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Structural insights into the BRAF monomer-to-dimer transition mediated by RAS binding

Author

Listed:
  • Juliana A. Martinez Fiesco

    (National Cancer Institute-Frederick)

  • David E. Durrant

    (National Cancer Institute-Frederick)

  • Deborah K. Morrison

    (National Cancer Institute-Frederick)

  • Ping Zhang

    (National Cancer Institute-Frederick)

Abstract

RAF kinases are essential effectors of RAS, but how RAS binding initiates the conformational changes needed for autoinhibited RAF monomers to form active dimers has remained unclear. Here, we present cryo-electron microscopy structures of full-length BRAF complexes derived from mammalian cells: autoinhibited, monomeric BRAF:14-3-32:MEK and BRAF:14-3-32 complexes, and an inhibitor-bound, dimeric BRAF2:14-3-32 complex, at 3.7, 4.1, and 3.9 Å resolution, respectively. In both autoinhibited, monomeric structures, the RAS binding domain (RBD) of BRAF is resolved, revealing that the RBD forms an extensive contact interface with the 14-3-3 protomer bound to the BRAF C-terminal site and that key basic residues required for RBD-RAS binding are exposed. Moreover, through structure-guided mutational studies, our findings indicate that RAS-RAF binding is a dynamic process and that RBD residues at the center of the RBD:14-3-3 interface have a dual function, first contributing to RAF autoinhibition and then to the full spectrum of RAS-RBD interactions.

Suggested Citation

  • Juliana A. Martinez Fiesco & David E. Durrant & Deborah K. Morrison & Ping Zhang, 2022. "Structural insights into the BRAF monomer-to-dimer transition mediated by RAS binding," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28084-3
    DOI: 10.1038/s41467-022-28084-3
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    Cited by:

    1. Brandon M. Murphy & Elizabeth M. Terrell & Venkat R. Chirasani & Tirzah J. Weiss & Rachel E. Lew & Andrea M. Holderbaum & Aastha Dhakal & Valentina Posada & Marie Fort & Michael S. Bodnar & Leiah M. C, 2022. "Enhanced BRAF engagement by NRAS mutants capable of promoting melanoma initiation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Aline Chessel & Noémie Crozé & Maria Dolores Molina & Laura Taberner & Philippe Dru & Luc Martin & Thierry Lepage, 2023. "RAS-independent ERK activation by constitutively active KSR3 in non-chordate metazoa," Nature Communications, Nature, vol. 14(1), pages 1-26, December.
    3. Eunyoung Park & Shaun Rawson & Anna Schmoker & Byeong-Won Kim & Sehee Oh & Kangkang Song & Hyesung Jeon & Michael J. Eck, 2023. "Cryo-EM structure of a RAS/RAF recruitment complex," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    4. Jasmeen Oberoi & Xavi Aran Guiu & Emily A. Outwin & Pascale Schellenberger & Theodoros I. Roumeliotis & Jyoti S. Choudhary & Laurence H. Pearl, 2022. "HSP90-CDC37-PP5 forms a structural platform for kinase dephosphorylation," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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