEB RESOURCE: Name=Wikipedia; Note=Melanocortin receptor entry; CC URL="https://en.wikipedia.org/wiki/Melanocortin_receptor"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; L08603; AAA35791.1; -; Genomic_DNA. DR EMBL; S77415; AAB33341.1; -; Genomic_DNA. DR EMBL; AY236539; AAO92061.1; -; Genomic_DNA. DR EMBL; AK314130; BAG36820.1; -; mRNA. DR EMBL; CH471096; EAW63105.1; -; Genomic_DNA. DR EMBL; BC069172; AAH69172.1; -; mRNA. DR EMBL; BC101802; AAI01803.1; -; mRNA. DR EMBL; BC111992; AAI11993.1; -; mRNA. DR CCDS; CCDS11976.1; -. DR PIR; A57055; A57055. DR RefSeq; NP_005903.2; NM_005912.2. DR UniGene; Hs.532833; -. DR PDB; 2IQP; Model; -; A=29-321. DR PDB; 2IQR; Model; -; A=28-321. DR PDB; 2IQS; Model; -; A=28-321. DR PDB; 2IQU; Model; -; A=28-321. DR PDB; 2IQV; Model; -; A=40-321. DR PDB; 2IQW; Model; -; A=40-321. DR PDBsum; 2IQP; -. DR PDBsum; 2IQR; -. DR PDBsum; 2IQS; -. DR PDBsum; 2IQU; -. DR PDBsum; 2IQV; -. DR PDBsum; 2IQW; -. DR ProteinModelPortal; P32245; -. DR SMR; P32245; 50-317. DR BioGrid; 110330; 6. DR DIP; DIP-48791N; -. DR IntAct; P32245; 3. DR STRING; 9606.ENSP00000299766; -. DR BindingDB; P32245; -. DR ChEMBL; CHEMBL2111323; -. DR GuidetoPHARMACOLOGY; 285; -. DR TCDB; 9.A.14.2.3; the g-protein-coupled receptor (gpcr) family. DR PhosphoSite; P32245; -. DR BioMuta; MC4R; -. DR DMDM; 60392672; -. DR PaxDb; P32245; -. DR PRIDE; P32245; -. DR Ensembl; ENST00000299766; ENSP00000299766; ENSG00000166603. DR GeneID; 4160; -. DR KEGG; hsa:4160; -. DR UCSC; uc002lie.1; human. DR CTD; 4160; -. DR GeneCards; MC4R; -. DR HGNC; HGNC:6932; MC4R. DR HPA; HPA016719; -. DR MIM; 155541; gene. DR MIM; 601665; phenotype. DR neXtProt; NX_P32245; -. DR Orphanet; 71529; Obesity due to melanocortin 4 receptor deficiency. DR PharmGKB; PA30676; -. DR eggNOG; KOG3656; Eukaryota. DR eggNOG; ENOG410XRW9; LUCA. DR GeneTree; ENSGT00770000120529; -. DR HOGENOM; HOG000246927; -. DR HOVERGEN; HBG108148; -. DR InParanoid; P32245; -. DR KO; K04202; -. DR OMA; GTGTIRQ; -. DR OrthoDB; EOG7QK0CF; -. DR PhylomeDB; P32245; -. DR TreeFam; TF332646; -. DR Reactome; R-HSA-375276; Peptide ligand-binding receptors. DR Reactome; R-HSA-418555; G alpha (s) signalling events. DR GeneWiki; Melanocortin_4_receptor; -. DR GenomeRNAi; 4160; -. DR NextBio; 16390; -. DR PRO; PR:P32245; -. DR Proteomes; UP000005640; Chromosome 18. DR Bgee; P32245; -. DR CleanEx; HS_MC4R; -. DR Genevisible; P32245; HS. DR GO; GO:0016021; C:integral component of membrane; TAS:ProtInc. DR GO; GO:0005634; C:nucleus; IEA:Ensembl. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0004977; F:melanocortin receptor activity; TAS:ProtInc. DR GO; GO:0004980; F:melanocyte-stimulating hormone receptor activity; IDA:UniProtKB. DR GO; GO:0042923; F:neuropeptide binding; IPI:UniProtKB. DR GO; GO:0017046; F:peptide hormone binding; IEA:Ensembl. