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 27-MAR-2024, entry version 218. DE RecName: Full=Melanocortin receptor 4; DE Short=MC4-R; GN Name=MC4R; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ILE-103. RX PubMed=8392067; DOI=10.1016/s0021-9258(18)82452-8; 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 and RT 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 sequenced by RT 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., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., 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., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA 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., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., 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 project: RT 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., Guasti L., RA Chapple J.P., Egertova M., Elphick M.R., Cheetham M.E., Metherell L.A., RA Clark A.J.; RT "MRAP and MRAP2 are bidirectional regulators of the melanocortin receptor RT 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., Garcia-Borron J.C.; RT "Mahogunin ring finger-1 (MGRN1) E3 ubiquitin ligase inhibits signaling RT 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 and RT functional significance."; RL Biochim. Biophys. Acta 1828:535-542(2013). RN [10] RP VARIANTS OBESITY PHE-30; VAL-37; LEU-78; TRP-165; SER-252 AND THR-317, AND RP VARIANTS MET-112 AND LEU-251. RX PubMed=10199800; DOI=10.1210/jcem.84.4.5728; 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 nonsense RT and a frameshift mutation associated with dominantly inherited obesity in RT 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 ILE-103 RP 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 protein, RT and alpha-melanocyte-stimulating hormone genes in severely obese RT 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 AND RP 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., O'Rahilly S.; RT "Mutations in the human melanocortin-4 receptor gene associated with severe RT familial obesity disrupts receptor function through multiple molecular RT mechanisms."; RL Hum. Mol. Genet. 12:561-574(2003). RN [14] RP VARIANT OBESITY 88-VAL--LEU-92 DEL, AND CHARACTERIZATION OF VARIANT OBESITY RP 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., O'Rahilly S.; RT "Clinical spectrum of obesity and mutations in the melanocortin 4 receptor RT 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 LEU-251, RP CHARACTERIZATION OF VARIANT OBESITY LEU-127, AND CHARACTERIZATION OF RP 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 AND RP PHE-325, VARIANTS ILE-103; MET-112 AND LEU-251, AND CHARACTERIZATION OF RP VARIANTS OBESITY TYR-36; THR-102; GLN-165; 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 receptor RT variants identified among 750 men with juvenile-onset obesity."; RL J. Clin. Endocrinol. Metab. 