内皮素受体 B 型与 Gs、Gi 和 Gq 相互作用的分子机制。
Molecular mechanism of the endothelin receptor type B interactions with Gs, Gi, and Gq.
机构信息
School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Republic of Korea.
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bumkyo-ku, Tokyo 113-0033, Japan.
出版信息
Structure. 2024 Oct 3;32(10):1632-1639.e4. doi: 10.1016/j.str.2024.06.020. Epub 2024 Jul 22.
The endothelin receptor type B (ET) exhibits promiscuous coupling with various heterotrimeric G protein subtypes including Gs, Gi/o, Gq/11, and G12/13. Recent fluorescence and structural studies have raised questions regarding the coupling efficiencies and determinants of these G protein subtypes. Herein, by utilizing an integrative approach, combining hydrogen/deuterium exchange mass spectrometry and NanoLuc Binary Technology-based cellular systems, we investigated conformational changes of Gs, Gi, and Gq triggered by ET activation. ET coupled to Gi and Gq but not with Gs. We underscored the critical roles of specific regions, including the C terminus of Gα and intracellular loop 2 (ICL2) of ET in ET-Gi1 or ET-Gq coupling. Although The C terminus of Gα is essential for ET-Gi1 and ET-Gq coupling, ET ICL2 influences Gq-coupling but not Gi1-coupling. Our results suggest a differential coupling efficiency of ET with Gs, Gi1, and Gq, accompanied by distinct conformational changes in G proteins upon ET-induced activation.
内皮素受体 B（ET）与各种异三聚体 G 蛋白亚型（包括 Gs、Gi/o、Gq/11 和 G12/13）表现出混杂偶联。最近的荧光和结构研究对这些 G 蛋白亚型的偶联效率和决定因素提出了质疑。在此，通过利用氢/氘交换质谱和基于 NanoLuc 双分子技术的细胞系统的综合方法，我们研究了 ET 激活引发的 Gs、Gi 和 Gq 构象变化。ET 与 Gi 和 Gq 偶联，但不与 Gs 偶联。我们强调了特定区域的关键作用，包括 Gα 的 C 末端和 ET 的细胞内环 2（ICL2）在 ET-Gi1 或 ET-Gq 偶联中的作用。虽然 Gα 的 C 末端对于 ET-Gi1 和 ET-Gq 偶联是必需的，但 ET ICL2 影响 Gq 偶联但不影响 Gi1 偶联。我们的结果表明，ET 与 Gs、Gi1 和 Gq 的偶联效率存在差异，并伴随着 ET 诱导激活时 G 蛋白的独特构象变化。
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