MC4R_HUMAN
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 03-AUG-2022, entry version 209.
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";
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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 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 GlyGen; P32245; 3 sites.
DR iPTMnet; P32245; -.
DR PhosphoSitePlus; P32245; -.
DR BioMuta; MC4R; -.
DR DMDM; 60392672; -.
DR PaxDb; P32245; -.
DR PeptideAtlas; P32245; -.
DR PRIDE; P32245; -.
DR ABCD; P32245; 7 sequenced antibodies.
DR Antibodypedia; 2947; 358 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 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; YCTCFMS; -.
DR OrthoDB; 869396at2759; -.
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 Reactome; R-HSA-9660821; ADORA2B mediated anti-inflammatory cytokines production.
DR SignaLink; P32245; -.
DR SIGNOR; P32245; -.
DR BioGRID-ORCS; 4160; 5 hits in 1064 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 tissues.
DR Genevisible; P32245; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
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; IBA:GO_Central.
DR GO; GO:0004930; F:G protein-coupled receptor activity; 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 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 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 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; 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 (common variant associated with lower body
FT mass index and obesity risk; also associated with lower
FT risk for type 2 diabetes and coronary artery disease;
FT increased MC4R signaling; increased surface expression;
FT 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
