6u2h
BRAF dimer bound to 14-3-3
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 PubMedThe RAS-RAF-MEK-ERK signaling axis is frequently activated in human cancers. Physiological concentrations of ATP prevent formation of RAF kinase-domain (RAF(KD)) dimers that are critical for activity. Here we present a 2.9-A-resolution crystal structure of human BRAF(KD) in complex with MEK and the ATP analog AMP-PCP, revealing interactions between BRAF and ATP that induce an inactive, monomeric conformation of BRAF(KD). We also determine how 14-3-3 relieves the negative regulatory effect of ATP through a 2.5-A-resolution crystal structure of the BRAF(KD)-14-3-3 complex, in which dimeric 14-3-3 enforces a dimeric BRAF(KD) assembly to increase BRAF activity. Our data suggest that most oncogenic BRAF mutations alter interactions with ATP and counteract the negative effects of ATP binding by lowering the threshold for RAF dimerization and pathway activation. Our study establishes a framework for rationalizing oncogenic BRAF mutations and provides new avenues for improved RAF-inhibitor discovery. Negative regulation of RAF kinase activity by ATP is overcome by 14-3-3-induced dimerization.,Liau NPD, Wendorff TJ, Quinn JG, Steffek M, Phung W, Liu P, Tang J, Irudayanathan FJ, Izadi S, Shaw AS, Malek S, Hymowitz SG, Sudhamsu J Nat Struct Mol Biol. 2020 Jan 27. pii: 10.1038/s41594-019-0365-0. doi:, 10.1038/s41594-019-0365-0. PMID:31988522[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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