Structures in G proteins important for subtype selective receptor binding and subsequent activation.
Structures in G proteins important for subtype selective receptor binding and subsequent activation.
复制标题
DOI：
10.1038/s42003-021-02143-9
复制
发表时间：
2021-05-27
影响因子：
5.9
通讯作者：
Bünemann M
中科院分区：
文献类型：
--
作者：
Jelinek V;Mösslein N;Bünemann M
G蛋白偶联受体(GPCRs)选择性地与由四个亚家族组成的特定异源三聚体G蛋白偶联，以诱导适当的生理反应。然而，Gα亚基的结构决定因素仍然难以捉摸，这些决定因素负责大约800个人类GPCR的选择性识别。在这里，我们直接比较了亚型特异性Gα结构对GPCRG蛋白复合体稳定性和两个GQ偶联受体激活的影响。我们使用FRET-分析来区分多个基于GO和GQ的G-α嵌合体，这些嵌合体选择性地被M_3和组胺H_1受体结合和激活。我们发现，包括αN/β1-铰链、β2/β3-环和Gα的α5螺旋在内的N端是关键的选择性决定因素，它们对选择性结合GPCRs和随后的激活的影响取决于特定的受体。总之，这些发现为G蛋白偶联选择性的分子基础提供了新的见解，甚至超出了Gα的C末端。通过嵌合体方法和生物物理(FRET)技术，Jelinek，Mösslein和Bünemann阐明了G蛋白对两个GQ偶联受体的偶联选择性决定因素。他们得出结论，不同的区域，特别是G-α亚单位C-末端尾部之外的区域，共同影响G-蛋白偶联的选择性。
G protein-coupled receptors (GPCRs) selectively couple to specific heterotrimeric G proteins comprised of four subfamilies in order to induce appropriate physiological responses. However, structural determinants in Gα subunits responsible for selective recognition by approximately 800 human GPCRs have remained elusive. Here, we directly compare the influence of subtype-specific Gα structures on the stability of GPCR-G protein complexes and the activation by two Gq-coupled receptors. We used FRET-assays designed to distinguish multiple Go and Gq-based Gα chimeras in their ability to be selectively bound and activated by muscarinic M3 and histaminic H1 receptors. We identify the N-terminus including the αN/β1-hinge, the β2/β3-loop and the α5 helix of Gα to be key selectivity determinants which differ in their impact on selective binding to GPCRs and subsequent activation depending on the specific receptor. Altogether, these findings provide new insights into the molecular basis of G protein-coupling selectivity even beyond the Gα C-terminus. With chimeric approach and biophysical (FRET) techniques, Jelinek, Mösslein & Bünemann elucidate coupling selectivity determinants of G proteins for two Gq-coupled receptors. They conclude that various regions, especially outside of the C-terminal tail of the Gα subunit, collectively affect G-protein-coupling selectivity.
登录
查看更多内容
影响因子：
64.8
作者：
Koehl A;Hu H;Maeda S;Zhang Y;Qu Q;Paggi JM;Latorraca NR;Hilger D;Dawson R;Matile H;Schertler GFX;Granier S;Weis WI;Dror RO;Manglik A;Skiniotis G;Kobilka BK
通讯作者：
Kobilka BK
影响因子：
64.5
作者：
Inoue, Asuka;Raimondi, Francesco;Russell, Robert B.
通讯作者：
Russell, Robert B.
影响因子：
48
作者：
Gibson, Daniel G.;Young, Lei;Smith, Hamilton O.
通讯作者：
Smith, Hamilton O.
影响因子：
64.5
作者：
Du, Yang;Duc, Nguyen Minh;Chung, Ka Young
通讯作者：
Chung, Ka Young
影响因子：
64.8
作者：
CONKLIN, BR;FARFEL, Z;BOURNE, HR
通讯作者：
BOURNE, HR