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Protein

Melanocortin receptor 4

Gene

MC4R

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Receptor specific to the heptapeptide core common to adrenocorticotropic hormone and alpha-, beta-, and gamma-MSH. Plays a central role in energy homeostasis and somatic growth. This receptor is mediated by G proteins that stimulate adenylate cyclase (cAMP).2 Publications

GO - Molecular functioni

  • melanocortin receptor activity Source: ProtInc
  • melanocyte-stimulating hormone receptor activity Source: UniProtKB
  • neuropeptide binding Source: UniProtKB
  • peptide hormone binding Source: Ensembl
  • ubiquitin protein ligase binding Source: UniProtKB

GO - Biological processi

Keywordsi

Molecular functionG-protein coupled receptor, Receptor, Transducer

Enzyme and pathway databases

ReactomeiR-HSA-375276 Peptide ligand-binding receptors
R-HSA-418555 G alpha (s) signalling events
SIGNORiP32245

Protein family/group databases

TCDBi9.A.14.2.3 the g-protein-coupled receptor (gpcr) family

Names & Taxonomyi

Protein namesi
Recommended name:
Melanocortin receptor 4
Short name:
MC4-R
Gene namesi
Name:MC4R
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 18

Organism-specific databases

EuPathDBiHostDB:ENSG00000166603.4
HGNCiHGNC:6932 MC4R
MIMi155541 gene
neXtProtiNX_P32245

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 43ExtracellularSequence analysisAdd BLAST43
Transmembranei44 – 69Helical; Name=1Sequence analysisAdd BLAST26
Topological domaini70 – 81CytoplasmicSequence analysisAdd BLAST12
Transmembranei82 – 106Helical; Name=2Sequence analysisAdd BLAST25
Topological domaini107 – 123ExtracellularSequence analysisAdd BLAST17
Transmembranei124 – 145Helical; Name=3Sequence analysisAdd BLAST22
Topological domaini146 – 165CytoplasmicSequence analysisAdd BLAST20
Transmembranei166 – 186Helical; Name=4Sequence analysisAdd BLAST21
Topological domaini187 – 191ExtracellularSequence analysis5
Transmembranei192 – 215Helical; Name=5Sequence analysisAdd BLAST24
Topological domaini216 – 248CytoplasmicSequence analysisAdd BLAST33
Transmembranei249 – 271Helical; Name=6Sequence analysisAdd BLAST23
Topological domaini272 – 280ExtracellularSequence analysis9
Transmembranei281 – 304Helical; Name=7Sequence analysisAdd BLAST24
Topological domaini305 – 332CytoplasmicSequence analysisAdd BLAST28

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Involvement in diseasei

Obesity (OBESITY)8 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat.
See also OMIM:601665

Keywords - Diseasei

Disease mutation, Obesity

Organism-specific databases

DisGeNETi4160
MalaCardsiMC4R
MIMi601665 phenotype
OpenTargetsiENSG00000166603
Orphaneti71529 Obesity due to melanocortin 4 receptor deficiency
PharmGKBiPA30676

Chemistry databases

ChEMBLiCHEMBL259
GuidetoPHARMACOLOGYi285

Polymorphism and mutation databases

BioMutaiMC4R
DMDMi60392672

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000697221 – 332Melanocortin receptor 4Add BLAST332

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi3N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi17N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi26N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi84Interchain
Lipidationi318S-palmitoyl cysteineSequence analysis1

Keywords - PTMi

Disulfide bond, Glycoprotein, Lipoprotein, Palmitate

Proteomic databases

PaxDbiP32245
PRIDEiP32245
ProteomicsDBi54853

PTM databases

iPTMnetiP32245
PhosphoSitePlusiP32245

Expressioni

Tissue specificityi

Brain, placental, and gut tissues.

Gene expression databases

BgeeiENSG00000166603
CleanExiHS_MC4R
GenevisibleiP32245 HS

Organism-specific databases

HPAiHPA016719

Interactioni

Subunit structurei

Interacts with ATRNL1 (By similarity). Homodimer; disulfide-linked, also forms higher order oligomers. Interacts with MGRN1, but does not undergo MGRN1-mediated ubiquitination; this interaction competes with GNAS-binding and thus inhibits agonist-induced cAMP production. Interacts with MRAP and MRAP2; these associated factors increase ligand-sensitivity and generation of cAMP.By similarity3 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
MRAPQ8TCY52EBI-3910694,EBI-9538727

GO - Molecular functioni

  • ubiquitin protein ligase binding Source: UniProtKB

Protein-protein interaction databases

BioGridi110330, 6 interactors
DIPiDIP-48791N
IntActiP32245, 3 interactors
STRINGi9606.ENSP00000299766