90:219-224(2005). RN [18] RP VARIANT OBESITY LYS-72, CHARACTERIZATION OF VARIANT OBESITY LYS-72, RP INVOLVEMENT IN EARLY ONSET OBESITY AND HYPERPHAGIA, FUNCTION, AND RP SUBCELLULAR LOCATION. RX PubMed=25163632; DOI=10.1007/s11033-014-3691-7; RA Delhanty P.J., Bouw E., Huisman M., Vervenne R.M., Themmen A.P., RA van der Lely A.J., van den Akker E.L.; RT "Functional characterization of a new human melanocortin-4 receptor RT homozygous mutation (N72K) that is associated with early-onset obesity."; RL Mol. Biol. Rep. 41:7967-7972(2014). RN [19] RP POLYMORPHISM, AND CHARACTERIZATION OF VARIANT ILE-103. RX PubMed=31002796; DOI=10.1016/j.cell.2019.03.044; RA Lotta L.A., Mokrosinski J., Mendes de Oliveira E., Li C., Sharp S.J., RA Luan J., Brouwers B., Ayinampudi V., Bowker N., Kerrison N., Kaimakis V., RA Hoult D., Stewart I.D., Wheeler E., Day F.R., Perry J.R.B., Langenberg C., RA Wareham N.J., Farooqi I.S.; RT "Human gain-of-function MC4R variants show signaling bias and protect RT against obesity."; RL Cell 177:597-607(2019). CC -!- FUNCTION: Receptor specific to the heptapeptide core common to CC adrenocorticotropic hormone and alpha-, beta-, and gamma-MSH. Plays a CC central role in energy homeostasis and somatic growth. This receptor is CC mediated by G proteins that stimulate adenylate cyclase (cAMP). CC {ECO:0000269|PubMed:12646665, ECO:0000269|PubMed:25163632}. CC -!- SUBUNIT: Interacts with ATRNL1 (By similarity). Homodimer; disulfide- CC linked, also forms higher order oligomers. Interacts with MGRN1, but CC does not undergo MGRN1-mediated ubiquitination; this interaction CC competes with GNAS-binding and thus inhibits agonist-induced cAMP CC production. Interacts with MRAP and MRAP2; these associated factors CC increase ligand-sensitivity and generation of cAMP. {ECO:0000250, CC ECO:0000269|PubMed:19329486, ECO:0000269|PubMed:19737927, CC ECO:0000269|PubMed:23088915}. CC -!- INTERACTION: CC P32245; Q8TCY5: MRAP; NbExp=2; IntAct=EBI-3910694, EBI-9538727; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:25163632}; CC Multi-pass membrane protein {ECO:0000255}. CC -!- TISSUE SPECIFICITY: Brain, placental, and gut tissues. CC -!- POLYMORPHISM: Genetic variations in MC4R define the body mass index CC quantitative trait locus 20 (BMIQ20) [MIM:618406]. MC4R loss-of- CC function variants are associated with higher body mass index, obesity, CC type 2 diabetes, and coronary artery disease. Gain-of-function variants CC have been reported to be associated with lower body mass index and CC resistance to obesity. {ECO:0000269|PubMed:31002796}. CC -!- DISEASE: Obesity (OBESITY) [MIM:601665]: A condition characterized by CC an increase of body weight beyond the limitation of skeletal and CC physical requirements, as the result of excessive accumulation of body CC fat. {ECO:0000269|PubMed:10199800, ECO:0000269|PubMed:11443223, CC ECO:0000269|PubMed:11487744, ECO:0000269|PubMed:12588803, CC ECO:0000269|PubMed:12646665, ECO:0000269|PubMed:14671178, CC ECO:0000269|PubMed:14764818, ECO:0000269|PubMed:15486053, CC ECO:0000269|PubMed:25163632}. Note=The disease is caused by variants CC 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 PDB; 6W25; X-ray; 2.75 A; A=16-222, A=236-320. DR PDB; 7AUE; EM; 2.97 A; R=1-332. DR PDB; 7F53; EM; 3.00 A; R=1-332. DR PDB; 7F54; EM; 3.00 A; R=1-332. DR PDB; 7F55; EM; 3.10 A; R=1-332. DR PDB; 7F58; EM; 3.10 A; R=1-332. DR PDB; 7PIU; EM; 2.58 A; R=1-332. DR PDB; 7PIV; EM; 2.86 A; R=1-332. DR PDBsum; 6W25; -. DR PDBsum; 7AUE; -. DR PDBsum; 7F53; -. DR PDBsum; 7F54; -. DR PDBsum; 7F55; -. DR PDBsum; 7F58; -. DR PDBsum; 7PIU; -. DR PDBsum; 7PIV; -. DR AlphaFoldDB; P32245; -. DR