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

Mingzhen Zhang, Hyunbum Jang, Zhigang Li, David B Sacks, Ruth Nussinov

Structure (London, England : 1993) 2021 Jul 01

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Raf-activating mutations are frequent in cancer. In the basal state, B-Raf is autoinhibited by its upstream Ras-binding 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 monomers into active B-Raf dimers. Copyright © 2021 Elsevier Ltd. All rights reserved.

Citation

Mingzhen Zhang, Hyunbum Jang, Zhigang Li, David B Sacks, Ruth Nussinov. B-Raf autoinhibition in the presence and absence of 14-3-3. Structure (London, England : 1993). 2021 Jul 01;29(7):768-777.e2