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

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. Mo

SUBMITTER: Martinez Fiesco JA 

PROVIDER: S-EPMC8789793 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature