Elucidating the structural basis of mitochondrial outer membrane permeabilization in apoptosis

摘要 线粒体凋亡是一种应激触发的细胞死亡途径，与健康和疾病密切相关。这 在癌症中，通路很容易被阻断。线粒体多孔化是线粒体凋亡的核心 受bcl2蛋白调控。这一过程调节从线粒体释放导致死亡的因子 激活半胱氨酸天冬氨酸氨基转移酶的级联反应来分解凋亡细胞。线粒体穿孔是由 BCL-2蛋白BAK。在这里，我们建议描绘线粒体穿孔的机制，即BAK，即 定义难以捉摸，也存在争议。特别是，我们建议阐明1)BAK激活的机制， 2)BAK与膜的结合和穿孔；3)BAK的识别和存留 Bc1-2蛋白。为了实现这些目标，我们将多管齐下，包括高分辨率 结构生物学、生物物理学、生物化学和细胞生物学，以生成线粒体的完整图景 由BAK进行的穿孔。在成功完成后，我们将重新定义我们对这一过程的机械性理解， 我们还将揭示在病理生理学中针对细胞凋亡的创新方法。

Abstract Mitochondrial apoptosis is a stress-triggered cell death pathway implicated in health and disease. This pathway is readily blocked in cancer. Mitochondrial poration is at the heart of mitochondrial apoptosis being regulated by the BCL-2 proteins. This process regulates the release from mitochondria of prodeath factors that activate the caspase cascade which dismantles apoptotic cells. Mitochondrial poration is executed by the BCL-2 protein BAK. Here we propose to delineate the mechanism of mitochondrial poration by BAK, which is elusively defined and controversial. In particular, we propose to elucidate 1) the mechanism of BAK activation, 2) BAK association with and poration of membranes, and 3) BAK recognition and sequestration by prosurvival BCL-2 proteins. To accomplish these aims we will use a multi-pronged approach including high-resolution structural biology, biophysics, biochemistry, and cell biology to generate a complete picture of mitochondrial poration by BAK. Upon successful completion we will redefine our mechanistic understanding of this process, and we will reveal innovative ways to target apoptosis in pathophysiology.