National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)
P50CA165962
米国
National Institutes of Health/National Cancer Institute (NIH/NCI)
R50CA221830
米国
引用
ジャーナル: Nature / 年: 2019 タイトル: Architecture of autoinhibited and active BRAF-MEK1-14-3-3 complexes. 著者: Eunyoung Park / Shaun Rawson / Kunhua Li / Byeong-Won Kim / Scott B Ficarro / Gonzalo Gonzalez-Del Pino / Humayun Sharif / Jarrod A Marto / Hyesung Jeon / Michael J Eck / 要旨: RAF family kinases are RAS-activated switches that initiate signalling through the MAP kinase cascade to control cellular proliferation, differentiation and survival. RAF activity is tightly ...RAF family kinases are RAS-activated switches that initiate signalling through the MAP kinase cascade to control cellular proliferation, differentiation and survival. RAF activity is tightly regulated and inappropriate activation is a frequent cause of cancer; however, the structural basis for RAF regulation is poorly understood at present. Here we use cryo-electron microscopy to determine autoinhibited and active-state structures of full-length BRAF in complexes with MEK1 and a 14-3-3 dimer. The reconstruction reveals an inactive BRAF-MEK1 complex restrained in a cradle formed by the 14-3-3 dimer, which binds the phosphorylated S365 and S729 sites that flank the BRAF kinase domain. The BRAF cysteine-rich domain occupies a central position that stabilizes this assembly, but the adjacent RAS-binding domain is poorly ordered and peripheral. The 14-3-3 cradle maintains autoinhibition by sequestering the membrane-binding cysteine-rich domain and blocking dimerization of the BRAF kinase domain. In the active state, these inhibitory interactions are released and a single 14-3-3 dimer rearranges to bridge the C-terminal pS729 binding sites of two BRAFs, which drives the formation of an active, back-to-back BRAF dimer. Our structural snapshots provide a foundation for understanding normal RAF regulation and its mutational disruption in cancer and developmental syndromes.
超分子 #1: Ternary complex of BRAF/MEK1/14-3-3 with MEK inhibitor
超分子
名称: Ternary complex of BRAF/MEK1/14-3-3 with MEK inhibitor タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#3 詳細: 14-3-3 is heterodimer of Insect epsilon and zeta. model was generated by Insect zeta sequence as a homo-dimer.