Hsp90 provides a platform for kinase dephosphorylation by PP5

Abstract

The Hsp90 molecular chaperone collaborates with the phosphorylated Cdc37 cochaperone to maintain kinase proteostasis through the folding and activation of its many client kinases. As with many kinases, the Hsp90 client kinase CRaf is activated by phosphorylation at specific regulatory sites. The cochaperone phosphatase PP5 dephosphorylates CRaf but also Cdc37 in an Hsp90-dependent manner. Although dephosphorylating Cdc37 has been proposed as a mechanism for releasing Hsp90-bound kinases, here we show that Hsp90 bound kinases sterically inhibit Cdc37 dephosphorylation indicating kinase release must occur before Cdc37 dephosphorylation. The cryo-EM structure of PP5 in complex with Hsp90:Cdc37:CRaf reveals how Hsp90 both activates PP5 and scaffolds its association with the bound CRaf to dephosphorylate a site at the C-terminus of the kinase domain. Thus, we directly show how Hsp90s role in maintaining protein homeostasis goes beyond folding and activation to include post translationally modifying its client kinases.