ID MC4R_MOUSE Reviewed; 332 AA.
AC P56450; Q49NR4; Q9EQM7;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 3.
DT 27-MAR-2024, entry version 163.
DE RecName: Full=Melanocortin receptor 4;
DE Short=MC4-R;
GN Name=Mc4r;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=129/Sv;
RA Dumont L.M., Wu C.S., Mountjoy K.G.;
RT "Characterization of the melanocortin-4 receptor gene.";
RL Submitted (NOV-1999) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 112-295.
RC STRAIN=ICR; TISSUE=Pituitary anterior lobe;
RA Morooka Y., Oomizu S., Takeuchi S., Takahashi S.;
RL Submitted (DEC-1997) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=A/J, AKR/J, C57BL/6J, CAST/EiJ, SJL/J, and SWR/J; TISSUE=Spleen;
RA Reichwald K., Petz U., Klingenspor M., Platzer M.;
RT "Analysis of Mc4r locus in DIO and DR mice.";
RL Submitted (JUL-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Diencephalon;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [5]
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 [6]
RP INTERACTION WITH ATRNL1.
RX PubMed=14531729; DOI=10.1042/bj20031241;
RA Haqq A.M., Rene P., Kishi T., Khong K., Lee C.E., Liu H., Friedman J.M.,
RA Elmquist J.K., Cone R.D.;
RT "Characterization of a novel binding partner of the melanocortin-4
RT receptor: attractin-like protein.";
RL Biochem. J. 376:595-605(2003).
RN [7]
RP FUNCTION, AND INTERACTION WITH MRAP2.
RX PubMed=23869016; DOI=10.1126/science.1233000;
RA Asai M., Ramachandrappa S., Joachim M., Shen Y., Zhang R., Nuthalapati N.,
RA Ramanathan V., Strochlic D.E., Ferket P., Linhart K., Ho C.,
RA Novoselova T.V., Garg S., Ridderstrale M., Marcus C., Hirschhorn J.N.,
RA Keogh J.M., O'Rahilly S., Chan L.F., Clark A.J., Farooqi I.S.,
RA Majzoub J.A.;
RT "Loss of function of the melanocortin 2 receptor accessory protein 2 is
RT associated with mammalian obesity.";
RL Science 341:275-278(2013).
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:23869016}.
CC -!- SUBUNIT: Interacts with ATRNL1. Homodimer; disulfide-linked, also forms
CC higher order oligomers. Interacts with MGRN1, but does not undergo
CC MGRN1-mediated ubiquitination; this interaction competes with GNAS-
CC binding and thus inhibits agonist-induced cAMP production (By
CC similarity). Interacts with MRAP and MRAP2; these associated factors
CC increase ligand-sensitivity and generation of cAMP. {ECO:0000250,
CC ECO:0000269|PubMed:14531729, ECO:0000269|PubMed:23869016}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P32245};
CC Multi-pass membrane protein {ECO:0000255}.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family.
CC {ECO:0000255|PROSITE-ProRule:PRU00521}.
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DR EMBL; AF201662; AAG35602.1; -; Genomic_DNA.
DR EMBL; AY684813; AAV92649.1; -; Genomic_DNA.
DR EMBL; AY684814; AAV92650.1; -; Genomic_DNA.
DR EMBL; AY684815; AAV92651.1; -; Genomic_DNA.
DR EMBL; AY684818; AAV92654.1; -; Genomic_DNA.
DR EMBL; AY684819; AAV92655.1; -; Genomic_DNA.
DR EMBL; AY684820; AAV92656.1; -; Genomic_DNA.
DR EMBL; AK136793; BAE23130.1; -; mRNA.
DR EMBL; BC116957; AAI16958.1; -; mRNA.
DR EMBL; BC116959; AAI16960.1; -; mRNA.
DR EMBL; AB009664; BAA24015.1; -; Genomic_DNA.
DR CCDS; CCDS29316.1; -.
DR RefSeq; NP_058673.2; NM_016977.4.
DR AlphaFoldDB; P56450; -.
DR SMR; P56450; -.
DR BioGRID; 201341; 2.
DR STRING; 10090.ENSMUSP00000054776; -.
DR BindingDB; P56450; -.
DR ChEMBL; CHEMBL3719; -.
DR GuidetoPHARMACOLOGY; 285; -.
DR GlyCosmos; P56450; 4 sites, No reported glycans.
DR GlyGen; P56450; 4 sites.
DR PhosphoSitePlus; P56450; -.
