biomolecules-12-00905 Published online.pdf (4.03 MB)
Recognition of BRAF by CDC37 and re-evaluation of the activation mechanism for the Class 2 BRAF-L597R mutant
journal contribution
posted on 2023-06-10, 04:07 authored by Dennis Bjorklund, R Marc L Morgan, Jasmeen OberoiJasmeen Oberoi, Katie L I M Day, Panagiota A Galliou, Chrisostomos ProdromouChrisostomos ProdromouThe kinome specific co-chaperone, CDC37 (cell division cycle 37), is responsible for delivering BRAF (B-Rapidly Accelerated Fibrosarcoma) to the Hsp90 (heat shock protein 90) complex, where it is then translocated to the RAS (protooncogene product p21) complex at the plasma membrane for RAS mediated dimerization and subsequent activation. We identify a bipartite interaction between CDC37 and BRAF and delimitate the essential structural elements of CDC37 involved in BRAF recognition. We find an extended and conserved CDC37 motif, 20HPNID---SL--W31, responsible for recognizing the C-lobe of BRAF kinase domain, while the c-terminal domain of CDC37 is responsible for the second of the bipartite interaction with BRAF. We show that dimerization of BRAF, independent of nucleotide binding, can act as a potent signal that prevents CDC37 recognition and discuss the implications of mutations in BRAF and the consequences on signaling in a clinical setting, particularly for class 2 BRAF mutations.
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Publication status
- Published
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- Published version
Journal
BiomoleculesISSN
2218-273XPublisher
MDPIExternal DOI
Issue
7Volume
12Page range
1-25Department affiliated with
- Biochemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2022-07-01First Open Access (FOA) Date
2022-07-01First Compliant Deposit (FCD) Date
2022-06-28Usage metrics
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