Elucidating the structural basis of mitochondrial outer membrane permeabilization in apoptosis

摘要 线粒体凋亡是与健康和疾病有关的应激触发的细胞死亡途径。这 在癌症中很容易被阻断。线粒体穿孔是线粒体凋亡的核心， 由BCL-2蛋白调控。这个过程调节线粒体释放促死亡因子， 激活抑制凋亡细胞的半胱天冬酶级联反应。线粒体穿孔是由 BCL-2蛋白巴克。在这里，我们建议描绘的机制，线粒体穿孔的巴克，这是 定义模糊且充满争议特别是，我们建议阐明1）巴克激活的机制， 2)巴克与膜的结合和穿孔，以及3）巴克通过促存活的识别和隔离 BCL-2蛋白。为了实现这些目标，我们将采用多管齐下的方法，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像 通过巴克进行穿孔。一旦成功完成，我们将重新定义我们对这一过程的机械理解， 我们将揭示在病理生理学中靶向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.