7mff
Dimeric (BRAF)2:(14-3-3)2 complex bound to SB590885 Inhibitor
Structural highlights
Function1433Z_HUMAN Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner.[1] [2] [3] [4] [5] Publication Abstract from PubMedRAF 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:14-3-3(2):MEK and BRAF:14-3-3(2) complexes, and an inhibitor-bound, dimeric BRAF(2):14-3-3(2) complex, at 3.7, 4.1, and 3.9 A 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. Structural insights into the BRAF monomer-to-dimer transition mediated by RAS binding.,Martinez Fiesco JA, Durrant DE, Morrison DK, Zhang P Nat Commun. 2022 Jan 25;13(1):486. doi: 10.1038/s41467-022-28084-3. PMID:35078985[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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