Bogner Christian, Kale Justin, Pogmore Justin, Chi Xiaoke, Shamas-Din Aisha, Fradin Cécile, Leber Brian, Andrews David W
Sunnybrook Research Institute, University of Toronto, Toronto, ON M5S 1A1, Canada; Third Department of Medicine, Klinikum Rechts der Isar, Technische Universität München, München 80333, Germany.
Sunnybrook Research Institute, University of Toronto, Toronto, ON M5S 1A1, Canada.
Mol Cell. 2020 Feb 20;77(4):901-912.e9. doi: 10.1016/j.molcel.2019.12.025. Epub 2020 Jan 27.
Current models of apoptosis regulation by the Bcl-2 family of proteins postulate that heterodimeric interactions between family members determine whether Bax and Bak are activated to trigger cell death. Thus, the relative abundance and binding affinities between pro- and anti-apoptotic proteins determines the outcome of these interactions. Examination of these interactions using purified mitochondria and liposomes with full-length recombinant proteins revealed that Bcl-x inhibits apoptosis as a higher-order complex that binds multiple BH3 proteins. Allosteric regulation of this complex by the BH3 sensitizer Bad confers switch-like activity to the indirect activation of Bax. The BH3 activator cBid sequestered by Bcl-x complexes changes from an inactive to an active form while bound to a Bcl-x complex only when Bad is also bound. Bcl-x complexes enable Bad to function as a non-competitive inhibitor of Bcl-x and allosterically activate cBid, dramatically enhancing the pro-apoptotic potency of Bad.
目前由Bcl-2蛋白家族调控细胞凋亡的模型假定，家族成员之间的异源二聚体相互作用决定了Bax和Bak是否被激活以触发细胞死亡。因此，促凋亡蛋白和抗凋亡蛋白之间的相对丰度和结合亲和力决定了这些相互作用的结果。使用纯化的线粒体和含有全长重组蛋白的脂质体对这些相互作用进行检测，结果显示Bcl-x作为一种能结合多种BH3蛋白的高阶复合物抑制细胞凋亡。BH3敏化剂Bad对该复合物的变构调节赋予了Bax间接激活的开关样活性。被Bcl-x复合物隔离的BH3激活剂cBid仅在Bad也结合时，从无活性形式转变为结合到Bcl-x复合物上时的活性形式。Bcl-x复合物使Bad能够作为Bcl-x的非竞争性抑制剂发挥作用，并变构激活cBid，显著增强Bad的促凋亡效力。
