HSP90-CDC37-PP5 forms a structural platform for kinase dephosphorylation.pdf (4.16 MB)
HSP90-CDC37-PP5 forms a structural platform for kinase dephosphorylation
journal contribution
posted on 2023-06-10, 07:05 authored by Jasmeen OberoiJasmeen Oberoi, Xavier Aran GuiuXavier Aran Guiu, Emily OutwinEmily Outwin, Pascale Schellenberger, Theodoros I Roumeliotis, Jyoti S Choudhary, Laurence PearlLaurence PearlActivation 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 BRAFV600E bound to HSP90-CDC37, showing how the V600E mutation favours BRAF association with HSP90-CDC37. Structures of HSP90-CDC37-BRAFV600E complexes with PP5 in autoinhibited and activated conformations, together with proteomic analysis of its phosphatase activity on BRAFV600E 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.
History
Publication status
- Published
File Version
- Published version
Journal
Nature CommunicationsISSN
2041-1723Publisher
Springer Science and Business Media LLCExternal DOI
Volume
13Page range
a7343 1-13Event location
EnglandDepartment affiliated with
- Biochemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2023-05-19First Open Access (FOA) Date
2023-05-19First Compliant Deposit (FCD) Date
2023-05-19Usage metrics
Categories
No categories selectedKeywords
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC