小柯机器人

美国加州大学David A. Agard解析了Hsp90–Hsp70–Hop–糖皮质激素受体 (GR)的结构，并揭示了Hsp90 “客户”- “加载”机制。2021年12月22日，国际知名学术期刊《自然》发表了这一成果。

他们报告了 GR 加载复合物的冷冻电镜结构，其中 Hsp70 将 GR 加载到 Hsp90 上，揭示了 Hsp90 和 Hsp70 直接协调的分子基础。该结构揭示了两种 Hsp70 蛋白，其中一种提供 GR，另一种提供 Hop 协同分子伴侣支架。Hop 与复合物的所有成分相互作用，包括 GR，并为随后的 ATP 水解准备好 Hsp90。GR 部分展开并通过由 Hsp90、Hsp70 和 Hop 组成的扩展结合口袋识别，揭示了 GR 加载和失活的机制。连同GR-成熟复合物结构，他们提出了一个完整的分子伴侣依赖的客户重塑分子机制，并建立了客户识别、抑制、转移和激活的一般原则。

据悉，保持健康的蛋白质组是所有生物体生存的基础。与此相关的是 Hsp90 和 Hsp70，它们是共同促进 Hsp90的许多“客户蛋白”的折叠、重塑和成熟的分子伴侣。GR是一种模型客户蛋白，其活性严格依赖于 Hsp90 和 Hsp70。伴侣 GR 涉及 Hsp70 失活的循环；形成无活性的 GR-Hsp90-Hsp70-Hop“加载”复合物；转化为活性 GR-Hsp90-p23“成熟”复合物；以及随后的 GR 版本。然而，据他们所知，任何客户蛋白质都缺乏对这种复杂的分子伴侣循环的分子理解。

附：英文原文

Title: Structure of Hsp90–Hsp70–Hop–GR reveals the Hsp90 client-loading mechanism

Author: Wang, Ray Yu-Ruei, Noddings, Chari M., Kirschke, Elaine, Myasnikov, Alexander G., Johnson, Jill L., Agard, David A.

Issue&Volume: 2021-12-22

Abstract: Maintaining a healthy proteome is fundamental for the survival of all organisms1. Integral to this are Hsp90 and Hsp70, molecular chaperones that together facilitate the folding, remodelling and maturation of the many ‘client proteins’ of Hsp902. The glucocorticoid receptor (GR) is a model client protein that is strictly dependent on Hsp90 and Hsp70 for activity3,4,5,6,7. Chaperoning GR involves a cycle of inactivation by Hsp70; formation of an inactive GR–Hsp90–Hsp70–Hop ‘loading’ complex; conversion to an active GR–Hsp90–p23 ‘maturation’ complex; and subsequent GR release8. However, to our knowledge, a molecular understanding of this intricate chaperone cycle is lacking for any client protein. Here we report the cryo-electron microscopy structure of the GR-loading complex, in which Hsp70 loads GR onto Hsp90, uncovering the molecular basis of direct coordination by Hsp90 and Hsp70. The structure reveals two Hsp70 proteins, one of which delivers GR and the other scaffolds the Hop cochaperone. Hop interacts with all components of the complex, including GR, and poises Hsp90 for subsequent ATP hydrolysis. GR is partially unfolded and recognized through an extended binding pocket composed of Hsp90, Hsp70 and Hop, revealing the mechanism of GR loading and inactivation. Together with the GR-maturation complex structure9, we present a complete molecular mechanism of chaperone-dependent client remodelling, and establish general principles of client recognition, inhibition, transfer and activation.

DOI: 10.1038/s41586-021-04252-1

Source: https://www.nature.com/articles/s41586-021-04252-1

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html