Molecular Identification of the Human Melanocortin-2 Receptor Responsible for Ligand Binding and Signaling

详细信息    查看全文

• 作者：Min Chen ; Charles J. Aprahamian ; Robert A. Kesterson ; Carroll M. Harmon ; Yingkui Yang
• 刊名：Biochemistry
• 出版年：2007
• 出版时间：October 9, 2007
• 年：2007
• 卷：46
• 期：40
• 页码：11389 - 11397
• 全文大小：357K
• 年卷期：v.46,no.40(October 9, 2007)
• ISSN：1520-4995

文摘

The melanocortin-2 receptor (MC2R), also known as the adrenocorticotropic hormone (ACTH)receptor, plays an important role in regulating and maintaining adrenocortical function, specificallysteroidogenesis. Mutations of the human MC2R (hMC2R) gene have also been identified in humans withfamilial glucocorticoid deficiency; however, the molecular basis responsible for hMC2R ligand bindingand signaling remains unclear. In this study, both truncated ACTH peptides and site-directed mutagenesisstudies were used to determine molecular mechanisms of hMC2R binding ACTH and signaling. Ourresults indicate that ACTH1-16 is the minimal peptide required for hMC2R binding and signaling.Mutations of common melanocortin receptor family amino acid residues E80 in transmembrane domain2 (TM2), D107 in TM3, F178 in TM4, F235 and H238 in TM6, and F258 in TM7 significantly reducedACTH-binding affinity and signaling. Furthermore, mutations of unique amino acids D104 and F108 inTM3 and F168 and F178 in TM4 significantly decreased ACTH binding and signaling. In conclusion,our results suggest that the residues in TM2, TM3, and TM6 of hMC2R share similar binding sites withother MCRs but the residues identified in TM4 and TM7 of hMC2R are unique and required for ACTHselectivity. Our study suggests that hMC2R may have a broad binding pocket in which both conservedand unique amino acid residues are required, which may be the reason why -MSH was not able to bindhMC2R.