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

• Published in: Nature (London) Vol. 601; no. 7893; pp. 465 - 469
• Main Authors: Noddings, Chari M., Wang, Ray Yu-Ruei, Johnson, Jill L., Agard, David A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.01.2022; Nature Publishing Group
• Subjects: 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)
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-021-04236-1

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.