Journal
STRUCTURE
Volume 29, Issue 7, Pages 768-+Publisher
CELL PRESS
DOI: 10.1016/j.str.2021.02.005
Keywords
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Funding
- National Cancer Institute, National Institutes of Health [HHSN261200800001E]
- Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research
- NIH Clinical Center
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In the presence of 14-3-3, the interaction with B-Raf stabilizes the RBD-CRD-KD interaction, interfering with the KD dimerization. The release of RBD-CRD promotes KD fluctuations and reorientation for dimerization, suggesting a mechanism where one KD monomer is donated by 14-3-3-free B-Raf KD and the other by 14-3-3-bound KD.
Raf-activating mutations are frequent in cancer. In the basal state, B-Raf is autoinhibited by its upstream Rasbinding domain (RBD) and cysteine-rich domain (RBD-CRD) interacting with its kinase domain (KD) and the 14-3-3 dimer. Our comprehensive molecular dynamics simulations explore two autoinhibition scenarios in the presence and absence of the 14-3-3 dimer. When present, the 14-3-3 interaction with B-Raf stabilizes the RBD-CRD-KD interaction, interfering with the KD dimerization. Raf's pSer365 removal fails to induce large disruption. RBD-CRD release promotes KD fluctuations and reorientation for dimerization, consistent with experimental data. In the absence of 14-3-3, our sampled B-Raf conformations suggest that RBD-CRD can block the KD dimerization surface. Our results suggest a B-Raf activation mechanism, whereby one KD monomer is donated by 14-3-3-free B-Raf KD and the other by 14-3-3-bound KD. This mechanism can lead to homo- and heterodimers. These autoinhibition scenarios can transform autoinhibited B-Raf mono-mers into active B-Raf dimers.
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