MC3R_HUMAN
ID MC3R_HUMAN Reviewed; 323 AA.
AC P41968; Q4KN27; Q9H517;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 11-JUL-2012, sequence version 3.
DT 03-AUG-2022, entry version 187.
DE RecName: Full=Melanocortin receptor 3;
DE Short=MC3-R;
GN Name=MC3R;
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-44.
RX PubMed=8463333; DOI=10.1016/s0021-9258(18)53088-x;
RA Gantz I., Konda Y., Tashiro T., Shimoto Y., Miwa H., Munzert G.,
RA Watson S.J., Delvalle J., Yamada T.;
RT "Molecular cloning of a novel melanocortin receptor.";
RL J. Biol. Chem. 268:8246-8250(1993).
RN [2]
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=11780052; DOI=10.1038/414865a;
RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P.,
RA Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., Buck D., Burrill W.D.,
RA Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G.,
RA Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E.,
RA Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D.,
RA Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M.,
RA Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D.,
RA Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M.,
RA Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A.,
RA Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L.,
RA Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L.,
RA Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 20.";
RL Nature 414:865-871(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [5]
RP TRANSLATIONAL START SITE.
RX PubMed=22433616; DOI=10.1159/000336070;
RA Tarnow P., Rediger A., Schulz A., Gruters A., Biebermann H.;
RT "Identification of the translation start site of the human melanocortin 3
RT receptor.";
RL Obes. Facts 5:45-51(2012).
RN [6]
RP VARIANT ASN-146, AND ASSOCIATION WITH SUSCEPTIBILITY TO OBESITY.
RX PubMed=11889220; DOI=10.1210/jcem.87.3.8461;
RA Lee Y.-S., Poh L.K.-S., Loke K.-Y.;
RT "A novel melanocortin 3 receptor gene (MC3R) mutation associated with
RT severe obesity.";
RL J. Clin. Endocrinol. Metab. 87:1423-1426(2002).
RN [7]
RP CHARACTERIZATION OF VARIANTS ILE-44 AND ASN-146.
RX PubMed=15292330; DOI=10.1210/jc.2004-0367;
RA Tao Y.-X., Segaloff D.L.;
RT "Functional characterization of melanocortin-3 receptor variants identify a
RT loss-of-function mutation involving an amino acid critical for G protein-
RT coupled receptor activation.";
RL J. Clin. Endocrinol. Metab. 89:3936-3942(2004).
RN [8]
RP VARIANT SER-298, CHARACTERIZATION OF VARIANT SER-298, AND ASSOCIATION WITH
RP SUSCEPTIBILITY TO OBESITY.
RX PubMed=18231126; DOI=10.1038/sj.ejhg.5202005;
RA Mencarelli M., Walker G.E., Maestrini S., Alberti L., Verti B., Brunani A.,
RA Petroni M.L., Tagliaferri M., Liuzzi A., Di Blasio A.M.;
RT "Sporadic mutations in melanocortin receptor 3 in morbid obese
RT individuals.";
RL Eur. J. Hum. Genet. 16:581-586(2008).
CC -!- FUNCTION: Receptor for MSH (alpha, beta and gamma) and ACTH. This
CC receptor is mediated by G proteins which activate adenylate cyclase.
CC Required for expression of anticipatory patterns of activity and
CC wakefulness during periods of limited nutrient availability and for the
CC normal regulation of circadian clock activity in the brain.
CC {ECO:0000250|UniProtKB:P33033}.
CC -!- INTERACTION:
CC P41968; Q8TCY5: MRAP; NbExp=2; IntAct=EBI-9538510, EBI-9538727;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein.
CC -!- TISSUE SPECIFICITY: Brain, placental, and gut tissues.
CC -!- POLYMORPHISM: Genetic variations in MC3R define the body mass index
CC quantitative trait locus 9 (BMIQ9) [MIM:602025]. Variance in body mass
CC index is a susceptibility factor for obesity.
CC {ECO:0000269|PubMed:11889220, ECO:0000269|PubMed:18231126}.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family.
CC {ECO:0000255|PROSITE-ProRule:PRU00521}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC13541.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAH69105.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAH69599.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAH96702.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAH96737.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAH98169.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAH98351.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAO72726.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; L06155; AAC13541.1; ALT_INIT; Genomic_DNA.