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB. DR GO; GO:0007188; P:adenylate cyclase-modulating G-protein coupled receptor signaling pathway; TAS:ProtInc. DR GO; GO:0002024; P:diet induced thermogenesis; IEA:Ensembl. DR GO; GO:0006112; P:energy reserve metabolic process; IEA:Ensembl. DR GO; GO:0007631; P:feeding behavior; TAS:ProtInc. DR GO; GO:0030073; P:insulin secretion; IEA:Ensembl. DR GO; GO:2000252; P:negative regulation of feeding behavior; IEA:Ensembl. DR GO; GO:0045780; P:positive regulation of bone resorption; IMP:HGNC. DR GO; GO:0030819; P:positive regulation of cAMP biosynthetic process; IDA:BHF-UCL. DR GO; GO:2000821; P:regulation of grooming behavior; IEA:Ensembl. DR GO; GO:0032868; P:response to insulin; IEA:Ensembl. DR InterPro; IPR000276; GPCR_Rhodpsn. DR InterPro; IPR017452; GPCR_Rhodpsn_7TM. DR InterPro; IPR000155; Mcort_rcpt_4. DR InterPro; IPR001908; Melancort_rcpt. DR InterPro; IPR001671; Melcrt_ACTH_rcpt. DR Pfam; PF00001; 7tm_1; 1. DR PRINTS; PR00237; GPCRRHODOPSN. DR PRINTS; PR00534; MCRFAMILY. DR PRINTS; PR00535; MELNOCORTINR. DR PRINTS; PR01062; MELNOCORTN4R. DR PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1. DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Cell membrane; Complete proteome; Disease mutation; KW Disulfide bond; G-protein coupled receptor; Glycoprotein; Lipoprotein; KW Membrane; Obesity; Palmitate; Polymorphism; Receptor; KW Reference proteome; Transducer; Transmembrane; Transmembrane helix. FT CHAIN 1 332 Melanocortin receptor 4. FT /FTId=PRO_0000069722. FT TOPO_DOM 1 43 Extracellular. {ECO:0000255}. FT TRANSMEM 44 69 Helical; Name=1. {ECO:0000255}. FT TOPO_DOM 70 81 Cytoplasmic. {ECO:0000255}. FT TRANSMEM 82 106 Helical; Name=2. {ECO:0000255}. FT TOPO_DOM 107 123 Extracellular. {ECO:0000255}. FT TRANSMEM 124 145 Helical; Name=3. {ECO:0000255}. FT TOPO_DOM 146 165 Cytoplasmic. {ECO:0000255}. FT TRANSMEM 166 186 Helical; Name=4. {ECO:0000255}. FT TOPO_DOM 187 191 Extracellular. {ECO:0000255}. FT TRANSMEM 192 215 Helical; Name=5. {ECO:0000255}. FT TOPO_DOM 216 248 Cytoplasmic. {ECO:0000255}. FT TRANSMEM 249 271 Helical; Name=6. {ECO:0000255}. FT TOPO_DOM 272 280 Extracellular. {ECO:0000255}. FT TRANSMEM 281 304 Helical; Name=7. {ECO:0000255}. FT TOPO_DOM 305 332 Cytoplasmic. {ECO:0000255}. FT LIPID 318 318 S-palmitoyl cysteine. {ECO:0000255}. FT CARBOHYD 3 3 N-linked (GlcNAc...). {ECO:0000255}. FT CARBOHYD 17 17 N-linked (GlcNAc...). {ECO:0000255}. FT CARBOHYD 26 26 N-linked (GlcNAc...). {ECO:0000255}. FT DISULFID 84 84 Interchain. FT VARIANT 11 11 T -> A (in obesity; partial activity). FT {ECO:0000269|PubMed:12646665}. FT /FTId=VAR_038632. FT VARIANT 30 30 S -> R (in obesity). FT {ECO:0000269|PubMed:10199800}. FT /FTId=VAR_010704. FT VARIANT 36 36 S -> Y (in obesity; shows the same FT affinity as the wild-type but significant FT impairment of cAMP-induced activity in FT response to