Journal Article

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

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

2022

Overview

Hsp90 is a conserved and essential molecular chaperone responsible for the folding and activation of hundreds of ‘client’ proteins 1 – 3 . The glucocorticoid receptor (GR) is a model client that constantly depends on Hsp90 for activity 4 – 9 . GR ligand binding was previously shown to be inhibited by Hsp70 and restored by Hsp90, aided by the co-chaperone p23 10 . 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 structure 11 . Thus, aided by direct co-chaperone–client interactions, Hsp90 can directly dictate client-specific folding outcomes. Together with the GR-loading complex structure 12 , we present the molecular mechanism of chaperone-mediated GR remodelling, establishing the first, to our knowledge, complete chaperone cycle for any Hsp90 client. Studies based on cryo-electron microscopy structures of Hsp90 chaperone complexes reveal the molecular mechanism of the chaperone-mediated maturation of the human glucocorticoid receptor.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/28 / 38/1 / 631/45/470 / 631/45/470/1981 / 631/45/612/388 / 631/45/776/812 / 631/535/1258/1259 / 82/80 / 82/83 / 96/34 / Binding / Conformation / Cryoelectron Microscopy / Crystal structure / Electron microscopy / Folding / Glucocorticoids / HSP70 Heat-Shock Proteins - chemistry / HSP70 Heat-Shock Proteins - metabolism / HSP70 Heat-Shock Proteins - ultrastructure / Hsp70 protein / HSP90 Heat-Shock Proteins - chemistry / HSP90 Heat-Shock Proteins - metabolism / HSP90 Heat-Shock Proteins - ultrastructure / Hsp90 protein / Humanities and Social Sciences / Humans / Interfaces / Kinases / Ligands / Maturation / Molecular Chaperones - chemistry / Molecular Chaperones - metabolism / Molecular Chaperones - ultrastructure / multidisciplinary / Packaging / Peptides / Prostaglandin-E Synthases - chemistry / Prostaglandin-E Synthases - metabolism / Prostaglandin-E Synthases - ultrastructure / Protein Binding / Proteins / Receptors, Glucocorticoid - chemistry / Receptors, Glucocorticoid - metabolism / Receptors, Glucocorticoid - ultrastructure / Science / Science (multidisciplinary)