小柯机器人

中国科学院上海药物研究所吴蓓丽等研究人员合作揭示胰高血糖素受体上的抑制蛋白尾部结合。相关论文于2023年8月9日在线发表在《自然》杂志上。

研究人员报告了胰高血糖素受体（GCGR）在与胰高血糖素结合和无配体状态下与β-抑制蛋白1（βarr1）结合的两种结构。这些结构揭示了一种受体尾部与βarr1结合的模式，这种模式具有许多以前从未观察到的独特特征。第八螺旋（而不是受体核心）通过与βarr1的中心嵴形成广泛的相互作用，在容纳βarr1方面发挥了重要作用。βarr1的C边缘与受体螺旋束之间的紧密联系进一步确定了尾部结合的姿势，并通过磷脂衍生物将βarr1与GCGR的螺旋I和VIII连接起来而使其稳定。

由于缺乏与抑制蛋白的任何接触，受体核心处于非活性状态，并与胰高血糖素松散地结合。进一步的功能研究表明，GCGR-βarr的尾部构象控制着βarr在质膜上的招募和GCGR的内吞，并为该受体与G蛋白和βarr同时形成超级复合物以促进内体中的持续信号传导提供了分子基础。这些发现扩展了人们对抑制蛋白介导的GPCR功能调节的认识。

据介绍，抑制蛋白通过对G蛋白激活脱敏和介导受体内化，在调节G蛋白偶联受体（GPCR）信号传导方面发挥着关键作用。有人提出，抑制蛋白以两种不同的构象（“尾部”和“核心”）与受体结合，这两种构象被认为支配着受体信号传导和贩运的不同过程。然而，关于抑制蛋白与受体尾部结合的结构信息却很少。

附：英文原文

Title: Tail engagement of arrestin at the glucagon receptor

Author: Chen, Kun, Zhang, Chenhui, Lin, Shuling, Yan, Xinyu, Cai, Heng, Yi, Cuiying, Ma, Limin, Chu, Xiaojing, Liu, Yuchen, Zhu, Ya, Han, Shuo, Zhao, Qiang, Wu, Beili

Issue&Volume: 2023-08-09

Abstract: Arrestins have pivotal roles in regulating G protein-coupled receptor (GPCR) signalling by desensitizing G protein activation and mediating receptor internalization1,2. It has been proposed that the arrestin binds to the receptor in two different conformations, ‘tail’ and ‘core’, which were suggested to govern distinct processes of receptor signalling and trafficking3,4. However, little structural information is available for the tail engagement of the arrestins. Here we report two structures of the glucagon receptor (GCGR) bound to β-arrestin 1 (βarr1) in glucagon-bound and ligand-free states. These structures reveal a receptor tail-engaged binding mode of βarr1 with many unique features, to our knowledge, not previously observed. Helix VIII, instead of the receptor core, has a major role in accommodating βarr1 by forming extensive interactions with the central crest of βarr1. The tail-binding pose is further defined by a close proximity between the βarr1 C-edge and the receptor helical bundle, and stabilized by a phosphoinositide derivative that bridges βarr1 with helices I and VIII of GCGR. Lacking any contact with the arrestin, the receptor core is in an inactive state and loosely binds to glucagon. Further functional studies suggest that the tail conformation of GCGR–βarr governs βarr recruitment at the plasma membrane and endocytosis of GCGR, and provides a molecular basis for the receptor forming a super-complex simultaneously with G protein and βarr to promote sustained signalling within endosomes. These findings extend our knowledge about the arrestin-mediated modulation of GPCR functionalities.

DOI: 10.1038/s41586-023-06420-x

Source: https://www.nature.com/articles/s41586-023-06420-x

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
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