DR EMBL; AY227893; AAO72726.1; ALT_INIT; mRNA.
DR EMBL; AL139824; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC069105; AAH69105.1; ALT_INIT; mRNA.
DR EMBL; BC069599; AAH69599.1; ALT_INIT; mRNA.
DR EMBL; BC096702; AAH96702.1; ALT_INIT; mRNA.
DR EMBL; BC096737; AAH96737.1; ALT_INIT; mRNA.
DR EMBL; BC098169; AAH98169.1; ALT_INIT; mRNA.
DR EMBL; BC098351; AAH98351.1; ALT_INIT; mRNA.
DR CCDS; CCDS13449.2; -.
DR PIR; B46647; B46647.
DR RefSeq; NP_063941.3; NM_019888.3.
DR AlphaFoldDB; P41968; -.
DR SMR; P41968; -.
DR BioGRID; 110329; 2.
DR DIP; DIP-48790N; -.
DR IntAct; P41968; 2.
DR STRING; 9606.ENSP00000243911; -.
DR BindingDB; P41968; -.
DR ChEMBL; CHEMBL4644; -.
DR DrugBank; DB11653; Bremelanotide.
DR DrugCentral; P41968; -.
DR GuidetoPHARMACOLOGY; 284; -.
DR GlyGen; P41968; 3 sites.
DR BioMuta; MC3R; -.
DR DMDM; 395398606; -.
DR PaxDb; P41968; -.
DR PeptideAtlas; P41968; -.
DR PRIDE; P41968; -.
DR Antibodypedia; 2935; 346 antibodies from 37 providers.
DR DNASU; 4159; -.
DR Ensembl; ENST00000243911.2; ENSP00000243911.2; ENSG00000124089.4.
DR GeneID; 4159; -.
DR KEGG; hsa:4159; -.
DR MANE-Select; ENST00000243911.2; ENSP00000243911.2; NM_019888.3; NP_063941.3.
DR UCSC; uc002xxb.2; human.
DR CTD; 4159; -.
DR DisGeNET; 4159; -.
DR GeneCards; MC3R; -.
DR HGNC; HGNC:6931; MC3R.
DR HPA; ENSG00000124089; Tissue enriched (brain).
DR MalaCards; MC3R; -.
DR MIM; 155540; gene.
DR MIM; 602025; phenotype.
DR neXtProt; NX_P41968; -.
DR OpenTargets; ENSG00000124089; -.
DR Orphanet; 217031; NON RARE IN EUROPE: Obesity due to MC3R deficiency.
DR PharmGKB; PA30675; -.
DR VEuPathDB; HostDB:ENSG00000124089; -.
DR eggNOG; KOG3656; Eukaryota.
DR GeneTree; ENSGT01030000234510; -.
DR HOGENOM; CLU_009579_13_0_1; -.
DR InParanoid; P41968; -.
DR OMA; TCMKGAV; -.
DR OrthoDB; 1037679at2759; -.
DR PhylomeDB; P41968; -.
DR TreeFam; TF332646; -.
DR PathwayCommons; P41968; -.
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; P41968; -.
DR SIGNOR; P41968; -.
DR BioGRID-ORCS; 4159; 10 hits in 1061 CRISPR screens.
DR GeneWiki; Melanocortin_3_receptor; -.
DR GenomeRNAi; 4159; -.
DR Pharos; P41968; Tchem.
DR PRO; PR:P41968; -.
DR Proteomes; UP000005640; Chromosome 20.
DR RNAct; P41968; protein.
DR Bgee; ENSG00000124089; Expressed in deltoid and 11 other tissues.
DR Genevisible; P41968; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005887; C:integral component of plasma membrane; TAS:ProtInc.
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; IPI:BHF-UCL.
DR GO; GO:0042923; F:neuropeptide binding; IMP:UniProtKB.
DR GO; GO:0017046; F:peptide hormone binding; IBA:GO_Central.
DR GO; GO:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0032922; P:circadian regulation of gene expression; ISS:UniProtKB.
DR GO; GO:0007187; P:G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger; TAS:ProtInc.
DR GO; GO:0042309; P:homoiothermy; IEA:Ensembl.
DR GO; GO:0045475; P:locomotor rhythm; IEA:Ensembl.
DR GO; GO:0007200; P:phospholipase C-activating G protein-coupled receptor signaling pathway; TAS:ProtInc.