EMDB; EMD-11927; -. DR EMDB; EMD-13453; -. DR EMDB; EMD-13454; -. DR EMDB; EMD-31456; -. DR EMDB; EMD-31457; -. DR EMDB; EMD-31458; -. DR EMDB; EMD-31461; -. DR SMR; P32245; -. DR BioGRID; 110330; 18. DR DIP; DIP-48791N; -. DR IntAct; P32245; 14. DR MINT; P32245; -. DR STRING; 9606.ENSP00000299766; -. DR BindingDB; P32245; -. DR ChEMBL; CHEMBL259; -. DR DrugBank; DB11653; Bremelanotide. DR DrugBank; DB11700; Setmelanotide. DR DrugCentral; P32245; -. DR GuidetoPHARMACOLOGY; 285; -. DR TCDB; 9.A.14.2.3; the g-protein-coupled receptor (gpcr) family. DR GlyCosmos; P32245; 3 sites, No reported glycans. DR GlyGen; P32245; 3 sites. DR iPTMnet; P32245; -. DR PhosphoSitePlus; P32245; -. DR BioMuta; MC4R; -. DR DMDM; 60392672; -. DR PaxDb; 9606-ENSP00000299766; -. DR PeptideAtlas; P32245; -. DR ABCD; P32245; 7 sequenced antibodies. DR Antibodypedia; 2947; 406 antibodies from 38 providers. DR DNASU; 4160; -. DR Ensembl; ENST00000299766.5; ENSP00000299766.3; ENSG00000166603.5. DR GeneID; 4160; -. DR KEGG; hsa:4160; -. DR MANE-Select; ENST00000299766.5; ENSP00000299766.3; NM_005912.3; NP_005903.2. DR UCSC; uc002lie.2; human. DR AGR; HGNC:6932; -. DR CTD; 4160; -. DR DisGeNET; 4160; -. DR GeneCards; MC4R; -. DR HGNC; HGNC:6932; MC4R. DR HPA; ENSG00000166603; Group enriched (brain, fallopian tube, retina). DR MalaCards; MC4R; -. DR MIM; 155541; gene. DR MIM; 601665; phenotype. DR neXtProt; NX_P32245; -. DR OpenTargets; ENSG00000166603; -. DR Orphanet; 71529; Obesity due to melanocortin 4 receptor deficiency. DR PharmGKB; PA30676; -. DR VEuPathDB; HostDB:ENSG00000166603; -. DR eggNOG; KOG3656; Eukaryota. DR GeneTree; ENSGT01030000234510; -. DR HOGENOM; CLU_009579_13_0_1; -. DR InParanoid; P32245; -. DR OMA; MNSTHHH; -. DR OrthoDB; 4160596at2759; -. DR PhylomeDB; P32245; -. DR TreeFam; TF332646; -. DR PathwayCommons; P32245; -. DR Reactome; R-HSA-375276; Peptide ligand-binding receptors. DR Reactome; R-HSA-418555; G alpha (s) signalling events. DR SignaLink; P32245; -. DR SIGNOR; P32245; -. DR BioGRID-ORCS; 4160; 8 hits in 1134 CRISPR screens. DR GeneWiki; Melanocortin_4_receptor; -. DR GenomeRNAi; 4160; -. DR Pharos; P32245; Tclin. DR PRO; PR:P32245; -. DR Proteomes; UP000005640; Chromosome 18. DR RNAct; P32245; Protein. DR Bgee; ENSG00000166603; Expressed in right uterine tube and 51 other cell types or tissues. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0016020; C:membrane; TAS:ProtInc. DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central. 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; IMP: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:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; IDA:BHF-UCL. 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-UCL. DR GO; GO:1903998; P:regulation of eating behavior; ISS:ARUK-UCL. DR GO; GO:2000821; P:regulation of grooming behavior; IEA:Ensembl. DR GO; GO:0019222; P:regulation of metabolic process; IBA:GO_Central. DR GO; GO:0032868; P:response to insulin; IEA:Ensembl. DR GO; GO:1990680; P:response to melanocyte-stimulating hormone; ISS:ARUK-UCL. DR CDD; cd15353; 7tmA_MC4R; 1. DR Gene3D; 1.20.1070.10; Rhodopsin 7-helix transmembrane proteins; 1. DR InterPro; IPR000276; GPCR_Rhodpsn. DR InterPro; IPR017452; GPCR_Rhodpsn_7TM. DR InterPro; IPR001908; MC3-5R. DR