Mechanism of client kinase dephosphorylation by the HSP90-CDC37-PP5 complex

Activation of client protein kinases by the HSP90 molecular chaperone system is affected by phosphorylation at multiple sites on HSP90, on the kinase specific co-chaperone CDC37, and the client itself. Removal of regulatory phosphorylation from client kinases and release from the HSP90-CDC37 system depends on a Ser/Thr phosphatase PP5, which associates with HSP90 via its N-terminal TPR domain. Here we present the cryoEM structure of the oncogenic client kinase BRAFV600E bound to HSP90-CDC37, and structures of complexes of PP5 with that. Together with proteomic analysis of its phosphatase activity, our results reveal how PP5 is activated by recruitment to HSP90 complexes to dephosphorylate client proteins.