Journal Article

Cryo-EM reveals how Hsp90 and FKBP immunophilins co-regulate the glucocorticoid receptor

Noddings, Chari M., Agard, David A., Johnson, Jill L.

2023

Overview

Hsp90 is an essential molecular chaperone responsible for the folding and activation of hundreds of ‘client’ proteins, including the glucocorticoid receptor (GR). Previously, we revealed that Hsp70 and Hsp90 remodel the conformation of GR to regulate ligand binding, aided by co-chaperones. In vivo, the co-chaperones FKBP51 and FKBP52 antagonistically regulate GR activity, but a molecular understanding is lacking. Here we present a 3.01 Å cryogenic electron microscopy structure of the human GR:Hsp90:FKBP52 complex, revealing how FKBP52 integrates into the GR chaperone cycle and directly binds to the active client, potentiating GR activity in vitro and in vivo. We also present a 3.23 Å cryogenic electron microscopy structure of the human GR:Hsp90:FKBP51 complex, revealing how FKBP51 competes with FKBP52 for GR:Hsp90 binding and demonstrating how FKBP51 can act as a potent antagonist to FKBP52. Altogether, we demonstrate how FKBP51 and FKBP52 integrate into the GR chaperone cycle to advance GR to the next stage of maturation. Cryogenic electron microscopy structures reveal how the immunophilin co-chaperones, FKBP51 and FKBP52, each engage Hsp90–client complexes to directly stabilize a folded, ligand-bound client, the glucocorticoid receptor, and promote the next stage of client maturation.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 101/28 / 631/337/470/1981 / 631/45/612/388 / 631/535/1258/1259 / 82/16 / 82/80 / 82/83 / Binding / Biochemistry / Biological Microscopy / Biomedical and Life Sciences / Chaperones / Conformation / Cryoelectron Microscopy / Electron microscopy / Glucocorticoid receptors / Glucocorticoids / Hsp70 protein / HSP90 Heat-Shock Proteins - chemistry / Hsp90 protein / Humans / Immunophilins / Life Sciences / Ligands / Maturation / Membrane Biology / Microscopy / Molecular Chaperones - metabolism / Protein Binding / Protein Structure / Receptors / Receptors, Glucocorticoid - metabolism / Tacrolimus Binding Proteins - chemistry / Tacrolimus Binding Proteins - metabolism / Tacrolimus-binding protein