New Insights into Hsp90 Structural Plasticity Revealed by cryoEM

Abstract

Heat Shock Protein 90 (Hsp90) acts as a crucial molecular chaperone, playing an essential role in activating numerous signaling proteins. The intricate mechanism of Hsp90 involving ATPase-coupled conformational changes and interactions with cochaperone proteins has been elucidated through biochemical and structural analyses, revealing its activation mechanism and its diverse set of “client” proteins. Despite recent advancements, certain aspects of Hsp90’s ATPase-coupled mechanism remain contentious, and the specific nature of the alterations induced by Hsp90 in client proteins remains largely undiscovered. In this review, we explore the current understanding of Hsp90’s structure and function, drawing insights from single-particle cryoEM studies. Structural studies on Hsp90 using cryoEM have provided valuable insights into the structural dynamics and interactions of this molecular chaperone. CryoEM structures have been instrumental in understanding the ATPase-coupled conformational changes that Hsp90 undergoes during its chaperone cycle. We also highlight recent progress in elucidating the structure of the ATP-bound state of the complete dimeric chaperone. Furthermore, we delve into the roles played by the multitude of cochaperones that collaborate with Hsp90, providing a glimpse into their biochemical mechanisms through the newly obtained cryoEM structures of Hsp90 cochaperone complexes.