7ZR5

CryoEM structure of HSP90-CDC37-BRAF(V600E)-PP5(closed) complex

Summary for 7ZR5

• Entry DOI: 10.2210/pdb7zr5/pdb
• EMDB information: 14883
• Descriptor: Heat shock protein HSP 90-beta, Hsp90 co-chaperone Cdc37, Serine/threonine-protein kinase B-raf, ... (5 entities in total)
• Functional Keywords: complex, protein binding
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 367270.01

Authors

Oberoi, J.,Pearl, L.H. (deposition date: 2022-05-03, release date: 2022-12-14, Last modification date: 2024-11-06)

Primary citation

Oberoi, J.,Guiu, X.A.,Outwin, E.A.,Schellenberger, P.,Roumeliotis, T.I.,Choudhary, J.S.,Pearl, L.H.
HSP90-CDC37-PP5 forms a structural platform for kinase dephosphorylation.
Nat Commun, 13:7343-7343, 2022

PubMed Abstract: Activation of client protein kinases by the HSP90 molecular chaperone system is affected by phosphorylation at multiple sites on HSP90, the kinase-specific co-chaperone CDC37, and the kinase client itself. Removal of regulatory phosphorylation from client kinases and their release from the HSP90-CDC37 system depends on the Ser/Thr phosphatase PP5, which associates with HSP90 via its N-terminal TPR domain. Here, we present the cryoEM structure of the oncogenic protein kinase client BRAF bound to HSP90-CDC37, showing how the V600E mutation favours BRAF association with HSP90-CDC37. Structures of HSP90-CDC37-BRAF complexes with PP5 in autoinhibited and activated conformations, together with proteomic analysis of its phosphatase activity on BRAF and CRAF, reveal how PP5 is activated by recruitment to HSP90 complexes. PP5 comprehensively dephosphorylates client proteins, removing interaction sites for regulatory partners such as 14-3-3 proteins and thus performing a 'factory reset' of the kinase prior to release.

PubMed: 36446791
DOI: 10.1038/s41467-022-35143-2

Experimental method

ELECTRON MICROSCOPY (3.9 Å)