EMD-23055

Single-particle
3.64 Å
EMD-23055 Deposition: 01/12/2020
Map released: 08/12/2021
Last modified: 02/02/2022
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-23055

Focused map of the Hsp90-Hsp70-Hop-GR complex: Hsp70D-NBD:Hop-TPR2A

EMD-23055

Single-particle
3.64 Å
EMD-23055 Deposition: 01/12/2020
Map released: 08/12/2021
Last modified: 02/02/2022
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: Hsp90-Hsp70-Hop-GR complex

Deposition Authors: Wang RY, Agard DA
Structure of Hsp90-Hsp70-Hop-GR reveals the Hsp90 client-loading mechanism.
Wang RY, Noddings CM , Kirschke E, Myasnikov AG , Johnson JL , Agard DA
(2022) Nature , 601 , 460 - 464
PUBMED: 34937942
DOI: doi:10.1038/s41586-021-04252-1
ISSN: 1476-4687
ASTM: NATUAS
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 activity3-7. 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.