Molecular Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Mol Cell. 2009 Nov 13;36(3):487-99. doi: 10.1016/j.molcel.2009.09.030.
While activation of BAX/BAK by BH3-only molecules (BH3s) is essential for mitochondrial apoptosis, the underlying mechanisms remain unsettled. Here we demonstrate that BAX undergoes stepwise structural reorganization leading to mitochondrial targeting and homo-oligomerization. The alpha1 helix of BAX keeps the alpha9 helix engaged in the dimerization pocket, rendering BAX as a monomer in cytosol. The activator BH3s, tBID/BIM/PUMA, attack and expose the alpha1 helix of BAX, resulting in secondary disengagement of the alpha9 helix and thereby mitochondrial insertion. Activator BH3s remain associated with the N-terminally exposed BAX through the BH1 domain to drive homo-oligomerization. BAK, an integral mitochondrial membrane protein, has bypassed the first activation step, explaining why its killing kinetics are faster than those of BAX. Furthermore, death signals initiated at ER induce BIM and PUMA to activate mitochondrial apoptosis. Accordingly, deficiency of Bim/Puma impedes ER stress-induced BAX/BAK activation and apoptosis. Our study provides mechanistic insights regarding the spatiotemporal execution of BAX/BAK-governed cell death.
虽然 BAX/BAK 被 BH3 仅分子（BH3s）激活对于线粒体凋亡是必不可少的，但潜在的机制仍未解决。在这里，我们证明 BAX 经历了逐步的结构重排，导致线粒体靶向和同源寡聚化。BAX 的 alpha1 螺旋使 alpha9 螺旋保持在二聚化口袋中，使 BAX 在细胞质中保持单体状态。激活剂 BH3s（tBID/BIM/PUMA）攻击并暴露 BAX 的 alpha1 螺旋，导致 alpha9 螺旋的二次脱离，从而导致线粒体插入。激活剂 BH3s 通过 BH1 结构域与 N 端暴露的 BAX 保持关联，以驱动同源寡聚化。BAK 是一种完整的线粒体膜蛋白，已经绕过了第一个激活步骤，这解释了为什么它的杀伤动力学比 BAX 更快。此外，内质网引发的死亡信号诱导 BIM 和 PUMA 激活线粒体凋亡。因此，Bim/Puma 的缺乏会阻碍 ER 应激诱导的 BAX/BAK 激活和凋亡。我们的研究提供了关于 BAX/BAK 控制的细胞死亡的时空执行的机制见解。
