Dores Robert M, Liang Liang
University of Denver, Department of Biological Sciences, Denver, CO 80210, USA.
University of Denver, Department of Biological Sciences, Denver, CO 80210, USA.
Gen Comp Endocrinol. 2014 Jul 1;203:3-9. doi: 10.1016/j.ygcen.2014.03.039. Epub 2014 Apr 5.
Following the biochemical characterization of the pituitary hormone, adrenocorticotropin (ACTH), in the 1950's, a number of structure/function studies were done which identifies two amino acid motifs in ACTH, the HFRW motif and KKRR motif, as critical for the activation of the "ACTH" receptor on adrenal cortex cells. In the 1990's the "ACTH" receptor was identified as a member of the melanocortin receptor gene family, and given the name melanocortin-2 receptor (MC2R). Since that time a number of studies on both tetrapod and teleost MC2R orthologs have established that these orthologs can only be activated by ACTH, but not by any of the MSH-sized melanocortin ligands, and these orthologs require interaction with the melanocortin-2 receptor accessory protein (MRAP) for functional expression. This review summarizes recent structure/function studies on human ACTH, and points out the importance of the GKPVG motif in ACTH for the activation of the receptor. In this regard, a multiple-step model for the activation of tetrapod and teleost MC2R orthologs is presented, and the evolution of gnathostome MC2R ligand selectivity and the requirement for MRAP interaction is discussed in light of a recent study on a cartilaginous fish MC2R ortholog. This review contains excerpts from the Gorbman/Bern Lecture presented at the Second Meeting of the North American Society for Comparative Endocrinology (NASCE).
在20世纪50年代对垂体激素促肾上腺皮质激素（ACTH）进行生化特性鉴定之后，开展了一系列结构/功能研究，这些研究确定了ACTH中的两个氨基酸基序，即HFRW基序和KKRR基序，对肾上腺皮质细胞上“ACTH”受体的激活至关重要。在20世纪90年代，“ACTH”受体被鉴定为黑皮质素受体基因家族的成员，并被命名为黑皮质素-2受体（MC2R）。从那时起，对四足动物和硬骨鱼MC2R直系同源物的多项研究证实，这些直系同源物只能被ACTH激活，而不能被任何MSH大小的黑皮质素配体激活，并且这些直系同源物需要与黑皮质素-2受体辅助蛋白（MRAP）相互作用才能进行功能性表达。本综述总结了近期关于人ACTH的结构/功能研究，并指出ACTH中GKPVG基序对受体激活的重要性。在这方面，提出了一个激活四足动物和硬骨鱼MC2R直系同源物的多步骤模型，并根据最近对一种软骨鱼MC2R直系同源物的研究，讨论了有颌类动物MC2R配体选择性的进化以及对MRAP相互作用的需求。本综述包含在北美比较内分泌学会（NASCE）第二次会议上发表的戈尔布曼/伯恩讲座的节选内容。
