Molecular mechanism of BCL2-dependent apoptosis

描述(申请人提供)：程序性细胞死亡在人类健康和疾病中起着关键作用。细胞生存和死亡的信号由bcl2家族蛋白调节，并汇聚在线粒体，在那里最终决定细胞的命运。BCL-2蛋白活性对维持线粒体和细胞生理学至关重要，也与人类主要疾病，特别是癌症有关。因此，了解它们的作用机制具有很高的生物医学优先级。Bcl2家族包括亲生命蛋白(如bclxl)和促死亡蛋白(如bax)，当它们在细胞质和线粒体外膜之间转移时，通过分子间相互作用网络发挥其调节功能。线粒体膜结合是细胞程序性死亡的关键早期步骤，然而，膜结合介导bcl2蛋白功能的确切机制尚不清楚。本项目重点回答了核心问题：bcl-xl、bax和Bid这三个关键的bcl2相关基因如何在可溶状态和膜插入状态之间转换，发挥其促凋亡和抗凋亡活性？

DESCRIPTION (provided by applicant): Programmed cell death plays key roles in human health and disease. Signals for cellular life and death are regulated by the BCL-2 family proteins and converge at the mitochondria, where cell fate is ultimately decided. BCL-2 protein activities are critical for maintaining mitochondrial and cellular physiology, and are also linked with major human diseases, especially cancer. Thus, understanding their mechanisms of action has high biomedical priority. The BCL-2 family includes both pro-life (e.g. BCL-XL) and pro-death (e.g. BAX) proteins that exert their regulatory functions through a network of intermolecular interactions as they translocate between the cytoplasm and the mitochondrial outer membrane. Mitochondrial membrane association is a key early step of programmed cell death; however, the exact mechanism through which membrane association mediates BCL-2 protein function is not known. This project focuses on answering the central question: how do the three key BCL-2 relatives, BCL-XL, BAX and BID, transition between soluble and membrane-inserted states to exert their pro- and anti-apoptotic activities?