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Protein

Melanocortin receptor 4

Gene

MC4R

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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).1 Publication

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

  • adenylate cyclase-modulating G-protein coupled receptor signaling pathway Source: ProtInc
  • diet induced thermogenesis Source: Ensembl
  • energy reserve metabolic process Source: Ensembl
  • feeding behavior Source: ProtInc
  • insulin secretion Source: Ensembl
  • negative regulation of feeding behavior Source: Ensembl
  • positive regulation of bone resorption Source: HGNC
  • positive regulation of cAMP biosynthetic process Source: BHF-UCL
  • regulation of grooming behavior Source: Ensembl
  • response to insulin Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

G-protein coupled receptor, Receptor, Transducer

Enzyme and pathway databases

BioCyciZFISH:ENSG00000166603-MONOMER.
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

HGNCiHGNC:6932. MC4R.

Subcellular locationi

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

GO - Cellular componenti

  • integral component of membrane Source: ProtInc
  • nucleus Source: Ensembl
  • plasma membrane Source: Reactome
Complete GO annotation...

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...)Sequence analysis1
Glycosylationi17N-linked (GlcNAc...)Sequence analysis1
Glycosylationi26N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi84Interchain
Lipidationi318S-palmitoyl cysteineSequence analysis1

Keywords - PTMi

Disulfide bond, Glycoprotein, Lipoprotein, Palmitate

Proteomic databases

PaxDbiP32245.
PRIDEiP32245.

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

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.
OMAiGTGTIRQ.
OrthoDBiEOG091G0BVW.
PhylomeDBiP32245.
TreeFamiTF332646.

Family and domain databases

InterProiIPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
IPR000155. Mcort_rcpt_4.
IPR001908. Melancort_rcpt.
IPR001671. Melcrt_ACTH_rcpt.
[Graphical view]
PfamiPF00001. 7tm_1. 1 hit.
[Graphical view]
PRINTSiPR00237. GPCRRHODOPSN.
PR00534. MCRFAMILY.
PR00535. MELNOCORTINR.
PR01062. MELNOCORTN4R.
SMARTiSM01381. 7TM_GPCR_Srsx. 1 hit.
[Graphical view]
PROSITEiPS00237. G_PROTEIN_RECEP_F1_1. 1 hit.
PS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
[Graphical view]

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 rs372794914dbSNPEnsembl.1
Natural variantiVAR_01070430S → F in obesity. 1 PublicationCorresponds to variant rs13447323dbSNPEnsembl.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 rs13447325dbSNPEnsembl.1
Natural variantiVAR_03863450V → M in obesity. 1 PublicationCorresponds to variant rs121913557dbSNPEnsembl.1
Natural variantiVAR_03863558S → C in obesity. 1 PublicationCorresponds to variant rs121913558dbSNPEnsembl.1
Natural variantiVAR_03863662N → S in obesity; shows a partial cAMP response to alpha-MSH. 2 PublicationsCorresponds to variant rs121913566dbSNPEnsembl.1
Natural variantiVAR_01070678P → L in obesity. 1 PublicationCorresponds to variant rs13447326dbSNPEnsembl.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 rs121913565dbSNPEnsembl.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 rs121913559dbSNPEnsembl.1
Natural variantiVAR_038640102I → T in obesity. 1 PublicationCorresponds to variant rs121913559dbSNPEnsembl.1
Natural variantiVAR_010707103V → I.6 PublicationsCorresponds to variant rs2229616dbSNPEnsembl.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 rs13447329dbSNPEnsembl.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 rs13447331dbSNPEnsembl.1
Natural variantiVAR_038644165R → Q in obesity; shows a partial cAMP response to alpha-MSH. 3 PublicationsCorresponds to variant rs13447332dbSNPEnsembl.1
Natural variantiVAR_010709165R → W in obesity. 1 PublicationCorresponds to variant rs13447332dbSNPEnsembl.1
Natural variantiVAR_038645170I → V in obesity. 1 PublicationCorresponds to variant rs121913560dbSNPEnsembl.1
Natural variantiVAR_038646175A → T in obesity; shows a partial cAMP response to alpha-MSH. 3 PublicationsCorresponds to variant rs121913563dbSNPEnsembl.1
Natural variantiVAR_038647181G → D in obesity; does not bind alpha-MSH. 1 PublicationCorresponds to variant rs13447333dbSNPEnsembl.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 rs121913567dbSNPEnsembl.1
Natural variantiVAR_038649226I → T.1 PublicationCorresponds to variant rs193922686dbSNPEnsembl.1
Natural variantiVAR_010710251I → L.5 PublicationsCorresponds to variant rs52820871dbSNPEnsembl.1
Natural variantiVAR_010711252G → S in obesity. 1 PublicationCorresponds to variant rs13447336dbSNPEnsembl.1
Natural variantiVAR_038650253V → I in obesity; shows a partial cAMP response to alpha-MSH. 1 PublicationCorresponds to variant rs187152753dbSNPEnsembl.1
Natural variantiVAR_038651271C → R in obesity; completely unable to generate cAMP in response to ligand; shows impaired cell surface expression. 1 Publication1
Natural variantiVAR_038652271C → Y in obesity; no activity. 2 PublicationsCorresponds to variant rs121913562dbSNPEnsembl.1
Natural variantiVAR_015357274N → S in obesity. 1 PublicationCorresponds to variant rs121913561dbSNPEnsembl.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 rs121913564dbSNPEnsembl.1
Natural variantiVAR_010712317I → T in obesity. 1 PublicationCorresponds to variant rs13447337dbSNPEnsembl.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

