在促肾上腺皮质激素受体中，氨基酸残基 L112 在促肾上腺皮质激素或 α-MSH 的选择性中起着关键作用。
Amino acid residue L112 in the ACTH receptor plays a key role in ACTH or α-MSH selectivity.
机构信息
Department of Surgery, State University of New York at Buffalo, United States.
Department of Surgery, State University of New York at Buffalo, United States.
出版信息
Mol Cell Endocrinol. 2019 Feb 15;482:11-17. doi: 10.1016/j.mce.2018.12.002. Epub 2018 Dec 13.
The adrenocorticotropic hormone (ACTH) receptor, known as the melanocortin-2 receptor (MC2R), plays a key role in regulating adrenocortical function. MC2R is a subtype of the melanocortin receptor family and ACTH is only agonist for MC2R. Our previous result indicates that ACTH1-17 is the minimal peptide required for MC2R activation but DPhe7-ACTH1-17 has no activity at MC2R. In this study, we examined the molecular basis of the MC2R responsible for ligand selectivity using ACTH analogues and MC2R mutagenesis. Our results indicate that substitution of the 3TM of the MC2R with the corresponding region of the MC3R switches DPhe-ACTH1-17 from no activity to agonist. Further experiment indicates that substitution of the amino acid residue leucine to isoleucine in 112 (L112I) of the 3TM of the MC2R changes both DPhe-ACTH1-17 and ACTH1-15 from no activity to agonists. Surprisingly, mutation L112I switches α-MSH from no activity to agonist, suggesting that this residue plays a key role at MC2R for ligand ACTH or α-MSH selectivity.
促肾上腺皮质激素（ACTH）受体，又称黑素皮质素-2 受体（MC2R），在调节肾上腺皮质功能方面发挥着关键作用。MC2R 是黑素皮质素受体家族的一种亚型，而 ACTH 是 MC2R 的唯一激动剂。我们之前的研究结果表明，ACTH1-17 是激活 MC2R 所必需的最小肽，但 DPhe7-ACTH1-17 在 MC2R 上没有活性。在这项研究中，我们使用 ACTH 类似物和 MC2R 突变体检查了负责配体选择性的 MC2R 的分子基础。我们的研究结果表明，用 MC3R 的相应区域替换 MC2R 的 3TM，可将 DPhe-ACTH1-17 从无活性转变为激动剂。进一步的实验表明，在 MC2R 的 3TM 中，将第 112 位的亮氨酸替换为异亮氨酸（L112I），可将 DPhe-ACTH1-17 和 ACTH1-15 从无活性转变为激动剂。令人惊讶的是，突变 L112I 将 α-MSH 从无活性转变为激动剂，表明该残基在 MC2R 上对配体 ACTH 或 α-MSH 的选择性起着关键作用。
Zotero 插件