Department of Molecular and Cell Biology, University of California, Berkeley, CA, 94720, USA; California Institute for Quantitative Biosciences, University of California, Berkeley, CA, 94720, USA.
The University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
Curr Opin Struct Biol. 2021 Dec;71:223-231. doi: 10.1016/j.sbi.2021.07.005. Epub 2021 Aug 25.
BRAF is a highly regulated protein kinase that controls cell fate in animal cells. Recent structural analyses have revealed how active and inactive forms of BRAF bind to dimers of the scaffold protein 14-3-3. Inactive BRAF binds to 14-3-3 as a monomer and is held in an inactive conformation by interactions with ATP and the substrate kinase MEK, a striking example of enzyme inhibition by substrate binding. A change in the phosphorylation state of BRAF shifts the stoichiometry of the BRAF:14-3-3 complex from 1:2 to 2:2, resulting in stabilization of the active dimeric form of the kinase. These new findings uncover unexpected features of the regulatory mechanisms underlying Raf biology and help explain the paradoxical activation of Raf by small-molecule inhibitors.
BRAF 是一种高度调控的蛋白激酶，控制着动物细胞的命运。最近的结构分析揭示了活性和非活性形式的 BRAF 如何与支架蛋白 14-3-3 的二聚体结合。非活性 BRAF 作为单体与 14-3-3 结合，并通过与 ATP 和底物激酶 MEK 的相互作用保持在非活性构象，这是底物结合抑制酶的一个显著例子。BRAF 磷酸化状态的改变将 BRAF:14-3-3 复合物的计量比从 1:2 转变为 2:2，导致激酶的活性二聚体形式的稳定。这些新发现揭示了 Raf 生物学的调控机制的意外特征，并有助于解释小分子抑制剂对 Raf 的悖论性激活。