DR PaxDb; 10090-ENSMUSP00000054776; -.
DR Antibodypedia; 2947; 406 antibodies from 38 providers.
DR DNASU; 17202; -.
DR Ensembl; ENSMUST00000057942.4; ENSMUSP00000054776.3; ENSMUSG00000047259.4.
DR GeneID; 17202; -.
DR KEGG; mmu:17202; -.
DR UCSC; uc008ffv.2; mouse.
DR AGR; MGI:99457; -.
DR CTD; 4160; -.
DR MGI; MGI:99457; Mc4r.
DR VEuPathDB; HostDB:ENSMUSG00000047259; -.
DR eggNOG; KOG3656; Eukaryota.
DR GeneTree; ENSGT01030000234510; -.
DR HOGENOM; CLU_009579_13_0_1; -.
DR InParanoid; P56450; -.
DR OMA; MNSTHHH; -.
DR OrthoDB; 4160596at2759; -.
DR PhylomeDB; P56450; -.
DR TreeFam; TF332646; -.
DR Reactome; R-MMU-375276; Peptide ligand-binding receptors.
DR Reactome; R-MMU-418555; G alpha (s) signalling events.
DR BioGRID-ORCS; 17202; 2 hits in 77 CRISPR screens.
DR PRO; PR:P56450; -.
DR Proteomes; UP000000589; Chromosome 18.
DR RNAct; P56450; Protein.
DR Bgee; ENSMUSG00000047259; Expressed in cortical plate and 30 other cell types or tissues.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0042562; F:hormone binding; ISO:MGI.
DR GO; GO:0004977; F:melanocortin receptor activity; IDA:MGI.
DR GO; GO:0004980; F:melanocyte-stimulating hormone receptor activity; IDA:MGI.
DR GO; GO:0042923; F:neuropeptide binding; ISO:MGI.
DR GO; GO:0017046; F:peptide hormone binding; ISO:MGI.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:MGI.
DR GO; GO:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; ISO:MGI.
DR GO; GO:0002024; P:diet induced thermogenesis; ISO:MGI.
DR GO; GO:0006112; P:energy reserve metabolic process; ISO:MGI.
DR GO; GO:0007631; P:feeding behavior; IMP:MGI.
DR GO; GO:0030073; P:insulin secretion; IGI:MGI.
DR GO; GO:2000252; P:negative regulation of feeding behavior; ISO:MGI.
DR GO; GO:0045780; P:positive regulation of bone resorption; IMP:HGNC-UCL.
DR GO; GO:1903998; P:regulation of eating behavior; IMP:ARUK-UCL.
DR GO; GO:0060259; P:regulation of feeding behavior; ISO:MGI.
DR GO; GO:2000821; P:regulation of grooming behavior; ISO:MGI.
DR GO; GO:0019222; P:regulation of metabolic process; IMP:MGI.
DR GO; GO:0032868; P:response to insulin; IMP:MGI.
DR GO; GO:1990680; P:response to melanocyte-stimulating hormone; IMP: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.
PE 1: Evidence at protein level;
KW Cell membrane; Disulfide bond; G-protein coupled receptor; Glycoprotein;
KW Lipoprotein; Membrane; Palmitate; Receptor; Reference proteome; Transducer;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1..332
FT /note="Melanocortin receptor 4"
FT /id="PRO_0000069724"
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 2
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 CARBOHYD 108
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 84
FT /note="Interchain"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00521"
FT CONFLICT 25
FT /note="G -> S (in Ref. 1; AAG35602)"
FT /evidence="ECO:0000305"
FT CONFLICT 291
FT /note="I -> M (in Ref. 2; BAA24015)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 332 AA; 36959 MW; BAD7018E30CF4FC1 CRC64;
MNSTHHHGMY TSLHLWNRSS YGLHGNASES LGKGHPDGGC YEQLFVSPEV FVTLGVISLL
ENILVIVAIA KNKNLHSPMY FFICSLAVAD MLVSVSNGSE TIVITLLNST DTDAQSFTVN
IDNVIDSVIC SSLLASICSL LSIAVDRYFT IFYALQYHNI MTVRRVGIII SCIWAACTVS
GVLFIIYSDS SAVIICLISM FFTMLVLMAS LYVHMFLMAR LHIKRIAVLP GTGTIRQGTN
MKGAITLTIL IGVFVVCWAP FFLHLLFYIS CPQNPYCVCF MSHFNLYLIL IMCNAVIDPL
IYALRSQELR KTFKEIICFY PLGGICELSS RY
//