melanotan II compared with FT the wild-type receptor). FT {ECO:0000269|PubMed:15486053}. FT /FTId=VAR_038633. FT VARIANT 37 37 D -> V (in obesity; dbSNP:rs13447325). FT {ECO:0000269|PubMed:10199800}. FT /FTId=VAR_010705. FT VARIANT 50 50 V -> M (in obesity). FT {ECO:0000269|PubMed:11487744}. FT /FTId=VAR_038634. FT VARIANT 58 58 S -> C (in obesity). FT {ECO:0000269|PubMed:11487744}. FT /FTId=VAR_038635. FT VARIANT 62 62 N -> S (in obesity; shows a partial cAMP FT response to alpha-MSH). FT {ECO:0000269|PubMed:12588803, FT ECO:0000269|PubMed:12646665}. FT /FTId=VAR_038636. FT VARIANT 78 78 P -> L (in obesity; dbSNP:rs13447326). FT {ECO:0000269|PubMed:10199800}. FT /FTId=VAR_010706. FT VARIANT 88 92 Missing (in obesity; the mutant receptor FT is expressed well on the cell surface but FT is completely devoid of ligand binding FT and cAMP generation in response to FT agonist stimulation). FT {ECO:0000269|PubMed:14671178}. FT /FTId=VAR_038637. FT VARIANT 97 97 N -> D (in obesity; completely unable to FT generate cAMP in response to ligand; FT shows evidence of impaired cell surface FT expression). FT {ECO:0000269|PubMed:12588803, FT ECO:0000269|PubMed:12646665}. FT /FTId=VAR_038638. FT VARIANT 102 102 I -> S (in obesity; shows the same FT affinity as the wild-type but significant FT impairment of cAMP-induced activity in FT response to melanotan II compared with FT the wild-type receptor). FT {ECO:0000269|PubMed:11487744}. FT /FTId=VAR_038639. FT VARIANT 102 102 I -> T (in obesity). FT {ECO:0000269|PubMed:15486053}. FT /FTId=VAR_038640. FT VARIANT 103 103 V -> I (in dbSNP:rs2229616). FT {ECO:0000269|PubMed:11487744, FT ECO:0000269|PubMed:12646665, FT ECO:0000269|PubMed:14764818, FT ECO:0000269|PubMed:15486053, FT ECO:0000269|PubMed:7854347, FT ECO:0000269|PubMed:8392067}. FT /FTId=VAR_010707. FT VARIANT 106 106 L -> P (in obesity; completely unable to FT generate cAMP in response to ligand; FT shows evidence of impaired cell surface FT expression). FT {ECO:0000269|PubMed:12588803}. FT /FTId=VAR_038641. FT VARIANT 112 112 T -> M (polymorphism; no effect on MC4R FT signaling; dbSNP:rs13447329). FT {ECO:0000269|PubMed:10199800, FT ECO:0000269|PubMed:12646665, FT ECO:0000269|PubMed:14764818, FT ECO:0000269|PubMed:15486053}. FT /FTId=VAR_010708. FT VARIANT 125 125 I -> K (in obesity; completely unable to FT generate cAMP in response to ligand; FT shows evidence of impaired cell surface FT expression). FT {ECO:0000269|PubMed:12588803, FT ECO:0000269|PubMed:12646665}. FT /FTId=VAR_038642. FT VARIANT 127 127 S -> L (in obesity; signaling properties FT in response to alpha-MSH, beta-MSH and FT gamma-1-MSH are impaired; FT dbSNP:rs13447331). FT {ECO:0000269|PubMed:14764818}. FT /FTId=VAR_038643. FT VARIANT 165 165 R -> Q (in obesity; shows a partial cAMP FT response to alpha-MSH; dbSNP:rs13447332). FT {ECO:0000269|PubMed:12588803, FT