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9.A.14.2.3
Melanocortin receptor 4, MC4R, of 332 aas and 7 TMSs. At least 4% of childhood obesity is due to mutations in the hypothalamic MC4R which is important in the regulation of feeding behavior and body weight. MC4R activates the Galphaq/phospholipase C signaling pathway, resulting in alterations of cytoplasmic calcium in immortalized hypothalamic (GT1-1)neurons. Thus, upon agonist binding, MC4R mediates increases in intracellular calcium through the Galphaq-protein/phospholipase C dependent signaling pathway (Newman et al. 2006).  MC4R binds to two neuropeptides, α-melanocyte-stimulating hormone [αMSH] and agouti-related protein [AgRP] which exert opposing effects on downstream responses.  The 3-D structure of MC4R complexed with the cyclic peptide antogonist, SHU9119, revealed a Ca2+-binding site that influences downstream signaling (Chaturvedi and Shukla 2020). Israeli et al. 2021 presented the cryo-EM structure of the human MC4R-Gs signaling complex bound to the agonist setmelanotide, a cyclic peptide recently approved for the treatment of obesity. The work reveals the mechanism of MC4R activation, highlighting a molecular switch that initiates satiation signaling. Calcium (Ca2+) is required for agonist, but not antagonist, efficacy (Israeli et al. 2021).

Accession Number:P32245
Protein Name:Melanocortin receptor 4
Length:332
Molecular Weight:36943.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:7
Location1 / Topology2 / Orientation3: Cell membrane1 / Multi-pass membrane protein2
Substrate NONE

Cross database links:

DIP: DIP-48791N
Entrez Gene ID: 4160   
Pfam: PF00001   
KEGG: hsa:4160   

Gene Ontology

GO:0016021 C:integral to membrane
GO:0005886 C:plasma membrane
GO:0004980 F:melanocyte-stimulating hormone receptor activity
GO:0042923 F:neuropeptide binding
GO:0031625 F:ubiquitin protein ligase binding
GO:0007631 P:feeding behavior
GO:0007188 P:G-protein signaling, coupled to cAMP nucleotide second messenger
GO:0045780 P:positive regulation of bone resorption
GO:0030819 P:positive regulation of cAMP biosynthetic process

References (13)

[1] “Molecular cloning, expression, and gene localization of a fourth melanocortin receptor.”  Gantz I.et.al.   8392067
[2] “Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain.”  Mountjoy K.G.et.al.   7854347
[3] “Complete sequencing and characterization of 21,243 full-length human cDNAs.”  Ota T.et.al.   14702039
[4] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[5] “Mahogunin ring finger-1 (MGRN1) E3 ubiquitin ligase inhibits signaling from melanocortin receptor by competition with Galphas.”  Perez-Oliva A.B.et.al.   19737927
[6] “Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans.”  Hinney A.et.al.   10199800
[7] “A novel melanocortin 4 receptor (MC4R) gene mutation associated with morbid obesity.”  Mergen M.et.al.   11443223
[8] “Mutational analysis of melanocortin-4 receptor, agouti-related protein, and alpha-melanocyte-stimulating hormone genes in severely obese children.”  Dubern B.et.al.   11487744
[9] “Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms.”  Yeo G.S.H.et.al.   12588803
[10] “Deletion of codons 88-92 of the melanocortin-4 receptor gene: a novel deleterious mutation in an obese female.”  Donohoue P.A.et.al.   14671178
[11] “Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene.”  Farooqi I.S.et.al.   12646665
[12] “Identification and characterization of melanocortin-4 receptor gene mutations in morbidly obese finnish children and adults.”  Valli-Jaakola K.et.al.   14764818
[13] “Prevalence of mutations and functional analyses of melanocortin 4 receptor variants identified among 750 men with juvenile-onset obesity.”  Larsen L.H.et.al.   15486053
Structure:
6W25     

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MVNSTHRGMH TSLHLWNRSS YRLHSNASES LGKGYSDGGC YEQLFVSPEV FVTLGVISLL 
61:	ENILVIVAIA KNKNLHSPMY FFICSLAVAD MLVSVSNGSE TIVITLLNST DTDAQSFTVN 
121:	IDNVIDSVIC SSLLASICSL LSIAVDRYFT IFYALQYHNI MTVKRVGIII SCIWAACTVS 
181:	GILFIIYSDS SAVIICLITM FFTMLALMAS LYVHMFLMAR LHIKRIAVLP GTGAIRQGAN 
241:	MKGAITLTIL IGVFVVCWAP FFLHLIFYIS CPQNPYCVCF MSHFNLYLIL IMCNSIIDPL 
301:	IYALRSQELR KTFKEIICCY PLGGLCDLSS RY