Chemistry databases

BindingDBiP32245

Structurei

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2IQPmodel-A29-321[»]
2IQRmodel-A28-321[»]
2IQSmodel-A28-321[»]
2IQUmodel-A28-321[»]
2IQVmodel-A40-321[»]
2IQWmodel-A40-321[»]
ProteinModelPortaliP32245
SMRiP32245
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Belongs to the G-protein coupled receptor 1 family.PROSITE-ProRule annotation

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG3656 Eukaryota
ENOG410XRW9 LUCA
GeneTreeiENSGT00770000120529
HOGENOMiHOG000246927
HOVERGENiHBG108148
InParanoidiP32245
KOiK04202
OMAiMHTSLHF
OrthoDBiEOG091G0BVW
PhylomeDBiP32245
TreeFamiTF332646

Family and domain databases

CDDicd15353 7tmA_MC4R, 1 hit
InterProiView protein in InterPro
IPR000276 GPCR_Rhodpsn
IPR017452 GPCR_Rhodpsn_7TM
IPR000155 Mcort_rcpt_4
IPR001908 Melancort_rcpt
IPR001671 Melcrt_ACTH_rcpt
PfamiView protein in Pfam
PF00001 7tm_1, 1 hit
PRINTSiPR00237 GPCRRHODOPSN
PR00534 MCRFAMILY
PR00535 MELNOCORTINR
PR01062 MELNOCORTN4R
SMARTiView protein in SMART
SM01381 7TM_GPCR_Srsx, 1 hit
PROSITEiView protein in PROSITE
PS00237 G_PROTEIN_RECEP_F1_1, 1 hit
PS50262 G_PROTEIN_RECEP_F1_2, 1 hit

Sequencei

Sequence statusi: Complete.

