上海科技大学Yi Jiang等研究人员合作揭示MRAP1对人黑皮质素-2受体信号调节的结构基础。这一研究成果于2023年1月2日在线发表在国际学术期刊《细胞研究》上。

Title: Structural basis of signaling regulation of the human melanocortin-2 receptor by MRAP1

Author: Luo, Ping, Feng, Wenbo, Ma, Shanshan, Dai, Antao, Wu, Kai, Chen, Xianyue, Yuan, Qingning, Cai, Xiaoqing, Yang, Dehua, Wang, Ming-Wei, Eric Xu, H., Jiang, Yi

Issue&Volume: 2023-01-02

Abstract: G protein-coupled receptors (GPCRs) are regulated by various downstream proteins, of which the melanocortin receptor accessory protein 1 (MRAP1) is closely involved in the regulation of melanocortin receptor 2 (MC2R). Assisted by MRAP1, MC2R responds to adrenocorticotropic hormone (ACTH) and stimulates glucocorticoid biogenesis and cortisol secretion. MC2R activation plays an essential role in the hypothalamic-pituitary-adrenal (HPA) axis that regulates stress response, while its dysfunction causes glucocorticoid insufficiency- or cortisol excess-associated disorders. Here, we present a cryo-electron microscopy (cryo-EM) structure of the ACTH-bound MC2R–Gs–MRAP1 complex. Our structure, together with mutagenesis analysis, reveals a unique sharp kink at the extracellular region of MRAP1 and the ‘seat-belt’ effect of MRAP1 on stabilizing ACTH binding and MC2R activation. Mechanisms of ACTH recognition by MC2R and receptor activation are also demonstrated. These findings deepen our understanding of GPCR regulation by accessory proteins and provide valuable insights into the ab initio design of therapeutic agents targeting MC2R.

DOI: 10.1038/s41422-022-00751-6

Source: https://www.nature.com/articles/s41422-022-00751-6