Cross-referencesi

Web resourcesi

Wikipedia

Melanocortin receptor entry

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.

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...

Protein-protein interaction databases

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

Chemistry databases

BindingDBiP32245.
ChEMBLiCHEMBL259.
GuidetoPHARMACOLOGYi285.

Protein family/group databases

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

PTM databases

iPTMnetiP32245.
PhosphoSitePlusiP32245.

Polymorphism and mutation databases

BioMutaiMC4R.
DMDMi60392672.

Proteomic databases

PaxDbiP32245.
PRIDEiP32245.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

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

Organism-specific databases

CTDi4160.
DisGeNETi4160.
GeneCardsiMC4R.
HGNCiHGNC:6932. MC4R.
HPAiHPA016719.
MalaCardsiMC4R.
MIMi155541. gene.
601665. phenotype.
neXtProtiNX_P32245.
OpenTargetsiENSG00000166603.
Orphaneti71529. Obesity due to melanocortin 4 receptor deficiency.
PharmGKBiPA30676.
GenAtlasiSearch...

Phylogenomic databases

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

Enzyme and pathway databases

BioCyciZFISH:ENSG00000166603-MONOMER.
ReactomeiR-HSA-375276. Peptide ligand-binding receptors.
R-HSA-418555. G alpha (s) signalling events.
SIGNORiP32245.

Miscellaneous databases

GeneWikiiMelanocortin_4_receptor.
GenomeRNAii4160.
PROiP32245.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000166603.
CleanExiHS_MC4R.
GenevisibleiP32245. HS.

Family and domain databases

InterProiIPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
IPR000155. Mcort_rcpt_4.
IPR001908. Melancort_rcpt.
IPR001671. Melcrt_ACTH_rcpt.
[Graphical view]
PfamiPF00001. 7tm_1. 1 hit.
[Graphical view]
PRINTSiPR00237. GPCRRHODOPSN.
PR00534. MCRFAMILY.
PR00535. MELNOCORTINR.
PR01062. MELNOCORTN4R.
SMARTiSM01381. 7TM_GPCR_Srsx. 1 hit.
[Graphical view]
PROSITEiPS00237. G_PROTEIN_RECEP_F1_1. 1 hit.
PS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiMC4R_HUMAN
AccessioniPrimary (citable) accession number: P32245
Secondary accession number(s): B2RAC3, Q16317, Q3MIJ6
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 1, 1993
Last sequence update: October 25, 2004
Last modified: November 2, 2016
This is version 173 of the entry and version 2 of the sequence. [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

Documents

  1. 7-transmembrane G-linked receptors
    List of 7-transmembrane G-linked receptor entries
  2. Human chromosome 18
    Human chromosome 18: entries, gene names and cross-references to MIM
  3. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  4. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  5. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  6. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  7. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.