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B-Raf autoinhibition in the presence and absence of 14-3-3

  1. Author:
    Zhang,Mingzhen
    Jang,Hyunbum
    Li, Zhigang
    Sacks, David B.
    Nussinov,Ruth

  2. Author Address

    NCI, Computat Struct Biol Sect, Frederick Natl Lab Canc Res, Lab Canc ImmunoMetab, Frederick, MD 21702 USA.NIH, Dept Lab Med, Bethesda, MD 20892 USA.Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel.
    1. Year: 2021
    2. Date: Jul 1
  2. Journal: Structure
  3. CELL PRESS,
    1. 29
    2. 7
    3. Pages: 768-777.e2
  5. Type of Article: Article
  6. Article Number: e2
  7. ISSN: 0969-2126
  1. Abstract:

    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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External Sources

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  2. DOI: 10.1016/j.str.2021.02.005
  3. PMID: 33711246
  4. View record in Web of Science®
  5. WOS: 000668972400013

Library Notes

  1. Fiscal Year: FY2020-2021
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