小柯机器人

美国加州大学David A. Agard团队解析了Hsp90-p23-糖皮质激素受体 (GR)的结构，并揭示了 Hsp90 “客户”重塑机制。该项研究成果发表在2021年12月22日出版的《自然》上。

他们展示了人类 GR 成熟复合物（GR-Hsp90-p23）的冷冻电镜（cryo-EM）结构，揭示了 GR 配体结合结构域恢复为折叠的、配体结合的构象，同时穿过 Hsp90 管腔。此外，p23 使用 C 端螺旋直接稳定天然 GR，从而增强配体结合。这种以天然构象与 Hsp90 结合的客户结构与未折叠激酶 - Hsp90 结构形成鲜明对比。因此，在直接的共同伴侣-客户互动的帮助下，Hsp90 可以直接决定客户特定的折叠结果。连同 GR 加载复杂结构，他们展示了伴侣介导的 GR 重塑的分子机制，据他们所知，为任何 Hsp90 客户建立了第一个完整的伴侣循环。

据悉，Hsp90 是一种保守且必不可少的分子伴侣，负责折叠和激活数百种客户蛋白质。GR是一种模式客户，其活动持续依赖于 Hsp90。GR 配体结合先前被证明是在共同伴侣 p23的帮助下，由 Hsp70 抑制并由 Hsp90 恢复。然而，对于包括 GR 在内的任何客户，都缺乏对发生在非活性 Hsp70-Hsp90“客户加载复合物”和激活的 Hsp90-p23“客户成熟复合物”之间的分子伴侣介导的重塑的理解。

附：英文原文

Title: Structure of Hsp90–p23–GR reveals the Hsp90 client-remodelling mechanism

Author: Noddings, Chari M., Wang, Ray Yu-Ruei, Johnson, Jill L., Agard, David A.

Issue&Volume: 2021-12-22

Abstract: Hsp90 is a conserved and essential molecular chaperone responsible for the folding and activation of hundreds of ‘client’ proteins1,2,3. The glucocorticoid receptor (GR) is a model client that constantly depends on Hsp90 for activity4,5,6,7,8,9. GR ligand binding was previously shown to nr inhibited by Hsp70 and restored by Hsp90, aided by the co-chaperone p2310. However, a molecular understanding of the chaperone-mediated remodelling that occurs between the inactive Hsp70–Hsp90 ‘client-loading complex’ and an activated Hsp90–p23 ‘client-maturation complex’ is lacking for any client, including GR. Here we present a cryo-electron microscopy (cryo-EM) structure of the human GR-maturation complex (GR–Hsp90–p23), revealing that the GR ligand-binding domain is restored to a folded, ligand-bound conformation, while being simultaneously threaded through the Hsp90 lumen. In addition, p23 directly stabilizes native GR using a C-terminal helix, resulting in enhanced ligand binding. This structure of a client bound to Hsp90 in a native conformation contrasts sharply with the unfolded kinase–Hsp90 structure11. Thus, aided by direct co-chaperone–client interactions, Hsp90 can directly dictate client-specific folding outcomes. Together with the GR-loading complex structure12, we present the molecular mechanism of chaperone-mediated GR remodelling, establishing the first, to our knowledge, complete chaperone cycle for any Hsp90 client.

DOI: 10.1038/s41586-021-04236-1

Source: https://www.nature.com/articles/s41586-021-04236-1

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