InterPro; IPR000155; Mcort_rcpt_4. DR InterPro; IPR001671; Melcrt_ACTH_rcpt. DR PANTHER; PTHR22750; G-PROTEIN COUPLED RECEPTOR; 1. DR PANTHER; PTHR22750:SF6; MELANOCORTIN RECEPTOR 4; 1. DR Pfam; PF00001; 7tm_1; 1. DR PRINTS; PR00237; GPCRRHODOPSN. DR PRINTS; PR00534; MCRFAMILY. DR PRINTS; PR00535; MELNOCORTINR. DR PRINTS; PR01062; MELNOCORTN4R. DR SMART; SM01381; 7TM_GPCR_Srsx; 1. DR SUPFAM; SSF81321; Family A G protein-coupled receptor-like; 1. DR PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1. DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1. DR Genevisible; P32245; HS. PE 1: Evidence at protein level; KW 3D-structure; Cell membrane; Disease variant; Disulfide bond; KW G-protein coupled receptor; Glycoprotein; Lipoprotein; Membrane; Obesity; KW Palmitate; Receptor; Reference proteome; Transducer; Transmembrane; KW Transmembrane helix. FT CHAIN 1..332 FT /note="Melanocortin receptor 4" FT /id="PRO_0000069722" FT TOPO_DOM 1..43 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 44..69 FT /note="Helical; Name=1" FT /evidence="ECO:0000255" FT TOPO_DOM 70..81 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 82..106 FT /note="Helical; Name=2" FT /evidence="ECO:0000255" FT TOPO_DOM 107..123 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 124..145 FT /note="Helical; Name=3" FT /evidence="ECO:0000255" FT TOPO_DOM 146..165 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 166..186 FT /note="Helical; Name=4" FT /evidence="ECO:0000255" FT TOPO_DOM 187..191 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 192..215 FT /note="Helical; Name=5" FT /evidence="ECO:0000255" FT TOPO_DOM 216..248 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 249..271 FT /note="Helical; Name=6" FT /evidence="ECO:0000255" FT TOPO_DOM 272..280 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 281..304 FT /note="Helical; Name=7" FT /evidence="ECO:0000255" FT TOPO_DOM 305..332 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT LIPID 318 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000255" FT CARBOHYD 3 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 17 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 26 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 84 FT /note="Interchain" FT VARIANT 11 FT /note="T -> A (in obesity; partial activity; FT dbSNP:rs372794914)" FT /evidence="ECO:0000269|PubMed:12646665" FT /id="VAR_038632" FT VARIANT 30 FT /note="S -> F (in obesity; dbSNP:rs13447323)" FT /evidence="ECO:0000269|PubMed:10199800" FT /id="VAR_010704" FT VARIANT 36 FT /note="S -> Y (in obesity; shows the same affinity as the FT wild-type but significant impairment of cAMP-induced FT activity in response to melanotan II compared with the FT wild-type receptor)" FT /evidence="ECO:0000269|PubMed:15486053" FT /id="VAR_038633" FT VARIANT 37 FT /note="D -> V (in obesity; dbSNP:rs13447325)" FT /evidence="ECO:0000269|PubMed:10199800" FT /id="VAR_010705" FT VARIANT 50 FT /note="V -> M (in obesity; dbSNP:rs121913557)" FT /evidence="ECO:0000269|PubMed:11487744" FT /id="VAR_038634" FT VARIANT 58 FT /note="S -> C (in obesity; dbSNP:rs121913558)" FT /evidence="ECO:0000269|PubMed:11487744" FT /id="VAR_038635" FT VARIANT 62 FT /note="N -> S (in obesity; shows a partial cAMP response to FT