The highly conserved abundant molecular chaperone Hsp90 is a global cellular regulator
that interacts with client proteins in a dynamic ATP-dependent cycle to ensure client
protein folding, transport and/or assembly into multiprotein complexes. Hsp90-
dependent proteins have critical roles in many forms of cancer and neurodegenerative
disease as well as cystic fibrosis and other diseases. Our long-term goal is to
understand how Hsp90 and cochaperones cooperate in the folding of hundreds of
proteins with diverse sequences and structures sufficiently to develop small compounds
that only affect subsets of Hsp90 clients. In the first Aim, we will use a novel set of
Hsp90 mutants to understand how three cochaperones that bind the closed, ATP and
client-bound conformation of Hsp90 fine-tune client folding. The technically innovative
second Aim will identify and characterize Hsp90 mutants that affect different subsets of
client proteins. Together these studies will enable a better mechanistic understanding of
the function of cochaperones in regulating client selection, conformation and activity.
Identification of clusters of Hsp90 mutants with similar effects will pave a path towards
rational design of compounds with selective effects on Hsp90 clients in vivo.