Structural basis for the dynamic chaperoning of disordered clients by Hsp90

Abstract Molecular chaperone Hsp90 is a ubiquitous regulator that fine-tunes and remodels diverse client proteins, exerting profound effects on normal biology and diseases. However, the atomic-level chaperoning mechanism of Hsp90 remains elusive. Here, using NMR spectroscopy in combination with other techniques, we determined the solution structure of the initial encounter complex in the chaperone cycle, wherein Hsp90 adopts an open conformation while engaging with a disordered client. Our structure reveals a dual-binding mechanism, as Hsp90 utilizes two distinct sites that synergistically capture hydrophobic segments within client proteins, forming a bipartite complex that enables rapid conformational samplings. Furthermore, we demonstrate that the chaperone cycle triggers significant conformational and dynamic transformations. Distant client binding effectively primes Hsp90's global dynamics and conformational equilibrium, ultimately unleashing its ATPase potential for efficient client remodeling. These findings offer fundamental insights into the dynamic machinery of Hsp90, contributing to a unified conceptual and mechanistic understanding of Hsp90-client interactions.