alpha-MSH; dbSNP:rs121913566)" FT /evidence="ECO:0000269|PubMed:12588803, FT ECO:0000269|PubMed:12646665" FT /id="VAR_038636" FT VARIANT 72 FT /note="N -> K (in obesity; loss of plasma membrane FT localization; loss of receptor function)" FT /evidence="ECO:0000269|PubMed:25163632" FT /id="VAR_077570" FT VARIANT 78 FT /note="P -> L (in obesity; dbSNP:rs13447326)" FT /evidence="ECO:0000269|PubMed:10199800" FT /id="VAR_010706" FT VARIANT 88..92 FT /note="Missing (in obesity; the mutant receptor is FT expressed well on the cell surface but is completely devoid FT of ligand binding and cAMP generation in response to FT agonist stimulation)" FT /evidence="ECO:0000269|PubMed:14671178" FT /id="VAR_038637" FT VARIANT 97 FT /note="N -> D (in obesity; completely unable to generate FT cAMP in response to ligand; shows evidence of impaired cell FT surface expression; dbSNP:rs121913565)" FT /evidence="ECO:0000269|PubMed:12588803, FT ECO:0000269|PubMed:12646665" FT /id="VAR_038638" FT VARIANT 102 FT /note="I -> S (in obesity; shows the same affinity as the FT wild-type but significant impairment of cAMP-induced FT activity in response to melanotan II compared with the FT wild-type receptor; dbSNP:rs121913559)" FT /evidence="ECO:0000269|PubMed:11487744" FT /id="VAR_038639" FT VARIANT 102 FT /note="I -> T (in obesity; dbSNP:rs121913559)" FT /evidence="ECO:0000269|PubMed:15486053" FT /id="VAR_038640" FT VARIANT 103 FT /note="V -> I (probable protective factor against obesity, FT type 2 diabetes and coronary artery disease; common variant FT correlated with lower body mass index; increased MC4R FT signaling; increased surface expression; dbSNP:rs2229616)" FT /evidence="ECO:0000269|PubMed:11487744, FT ECO:0000269|PubMed:12646665, ECO:0000269|PubMed:14764818, FT ECO:0000269|PubMed:15486053, ECO:0000269|PubMed:31002796, FT ECO:0000269|PubMed:7854347, ECO:0000269|PubMed:8392067" FT /id="VAR_010707" FT VARIANT 106 FT /note="L -> P (in obesity; decreased MC4R signaling; shows FT evidence of impaired cell surface expression)" FT /evidence="ECO:0000269|PubMed:12588803" FT /id="VAR_038641" FT VARIANT 112 FT /note="T -> M (no effect on MC4R signaling; FT dbSNP:rs13447329)" FT /evidence="ECO:0000269|PubMed:10199800, FT ECO:0000269|PubMed:12646665, ECO:0000269|PubMed:14764818, FT ECO:0000269|PubMed:15486053" FT /id="VAR_010708" FT VARIANT 125 FT /note="I -> K (in obesity; completely unable to generate FT cAMP in response to ligand; shows evidence of impaired cell FT surface expression)" FT /evidence="ECO:0000269|PubMed:12588803, FT ECO:0000269|PubMed:12646665" FT /id="VAR_038642" FT VARIANT 127 FT /note="S -> L (in obesity; signaling properties in response FT to alpha-MSH, beta-MSH and gamma-1-MSH are impaired; FT dbSNP:rs13447331)" FT /evidence="ECO:0000269|PubMed:14764818" FT /id="VAR_038643" FT VARIANT 165 FT /note="R -> Q (in obesity; shows a partial cAMP response to FT alpha-MSH; dbSNP:rs747681609)" FT /evidence="ECO:0000269|PubMed:12588803, FT ECO:0000269|PubMed:12646665, ECO:0000269|PubMed:15486053" FT /id="VAR_038644" FT VARIANT 165 FT /note="R -> W (in obesity; dbSNP:rs13447332)" FT /evidence="ECO:0000269|PubMed:10199800" FT /id="VAR_010709" FT VARIANT 170 FT /note="I -> V (in obesity; dbSNP:rs121913560)" FT /evidence="ECO:0000269|PubMed:11487744" FT /id="VAR_038645" FT VARIANT 175 FT /note="A -> T (in obesity; shows a partial cAMP response to FT alpha-MSH; dbSNP:rs121913563)" FT /evidence="ECO:0000269|PubMed:12588803, FT ECO:0000269|PubMed:12646665, ECO:0000269|PubMed:15486053" FT /id="VAR_038646" FT VARIANT 181 FT /note="G -> D (in obesity; does not bind alpha-MSH; FT dbSNP:rs13447333)" FT /evidence="ECO:0000269|PubMed:15486053" FT /id="VAR_038647" FT VARIANT 219 FT /note="A -> V (in obesity; shows significantly impairment FT of cAMP-induced activity in response to melanotan II FT compared with the wild-type receptor; dbSNP:rs121913567)" FT /evidence="ECO:0000269|PubMed:15486053" FT /id="VAR_038648" FT VARIANT 226 FT /note="I -> T (in dbSNP:rs193922686)" FT /evidence="ECO:0000269|PubMed:14764818" FT /id="VAR_038649" FT VARIANT 251 FT /note="I -> L (in dbSNP:rs52820871)" FT /evidence="ECO:0000269|PubMed:10199800, FT ECO:0000269|PubMed:11487744, ECO:0000269|PubMed:12646665, FT ECO:0000269|PubMed:14764818, ECO:0000269|PubMed:15486053" FT /id="VAR_010710" FT VARIANT 252 FT /note="G -> S (in obesity; dbSNP:rs13447336)" FT /evidence="ECO:0000269|PubMed:10199800" FT /id="VAR_010711" FT VARIANT 253 FT /note="V -> I (in obesity; shows a partial cAMP response to FT alpha-MSH; dbSNP:rs187152753)" FT /evidence="ECO:0000269|PubMed:12588803" FT /id="VAR_038650" FT VARIANT 271 FT /note="C -> R (in obesity; completely unable to generate FT cAMP in response to ligand; shows impaired cell surface FT expression; dbSNP:rs1057517991)" FT /evidence="ECO:0000269|PubMed:12646665" FT /id="VAR_038651" FT VARIANT 271 FT /note="C -> Y (in obesity; no activity; dbSNP:rs121913562)" FT /evidence="ECO:0000269|PubMed:12588803, FT ECO:0000269|PubMed:12646665" FT /id="VAR_038652" FT VARIANT 274 FT /note="N -> S (in obesity; dbSNP:rs121913561)" FT /evidence="ECO:0000269|PubMed:11443223" FT /id="VAR_015357" FT VARIANT 316 FT /note="I -> S (in obesity; shows reduced cAMP response to FT alpha-MSH; retains normal affinity for the antagonist AGRP; FT dbSNP:rs121913564)" FT /evidence="ECO:0000269|PubMed:12588803, FT ECO:0000269|PubMed:12646665" FT /id="VAR_038653" FT VARIANT 317 FT /note="I -> T (in obesity; dbSNP:rs13447337)" FT /evidence="ECO:0000269|PubMed:10199800" FT /id="VAR_010712" FT VARIANT 325 FT /note="L -> F (in obesity; does not bind alpha-MSH)" FT /evidence="ECO:0000269|PubMed:15486053" FT /id="VAR_038654" FT CONFLICT 169 FT /note="I -> S (in Ref. 2; AAB33341)" FT /evidence="ECO:0000305" FT HELIX 48..70 FT /evidence="ECO:0007829|PDB:7PIU" FT HELIX 73..75 FT /evidence="ECO:0007829|PDB:7PIU" FT HELIX 78..106 FT /evidence="ECO:0007829|PDB:7PIU" FT HELIX 118..152 FT /evidence="ECO:0007829|PDB:7PIU" FT TURN 153..156 FT /evidence="ECO:0007829|PDB:7PIU" FT HELIX 157..160 FT /evidence="ECO:0007829|PDB:7PIU" FT HELIX 163..186 FT /evidence="ECO:0007829|PDB:7PIU" FT TURN 187..189 FT /evidence="ECO:0007829|PDB:7PIU" FT HELIX 192..226 FT /evidence="ECO:0007829|PDB:7PIU" FT HELIX 241..270 FT /evidence="ECO:0007829|PDB:7PIU" FT HELIX 275..281 FT /evidence="ECO:0007829|PDB:7PIU" FT HELIX 284..301 FT /evidence="ECO:0007829|PDB:7PIU" FT HELIX 303..305 FT /evidence="ECO:0007829|PDB:7PIU" FT HELIX 307..315 FT /evidence="ECO:0007829|PDB:7PIU" 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 //