The known unknowns of the Hsp90 chaperone

TL;DR

This paper reviews unresolved fundamental questions about Hsp90's molecular function, emphasizing the importance of understanding its mechanisms for advancing drug development and highlighting new research opportunities like single-molecule techniques.

Contribution

It identifies key unknowns in Hsp90's function and discusses innovative approaches to address these gaps, advancing the field's understanding.

Findings

Highlights three fundamental open questions about Hsp90

Discusses the potential of single-molecule technologies

Provides insights into future research directions

Abstract

Molecular chaperones are vital proteins that maintain protein homeostasis by assisting in protein folding, activation, degradation, and stress protection. Among them, heat-shock protein 90 (Hsp90) stands out as an essential proteostasis hub in eukaryotes, chaperoning hundreds of "clients" (substrates). After decades of research, several "known unknowns" about the molecular function of Hsp90 remain unanswered, hampering rational drug design for the treatment of cancers, neurodegenerative and other diseases. We highlight three fundamental open questions, reviewing the current state of the field for each, and discuss new opportunities, including single-molecule technologies, to answer the known unknowns of the Hsp90 chaperone.