Molecular identification of the human melanocortin-2 receptor responsible for ligand binding and signaling
Molecular identification of the human melanocortin-2 receptor responsible for ligand binding and signaling
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DOI：
10.1021/bi700125e
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发表时间：
2007-10-09
期刊：
影响因子：
2.9
通讯作者：
Yang, Yingkui
中科院分区：
文献类型：
--
作者：
Chen, Min;Aprahamian, Charles J.;Yang, Yingkui
黑皮质素-2受体（MC 2 R），也称为促肾上腺皮质激素（ACTH）受体，在调节和维持肾上腺皮质功能，特别是类固醇生成中起重要作用。人类MC 2 R（hMC 2 R）基因突变也已在家族性糖皮质激素缺乏症患者中发现;然而，负责hMC 2 R配体结合和信号传导的分子基础仍不清楚。在这项研究中，两个截短的ACTH肽和定点诱变研究被用来确定hMC 2 R结合ACTH和信号转导的分子机制。我们的结果表明，ACTH 1 -16是hMC 2 R结合和信号传导所需的最小肽。跨膜结构域2（TM 2）中常见黑皮质素受体家族氨基酸残基E80、TM 3中D107、TM 4中F178、TM 6中F235和H238以及TM 7中F258的突变显著降低ACTH结合亲和力和信号传导。此外，TM 3中的独特氨基酸D104和F108以及TM 4中的F168和F178的突变显著降低ACTH结合和信号传导。总之，我们的研究结果表明，TM 2，TM 3和TM 6中的残基hMC 2 R与其他MCR共享相似的结合位点，但TM 4和TM 7中鉴定的hMC 2 R的残基是独特的，是ACTH选择性所必需的。我们的研究表明，hMC 2 R可能有一个广泛的结合口袋，其中既需要保守的氨基酸残基，也需要独特的氨基酸残基，这可能是为什么α-MSH不能结合hMC 2 R的原因。
The melanocortin-2 receptor (MC2R), also known as the adrenocorticotropic hormone (ACTH) receptor, plays an important role in regulating and maintaining adrenocortical function, specifically steroidogenesis. Mutations of the human MC2R (hMC2R) gene have also been identified in humans with familial glucocorticoid deficiency; however, the molecular basis responsible for hMC2R ligand binding and signaling remains unclear. In this study, both truncated ACTH peptides and site-directed mutagenesis studies were used to determine molecular mechanisms of hMC2R binding ACTH and signaling. Our results 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 domain 2 (TM2), D107 in TM3, F178 in TM4, F235 and H238 in TM6, and F258 in TM7 significantly reduced ACTH-binding affinity and signaling. Furthermore, mutations of unique amino acids D104 and F108 in TM3 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 with other MCRs but the residues identified in TM4 and TM7 of hMC2R are unique and required for ACTH selectivity. Our study suggests that hMC2R may have a broad binding pocket in which both conserved and unique amino acid residues are required, which may be the reason why alpha-MSH was not able to bind hMC2R.