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构象选择指导β-arrestin在偏向G蛋白偶联受体上的募集
作者:小柯机器人 发布时间:2022/7/10 14:25:14

美国威斯康星医学院Brian F. Volkman团队近期取得重要工作进展,他们研究发现构象选择指导β-arrestin在偏向G蛋白偶联受体上的募集。相关研究成果2022年7月8日在线出版于《科学》杂志上。

在这里,研究人员对13CH3-ε-蛋氨酸标记的ACKR3进行了核磁共振 (NMR) 实验,揭示了β-arrestin募集与细胞外配体结合袋和细胞内β-arrestin偶联区关键区域的构象交换有关。对 ACKR3 突变体在β-arrestin募集中存在缺陷的NMR研究确定了受体核心中的一个变构中枢,该中枢协调异质分布和选定构象状态之间的转变。他们的数据表明,构象选择通过调节细胞内和细胞外区域的受体动力学来指导β-arrestin的募集。

据介绍,G蛋白偶联受体(GPCRs)招募β-arrestins来协调不同的细胞过程,但对驱动这一过程的结构动力学知之甚少。非典型趋化因子受体(ACKRs)是内在的偏向性GPCRs,与β-arrestin而非G蛋白结合,使其成为研究β-arrestin招募的结构基础的模型系统。

附:英文原文

Title: Conformational selection guides β-arrestin recruitment at a biased G protein–coupled receptor

Author: Andrew B. Kleist, Shawn Jenjak, Andrija Sente, Lauren J. Laskowski, Martyna Szpakowska, Maggie M. Calkins, Emilie I. Anderson, Lisa M. McNally, Raimond Heukers, Vladimir Bobkov, Francis C. Peterson, Monica A. Thomas, Andy Chevigné, Martine J. Smit, John D. McCorvy, M. Madan Babu, Brian F. Volkman

Issue&Volume: 2022-07-08

Abstract: G protein–coupled receptors (GPCRs) recruit β-arrestins to coordinate diverse cellular processes, but the structural dynamics driving this process are poorly understood. Atypical chemokine receptors (ACKRs) are intrinsically biased GPCRs that engage β-arrestins but not G proteins, making them a model system for investigating the structural basis of β-arrestin recruitment. Here, we performed nuclear magnetic resonance (NMR) experiments on 13CH3-ε–methionine–labeled ACKR3, revealing that β-arrestin recruitment is associated with conformational exchange at key regions of the extracellular ligand-binding pocket and intracellular β-arrestin–coupling region. NMR studies of ACKR3 mutants defective in β-arrestin recruitment identified an allosteric hub in the receptor core that coordinates transitions among heterogeneously populated and selected conformational states. Our data suggest that conformational selection guides β-arrestin recruitment by tuning receptor dynamics at intracellular and extracellular regions.

DOI: abj4922

Source: https://www.science.org/doi/10.1126/science.abj4922

 

期刊信息
Science:《科学》,创刊于1880年。隶属于美国科学促进会,最新IF:41.037