P32245-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MVNSTHRGMH TSLHLWNRSS YRLHSNASES LGKGYSDGGC YEQLFVSPEV
60 70 80 90 100
FVTLGVISLL ENILVIVAIA KNKNLHSPMY FFICSLAVAD MLVSVSNGSE
110 120 130 140 150
TIVITLLNST DTDAQSFTVN IDNVIDSVIC SSLLASICSL LSIAVDRYFT
160 170 180 190 200
IFYALQYHNI MTVKRVGIII SCIWAACTVS GILFIIYSDS SAVIICLITM
210 220 230 240 250
FFTMLALMAS LYVHMFLMAR LHIKRIAVLP GTGAIRQGAN MKGAITLTIL
260 270 280 290 300
IGVFVVCWAP FFLHLIFYIS CPQNPYCVCF MSHFNLYLIL IMCNSIIDPL
310 320 330
IYALRSQELR KTFKEIICCY PLGGLCDLSS RY
Length:332
Mass (Da):36,943
Last modified:October 25, 2004 - v2
Checksum:iE80010BAADBED2B4
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti169I → S in AAB33341 (PubMed:7854347).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_03863211T → A in obesity; partial activity. 1 PublicationCorresponds to variant dbSNP:rs372794914Ensembl.1
Natural variantiVAR_01070430S → F in obesity. 1 PublicationCorresponds to variant dbSNP:rs13447323Ensembl.1
Natural variantiVAR_03863336S → Y in obesity; shows the same affinity as the wild-type but significant impairment of cAMP-induced activity in response to melanotan II compared with the wild-type receptor. 1 Publication1
Natural variantiVAR_01070537D → V in obesity. 1 PublicationCorresponds to variant dbSNP:rs13447325EnsemblClinVar.1
Natural variantiVAR_03863450V → M in obesity. 1 PublicationCorresponds to variant dbSNP:rs121913557EnsemblClinVar.1
Natural variantiVAR_03863558S → C in obesity. 1 PublicationCorresponds to variant dbSNP:rs121913558EnsemblClinVar.1
Natural variantiVAR_03863662N → S in obesity; shows a partial cAMP response to alpha-MSH. 2 PublicationsCorresponds to variant dbSNP:rs121913566EnsemblClinVar.1
Natural variantiVAR_07757072N → K Probable disease-associated mutation found in a patient with early onset obesity and hyperphagia; loss of plasma membrane localization; loss of receptor function. 1 Publication1
Natural variantiVAR_01070678P → L in obesity. 1 PublicationCorresponds to variant dbSNP:rs13447326Ensembl.1
Natural variantiVAR_03863788 – 92Missing in obesity; the mutant receptor is expressed well on the cell surface but is completely devoid of ligand binding and cAMP generation in response to agonist stimulation. 1 Publication5
Natural variantiVAR_03863897N → D in obesity; completely unable to generate cAMP in response to ligand; shows evidence of impaired cell surface expression. 2 PublicationsCorresponds to variant dbSNP:rs121913565EnsemblClinVar.1
Natural variantiVAR_038639102I → S in obesity; shows the same affinity as the wild-type but significant impairment of cAMP-induced activity in response to melanotan II compared with the wild-type receptor. 1 PublicationCorresponds to variant dbSNP:rs121913559EnsemblClinVar.1
Natural variantiVAR_038640102I → T in obesity. 1 PublicationCorresponds to variant dbSNP:rs121913559EnsemblClinVar.1
Natural variantiVAR_010707103V → I6 PublicationsCorresponds to variant dbSNP:rs2229616EnsemblClinVar.1
Natural variantiVAR_038641106L → P in obesity; completely unable to generate cAMP in response to ligand; shows evidence of impaired cell surface expression. 1 Publication1
Natural variantiVAR_010708112T → M Polymorphism; no effect on MC4R signaling. 4 PublicationsCorresponds to variant dbSNP:rs13447329Ensembl.1
Natural variantiVAR_038642125I → K in obesity; completely unable to generate cAMP in response to ligand; shows evidence of impaired cell surface expression. 2 Publications1
Natural variantiVAR_038643127S → L in obesity; signaling properties in response to alpha-MSH, beta-MSH and gamma-1-MSH are impaired. 1 PublicationCorresponds to variant dbSNP:rs13447331EnsemblClinVar.1
Natural variantiVAR_038644165R → Q in obesity; shows a partial cAMP response to alpha-MSH. 3 PublicationsCorresponds to variant dbSNP:rs13447332Ensembl.1
Natural variantiVAR_010709165R → W in obesity. 1 PublicationCorresponds to variant dbSNP:rs13447332Ensembl.1
Natural variantiVAR_038645170I → V in obesity. 1 PublicationCorresponds to variant dbSNP:rs121913560EnsemblClinVar.1
Natural variantiVAR_038646175A → T in obesity; shows a partial cAMP response to alpha-MSH. 3 PublicationsCorresponds to variant dbSNP:rs121913563EnsemblClinVar.1
Natural variantiVAR_038647181G → D in obesity; does not bind alpha-MSH. 1 PublicationCorresponds to variant dbSNP:rs13447333Ensembl.1
Natural variantiVAR_038648219A → V in obesity; shows significantly impairment of cAMP-induced activity in response to melanotan II compared with the wild-type receptor. 1 PublicationCorresponds to variant dbSNP:rs121913567EnsemblClinVar.1
Natural variantiVAR_038649226I → T1 PublicationCorresponds to variant dbSNP:rs193922686EnsemblClinVar.1
Natural variantiVAR_010710251I → L5 PublicationsCorresponds to variant dbSNP:rs52820871EnsemblClinVar.1
Natural variantiVAR_010711252G → S in obesity. 1 PublicationCorresponds to variant dbSNP:rs13447336Ensembl.1
Natural variantiVAR_038650253V → I in obesity; shows a partial cAMP response to alpha-MSH. 1 PublicationCorresponds to variant dbSNP:rs187152753EnsemblClinVar.1
Natural variantiVAR_038651271C → R in obesity; completely unable to generate cAMP in response to ligand; shows impaired cell surface expression. 1 PublicationCorresponds to variant dbSNP:rs1057517991Ensembl.1
Natural variantiVAR_038652271C → Y in obesity; no activity. 2 PublicationsCorresponds to variant dbSNP:rs121913562EnsemblClinVar.1
Natural variantiVAR_015357274N → S in obesity. 1 PublicationCorresponds to variant dbSNP:rs121913561EnsemblClinVar.1
Natural variantiVAR_038653316I → S in obesity; shows reduced cAMP response to alpha-MSH; retains normal affinity for the antagonist AGRP. 2 PublicationsCorresponds to variant dbSNP:rs121913564EnsemblClinVar.1
Natural variantiVAR_010712317I → T in obesity. 1 PublicationCorresponds to variant dbSNP:rs13447337Ensembl.1
Natural variantiVAR_038654325L → F in obesity; does not bind alpha-MSH. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L08603 Genomic DNA Translation: AAA35791.1
S77415 Genomic DNA Translation: AAB33341.1
AY236539 Genomic DNA Translation: AAO92061.1
AK314130 mRNA Translation: BAG36820.1
CH471096 Genomic DNA Translation: EAW63105.1
BC069172 mRNA Translation: AAH69172.1
BC101802 mRNA Translation: AAI01803.1
BC111992 mRNA Translation: AAI11993.1
CCDSiCCDS11976.1
PIRiA57055
RefSeqiNP_005903.2, NM_005912.2
UniGeneiHs.532833

Genome annotation databases

EnsembliENST00000299766; ENSP00000299766; ENSG00000166603
GeneIDi4160
KEGGihsa:4160
UCSCiuc002lie.2 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiMC4R_HUMAN
AccessioniPrimary (citable) accession number: P32245
Secondary accession number(s): B2RAC3, Q16317, Q3MIJ6
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1993
Last sequence update: October 25, 2004
Last modified: June 20, 2018
This is version 185 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

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