Glucocorticoid Receptor Function Regulated by Coordinated Action of the Hsp90 and Hsp70 Chaperone Cycles

• Published in: Cell 2014-06, Vol.157 (7), p.1685-1697
• Main Authors: Kirschke, Elaine, Goswami, Devrishi, Southworth, Daniel, Griffin, Patrick R., Agard, David A.
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Amino Acid Sequence; HSP70 Heat-Shock Proteins - metabolism; HSP90 Heat-Shock Proteins - metabolism; Humans; Models, Molecular; Molecular Sequence Data; Protein Folding; Receptors, Glucocorticoid - chemistry; Receptors, Glucocorticoid - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2014.04.038

The glucocorticoid receptor (GR), like many signaling proteins, depends on the Hsp90 molecular chaperone for in vivo function. Although Hsp90 is required for ligand binding in vivo, purified apo GR is capable of binding ligand with no enhancement from Hsp90. We reveal that Hsp70, known to facilitate client delivery to Hsp90, inactivates GR through partial unfolding, whereas Hsp90 reverses this inactivation. Full recovery of ligand binding requires ATP hydrolysis on Hsp90 and the Hop and p23 cochaperones. Surprisingly, Hsp90 ATP hydrolysis appears to regulate client transfer from Hsp70, likely through a coupling of the two chaperone’s ATP cycles. Such coupling is embodied in contacts between Hsp90 and Hsp70 in the GR:Hsp70:Hsp90:Hop complex imaged by cryoelectron microscopy. Whereas GR released from Hsp70 is aggregation prone, release from Hsp90 protects GR from aggregation and enhances its ligand affinity. Together, this illustrates how coordinated chaperone interactions can enhance stability, function, and regulation. [Display omitted] •Hsp70 promotes GR ligand release and inactivation by inducing partial unfolding•Subsequent Hsp90 binding and ATP hydrolysis on Hsp90 reactivate GR ligand binding•Interaction with the Hsp90/Hsp70 chaperone systems results in enhanced GR function•Hsp90:Hop:Hsp70:GR complex reveals further interactions between Hsp70 and Hsp90 Hsp90 activation of the glucocorticoid receptor (GR) is intimately tied to GR’s interaction with Hsp70, which drives GR inactivation through partial unfolding. Hsp90 then utilizes ATP hydrolysis to reverse the Hsp70 inactivation and protects GR as it folds to a highly active state.