Hsp90 provides a platform for kinase dephosphorylation by PP5

PP5 requires the molecular chaperone Hsp90 to dephosphorylate CRaf kinase and the Hsp90 cochaperone Cdc37. Here, authors show how Hsp90 acts as a platform to allow for targeted dephosphorylation by PP5. The Hsp90 molecular chaperone collaborates with the phosphorylated Cdc37 cochaperone for 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 and 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. Our 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 phosphorylation sites neighboring the kinase domain. Thus, we directly show how Hsp90's role in maintaining protein homeostasis goes beyond folding and activation to include post translationally modifying its client kinases.

Automated summary

PP5 requires Hsp90 to dephosphorylate CRaf kinase and Cdc37. Hsp90 acts as a platform to facilitate targeted dephosphorylation by PP5 and collaborates with phosphorylated Cdc37 for the folding and activation of client kinases. The cryo-EM structure reveals how Hsp90 activates and scaffolds PP5 to dephosphorylate nearby phosphorylation sites of CRaf, showing the role of Hsp90 in post-translational modification of client kinases goes beyond folding and activation.