DR GO; GO:0008217; P:regulation of blood pressure; IEA:Ensembl.
DR GO; GO:0060259; P:regulation of feeding behavior; IEA:Ensembl.
DR GO; GO:0002027; P:regulation of heart rate; IEA:Ensembl.
DR GO; GO:0019222; P:regulation of metabolic process; IBA:GO_Central.
DR GO; GO:0055078; P:sodium ion homeostasis; IEA:Ensembl.
DR InterPro; IPR000276; GPCR_Rhodpsn.
DR InterPro; IPR017452; GPCR_Rhodpsn_7TM.
DR InterPro; IPR001908; MC3-5R.
DR InterPro; IPR002122; Mcort_3_rcpt.
DR InterPro; IPR001671; Melcrt_ACTH_rcpt.
DR PANTHER; PTHR22750:SF4; PTHR22750:SF4; 1.
DR Pfam; PF00001; 7tm_1; 1.
DR PRINTS; PR00237; GPCRRHODOPSN.
DR PRINTS; PR00534; MCRFAMILY.
DR PRINTS; PR00535; MELNOCORTINR.
DR PRINTS; PR01061; MELNOCORTN3R.
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 Biological rhythms; Cell membrane; G-protein coupled receptor;
KW Glycoprotein; Lipoprotein; Membrane; Palmitate; Receptor;
KW Reference proteome; Transducer; Transmembrane; Transmembrane helix.
FT CHAIN 1..323
FT /note="Melanocortin receptor 3"
FT /id="PRO_0000069718"
FT TOPO_DOM 1..37
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 38..63
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 64..75
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 76..100
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 101..118
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 119..140
FT /note="Helical; Name=3"
FT /evidence="ECO:0000255"
FT TOPO_DOM 141..160
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 161..181
FT /note="Helical; Name=4"
FT /evidence="ECO:0000255"
FT TOPO_DOM 182..186
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 187..210
FT /note="Helical; Name=5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 211..245
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 246..268
FT /note="Helical; Name=6"
FT /evidence="ECO:0000255"
FT TOPO_DOM 269..277
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 278..301
FT /note="Helical; Name=7"
FT /evidence="ECO:0000255"
FT TOPO_DOM 302..323
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT LIPID 315
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000255"
FT CARBOHYD 2
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 16
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 28
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VARIANT 44
FT /note="V -> I (have ligand binding and signaling properties
FT similar to wild-type; dbSNP:rs3827103)"
FT /evidence="ECO:0000269|PubMed:15292330,
FT ECO:0000269|PubMed:8463333"
FT /id="VAR_020070"
FT VARIANT 146
FT /note="I -> N (associated with susceptibility to obesity;
FT completely lacks signaling in response to agonist
FT stimulation; coexpression of the wild-type and the mutant
FT receptor shows that it does not exert dominant-negative
FT activity on wild-type; dbSNP:rs74315393)"
FT /evidence="ECO:0000269|PubMed:11889220,
FT ECO:0000269|PubMed:15292330"
FT /id="VAR_055000"
FT VARIANT 298
FT /note="I -> S (associated with susceptibility to obesity;
FT in vitro expression studies demonstrate that the mutation
FT causes complete loss of function; transfected cells show
FT diffuse cytoplasmic staining indicating intracellular
FT retention of the receptor; dbSNP:rs121913556)"
FT /evidence="ECO:0000269|PubMed:18231126"
FT /id="VAR_055001"
SQ SEQUENCE 323 AA; 36043 MW; 98B016FC80802A97 CRC64;
MNASCCLPSV QPTLPNGSEH LQAPFFSNQS SSAFCEQVFI KPEVFLSLGI VSLLENILVI
LAVVRNGNLH SPMYFFLCSL AVADMLVSVS NALETIMIAI VHSDYLTFED QFIQHMDNIF
DSMICISLVA SICNLLAIAV DRYVTIFYAL RYHSIMTVRK ALTLIVAIWV CCGVCGVVFI
VYSESKMVIV CLITMFFAMM LLMGTLYVHM FLFARLHVKR IAALPPADGV APQQHSCMKG
AVTITILLGV FIFCWAPFFL HLVLIITCPT NPYCICYTAH FNTYLVLIMC NSVIDPLIYA
FRSLELRNTF REILCGCNGM NLG
