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研究揭示粘附性GPCR的激活机制
2022-04-17 13:15
来源：小柯机器人

美国斯坦福大学医学院Georgios Skiniotis等研究人员合作揭示粘附性GPCR的激活机制。该项研究成果与2022年4月13日在线发表在《自然》杂志上。

据研究人员介绍，粘附性G蛋白偶联受体（aGPCR）的特点是存在参与细胞-细胞和细胞-细胞外基质相互作用的自动蛋白分解区域。 aGPCR自动蛋白分解诱导（GAIN）结构域内的自我切割产生两个原基（N-末端和C-末端片段），在受体到达细胞表面后仍以非共价方式连接。在N端片段解离后，GAIN结构域的C端作为拴住的激动剂（TA）肽来激活7个跨膜结构域，其机制一直不为人所知。
 
研究人员提供了aGPCR家族两个不同成员的冷冻电镜快照，GPR56（也称为ADGRG1）和Latrophilin 3（LPHN3（也称为ADGRL3）。受体在其N端片段结合状态下的低分辨率图表明，GAIN结构域灵活地投向细胞外空间，使加密的TA肽远离七跨膜结构域。GPR56和LPHN3在其活性、G-蛋白偶联状态下的高分辨率结构显示，在胞外区解离后，解密的TA肽与七跨膜结构域核心的相互作用明显保持，也涉及胞外环2。TA的结合稳定了跨膜螺旋6和7中间的断裂，有利于aGPCR的耦合和异源G蛋白的激活。总之，这些结果使研究人员能够提出一个关于aGPCR激活的通用模型。
 
附：英文原文
 
Title: The tethered peptide activation mechanism of adhesion GPCRs

Author: Barros-lvarez, Ximena, Nwokonko, Robert M., Vizurraga, Alexander, Matzov, Donna, He, Feng, Papasergi-Scott, Makaa M., Robertson, Michael J., Panova, Ouliana, Yardeni, Eliane Hadas, Seven, Alpay B., Kwarcinski, Frank E., Su, Hongyu, Peroto, Maria Claudia, Meyerowitz, Justin G., Shalev-Benami, Moran, Tall, Gregory G., Skiniotis, Georgios

Issue&Volume: 2022-04-13

Abstract: Adhesion G-protein-coupled receptors (aGPCRs) are characterized by the presence of auto-proteolysing extracellular regions that are involved in cell–cell and cell–extracellular matrix interactions1. Self cleavage within the aGPCR auto-proteolysis-inducing (GAIN) domain produces two protomers—N-terminal and C-terminal fragments—that remain non-covalently attached after receptors reach the cell surface1. Upon dissociation of the N-terminal fragment, the C-terminus of the GAIN domain acts as a tethered agonist (TA) peptide to activate the seven-transmembrane domain with a mechanism that has been poorly understood2,3,4,5. Here we provide cryo-electron microscopy snapshots of two distinct members of the aGPCR family, GPR56 (also known as ADGRG1) and latrophilin 3 (LPHN3 (also known as ADGRL3)). Low-resolution maps of the receptors in their N-terminal fragment-bound state indicate that the GAIN domain projects flexibly towards the extracellular space, keeping the encrypted TA peptide away from the seven-transmembrane domain. High-resolution structures of GPR56 and LPHN3 in their active, G-protein-coupled states, reveal that after dissociation of the extracellular region, the decrypted TA peptides engage the seven-transmembrane domain core with a notable conservation of interactions that also involve extracellular loop 2. TA binding stabilizes breaks in the middle of transmembrane helices 6 and 7 that facilitate aGPCR coupling and activation of heterotrimeric G proteins. Collectively, these results enable us to propose a general model for aGPCR activation.

DOI: 10.1038/s41586-022-04575-7

Source: https://www.nature.com/articles/s41586-022-04575-7

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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