环球速读：研究揭示肌动蛋白丝组装和老化的结构基础

德国马克斯普朗克分子生理学研究所Stefan Raunser课题组揭示肌动蛋白丝组装和老化的结构基础。这一研究成果于2022年10月26日在线发表在国际学术期刊《自然》上。

研究人员展示了所有核苷酸状态下的F-肌动蛋白的冷冻电镜结构，在有Mg2+或Ca2+的情况下聚合，分辨率约为2.2Å。这些结构显示，肌动蛋白的聚合诱发了核苷酸结合袋中水分子的迁移，激活了其中一个水分子对ATP的亲核攻击。出乎意料的是，随后释放无机磷酸盐（Pi）的后门在所有结构中都是关闭的，这表明Pi的释放是暂时性的。ATP水解和Pi释放后核苷酸结合口袋的微小变化被一个关键的氨基酸感知，并被放大和传送到丝外围。

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此外，核苷酸结合袋中水分子位置的差异解释了为什么Ca2+-肌动蛋白显示出比Mg2+-肌动蛋白更慢的聚合速率。这项工作阐明了支配肌动蛋白丝组装和老化的溶剂驱动的重排，为合理设计用于成像和治疗的药物和小分子奠定了基础。

据介绍，肌动蛋白丝（F-肌动蛋白）的动态周转控制着真核生物的细胞运动，并与F-肌动蛋白核苷酸状态的变化相联系。目前仍不清楚F-肌动蛋白如何水解ATP并随后发生微妙的构象重排，最终导致肌动蛋白结合蛋白的丝解聚。

附：英文原文

Title: Structural basis of actin filament assembly and aging

Author: Oosterheert, Wout, Klink, Bjrn U., Belyy, Alexander, Pospich, Sabrina, Raunser, Stefan

Issue&Volume: 2022-10-26

Abstract: The dynamic turnover of actin filaments (F-actin) controls cellular motility in eukaryotes and is coupled to changes in the F-actin nucleotide state1,2,3. It remains unclear how F-actin hydrolyses ATP and subsequently undergoes subtle conformational rearrangements that ultimately lead to filament depolymerization by actin-binding proteins. Here we present cryo-electron microscopy structures of F-actin in all nucleotide states, polymerized in the presence of Mg2+ or Ca2+ at approximately 2.2 resolution. The structures show that actin polymerization induces the relocation of water molecules in the nucleotide-binding pocket, activating one of them for the nucleophilic attack of ATP. Unexpectedly, the back door for the subsequent release of inorganic phosphate (Pi) is closed in all structures, indicating that Pi release occurs transiently. The small changes in the nucleotide-binding pocket after ATP hydrolysis and Pi release are sensed by a key amino acid, amplified and transmitted to the filament periphery. Furthermore, differences in the positions of water molecules in the nucleotide-binding pocket explain why Ca2+-actin shows slower polymerization rates than Mg2+-actin. Our work elucidates the solvent-driven rearrangements that govern actin filament assembly and aging and lays the foundation for the rational design of drugs and small molecules for imaging and therapeutic applications.

DOI: 10.1038/s41586-022-05241-8

Source: https://www.nature.com/articles/s41586-022-05241-8