浙江大学张岩等研究人员合作揭示蛋白酶激活受体的系链激动作用和G蛋白耦合的结构基础。相关论文于2024年7月12日在线发表在《细胞研究》杂志上。

研究人员展示了蛋白酶激活受体1（PAR1）在其天然缔合激动剂（TA）诱导下，与两种不同下游蛋白（Gq和Gi异三聚体）复合的冷冻电子显微镜结构。TA肽位于一个表面口袋内，通过显著的构象变化激活PAR1。与典型的受体激活涉及跨膜螺旋6（TM6）的外移不同，PAR1的激活特征在于TM6和TM7的同时向下移动，以及一组芳香族残基的旋转。这导致一个细胞内阴离子的位置移动，为下游G蛋白结合创造了空间。

研究结果描述了TA识别模式，并强调了PAR家族中第二细胞外环在与TA形成β-折叠方面的独特作用，这在其他TA激活的受体中未见。此外，细胞内环2/3与不同G蛋白的Gα亚基之间相互作用的细微差异，对于决定G蛋白偶联的特异性至关重要。这些见解有助于理解蛋白酶激活受体（PAR）的配体结合和激活机制，揭示了PAR1在G蛋白偶联中的多功能性基础。

据介绍，PAR是G蛋白偶联受体超家族中的一个独特群体，通过酶切割激活细胞外蛋白酶，从而触发细胞内信号通路。PAR1是该家族的一个关键成员，被认为是管理血栓性疾病的重要药理学目标。

附：英文原文

Title: Structural basis of tethered agonism and G protein coupling of protease-activated receptors

Author: Guo, Jia, Zhou, Yun-Li, Yang, Yixin, Guo, Shimeng, You, Erli, Xie, Xin, Jiang, Yi, Mao, Chunyou, Xu, H. Eric, Zhang, Yan

Issue&Volume: 2024-07-12

Abstract: Protease-activated receptors (PARs) are a unique group within the G protein-coupled receptor superfamily, orchestrating cellular responses to extracellular proteases via enzymatic cleavage, which triggers intracellular signaling pathways. Protease-activated receptor 1 (PAR1) is a key member of this family and is recognized as a critical pharmacological target for managing thrombotic disorders. In this study, we present cryo-electron microscopy structures of PAR1 in its activated state, induced by its natural tethered agonist (TA), in complex with two distinct downstream proteins, the Gq and Gi heterotrimers, respectively. The TA peptide is positioned within a surface pocket, prompting PAR1 activation through notable conformational shifts. Contrary to the typical receptor activation that involves the outward movement of transmembrane helix 6 (TM6), PAR1 activation is characterized by the simultaneous downward shift of TM6 and TM7, coupled with the rotation of a group of aromatic residues. This results in the displacement of an intracellular anion, creating space for downstream G protein binding. Our findings delineate the TA recognition pattern and highlight a distinct role of the second extracellular loop in forming β-sheets with TA within the PAR family, a feature not observed in other TA-activated receptors. Moreover, the nuanced differences in the interactions between intracellular loops 2/3 and the Gα subunit of different G proteins are crucial for determining the specificity of G protein coupling. These insights contribute to our understanding of the ligand binding and activation mechanisms of PARs, illuminating the basis for PAR1’s versatility in G protein coupling.

DOI: 10.1038/s41422-024-00997-2

Source: https://www.nature.com/articles/s41422-024-00997-2