Department of Pediatric Oncology and Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Mol Cell. 2010 Nov 12;40(3):481-92. doi: 10.1016/j.molcel.2010.10.019.
BAX is a proapoptotic BCL-2 family member that lies dormant in the cytosol until converted into a killer protein in response to cellular stress. Having recently identified the elusive trigger site for direct BAX activation, we now delineate by NMR and biochemical methods the essential allosteric conformational changes that transform ligand-triggered BAX into a fully activated monomer capable of propagating its own activation. Upon BAX engagement by a triggering BH3 helix, the unstructured loop between α helices 1 and 2 is displaced, the carboxy-terminal helix 9 is mobilized for membrane translocation, and the exposed BAX BH3 domain propagates the death signal through an autoactivating interaction with the trigger site of inactive BAX monomers. Our structure-activity analysis of this seminal apoptotic process reveals pharmacologic opportunities to modulate cell death by interceding at key steps of the BAX activation pathway.
BAX 是一种促凋亡的 BCL-2 家族成员，在细胞质中处于休眠状态，直到细胞应激将其转化为杀伤蛋白。最近我们发现了一个难以捉摸的直接激活 BAX 的触发位点，现在我们通过 NMR 和生化方法描绘了必需的变构构象变化，这些变化将配体触发的 BAX 转化为能够传播自身激活的完全激活的单体。当 BAX 与触发 BH3 螺旋结合时，α 螺旋 1 和 2 之间的无结构环被置换，羧基末端螺旋 9 被动员进行膜易位，暴露的 BAX BH3 结构域通过与失活 BAX 单体的触发位点的自动激活相互作用传播死亡信号。我们对这一重要凋亡过程的结构-活性分析揭示了通过在 BAX 激活途径的关键步骤进行干预来调节细胞死亡的药物机会。