ECO:0000269|PubMed:12646665, FT ECO:0000269|PubMed:15486053}. FT /FTId=VAR_038644. FT VARIANT 165 165 R -> W (in obesity; dbSNP:rs13447332). FT {ECO:0000269|PubMed:10199800}. FT /FTId=VAR_010709. FT VARIANT 170 170 I -> V (in obesity; dbSNP:rs121913560). FT {ECO:0000269|PubMed:11487744}. FT /FTId=VAR_038645. FT VARIANT 175 175 A -> T (in obesity; shows a partial cAMP FT response to alpha-MSH). FT {ECO:0000269|PubMed:12588803, FT ECO:0000269|PubMed:12646665, FT ECO:0000269|PubMed:15486053}. FT /FTId=VAR_038646. FT VARIANT 181 181 G -> D (in obesity; does not bind alpha- FT MSH; dbSNP:rs13447333). FT {ECO:0000269|PubMed:15486053}. FT /FTId=VAR_038647. FT VARIANT 219 219 A -> V (in obesity; shows significantly FT impairment of cAMP-induced activity in FT response to melanotan II compared with FT the wild-type receptor). FT {ECO:0000269|PubMed:15486053}. FT /FTId=VAR_038648. FT VARIANT 226 226 I -> T. {ECO:0000269|PubMed:14764818}. FT /FTId=VAR_038649. FT VARIANT 251 251 I -> L (in dbSNP:rs52820871). FT {ECO:0000269|PubMed:10199800, FT ECO:0000269|PubMed:11487744, FT ECO:0000269|PubMed:12646665, FT ECO:0000269|PubMed:14764818, FT ECO:0000269|PubMed:15486053}. FT /FTId=VAR_010710. FT VARIANT 252 252 G -> S (in obesity; dbSNP:rs13447336). FT {ECO:0000269|PubMed:10199800}. FT /FTId=VAR_010711. FT VARIANT 253 253 V -> I (in obesity; shows a partial cAMP FT response to alpha-MSH; FT dbSNP:rs187152753). FT {ECO:0000269|PubMed:12588803}. FT /FTId=VAR_038650. FT VARIANT 271 271 C -> R (in obesity; completely unable to FT generate cAMP in response to ligand; FT shows impaired cell surface expression). FT {ECO:0000269|PubMed:12646665}. FT /FTId=VAR_038651. FT VARIANT 271 271 C -> Y (in obesity; no activity). FT {ECO:0000269|PubMed:12588803, FT ECO:0000269|PubMed:12646665}. FT /FTId=VAR_038652. FT VARIANT 274 274 N -> S (in obesity). FT {ECO:0000269|PubMed:11443223}. FT /FTId=VAR_015357. FT VARIANT 316 316 I -> S (in obesity; shows reduced cAMP FT response to alpha-MSH; retains normal FT affinity for the antagonist AGRP). FT {ECO:0000269|PubMed:12588803, FT ECO:0000269|PubMed:12646665}. FT /FTId=VAR_038653. FT VARIANT 317 317 I -> T (in obesity; dbSNP:rs13447337). FT {ECO:0000269|PubMed:10199800}. FT /FTId=VAR_010712. FT VARIANT 325 325 L -> F (in obesity; does not bind alpha- FT MSH). {ECO:0000269|PubMed:15486053}. FT /FTId=VAR_038654. FT CONFLICT 169 169 I -> S (in Ref. 2; AAB33341). FT {ECO:0000305}. SQ SEQUENCE 332 AA; 36943 MW; E80010BAADBED2B4 CRC64; MVNSTHRGMH TSLHLWNRSS YRLHSNASES LGKGYSDGGC YEQLFVSPEV FVTLGVISLL ENILVIVAIA KNKNLHSPMY FFICSLAVAD MLVSVSNGSE TIVITLLNST DTDAQSFTVN IDNVIDSVIC SSLLASICSL LSIAVDRYFT IFYALQYHNI MTVKRVGIII SCIWAACTVS GILFIIYSDS SAVIICLITM FFTMLALMAS LYVHMFLMAR LHIKRIAVLP GTGAIRQGAN MKGAITLTIL IGVFVVCWAP FFLHLIFYIS CPQNPYCVCF MSHFNLYLIL IMCNSIIDPL IYALRSQELR KTFKEIICCY PLGGLCDLSS RY //