7KW7

Atomic cryoEM structure of Hsp90-Hsp70-Hop-GR

7KW7 の概要

• エントリーDOI: 10.2210/pdb7kw7/pdb
• EMDBエントリー: 23050
• 分子名称: Heat shock protein HSP 90-alpha, Heat shock 70 kDa protein 1A, Stress-induced-phosphoprotein 1, ... (7 entities in total)
• 機能のキーワード: client-loading, chaperone
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 459237.13

構造登録者

Wang, R.Y.,Noddings, C.M.,Kirschke, E.,Myasnikov, A.,Johnson, J.L.,Agard, D.A. (登録日: 2020-11-30, 公開日: 2021-12-08, 最終更新日: 2024-05-29)

主引用文献

Wang, R.Y.,Noddings, C.M.,Kirschke, E.,Myasnikov, A.G.,Johnson, J.L.,Agard, D.A.
Structure of Hsp90-Hsp70-Hop-GR reveals the Hsp90 client-loading mechanism.
Nature, 601:460-464, 2022

PubMed Abstract: Maintaining a healthy proteome is fundamental for the survival of all organisms. Integral to this are Hsp90 and Hsp70, molecular chaperones that together facilitate the folding, remodelling and maturation of the many 'client proteins' of Hsp90. The glucocorticoid receptor (GR) is a model client protein that is strictly dependent on Hsp90 and Hsp70 for activity. 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 release. 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 structure, we present a complete molecular mechanism of chaperone-dependent client remodelling, and establish general principles of client recognition, inhibition, transfer and activation.

PubMed: 34937942
DOI: 10.1038/s41586-021-04252-1

実験手法

ELECTRON MICROSCOPY (3.57 Å)