细胞凋亡中的Bcl-2家族蛋白及其BH3结构域的功能研究

凋亡相关蛋白中的Bcl-2家族是细胞凋亡的关键调节分子,由抗凋亡和促凋亡成员组成,这些成员之间通过相互协同作用调节了线粒体结构与功能的稳定性,从而在线粒体水平发挥着细胞凋亡的“开关”作用.抗凋亡成员大都分布于线粒体的外膜,与促凋亡成员的BH3结构域相互作用对细胞凋亡发挥抵抗作用.促凋亡成员则主要分布于细胞浆中,细胞接受死亡信号刺激后,促凋亡成员自身受到一系列的调节,如典型的Bax构象改变、BAD和Bik的磷酸化调节以及Bid和Bim的蛋白裂解效应等,使得促凋亡成员在凋亡信号的刺激下整合于线粒体外膜,最终导致线粒体通透转换孔的开放,进而释放包括细胞色素c、凋亡诱导因子、Smac等重要的凋亡因子,随后caspase被激活进而断裂重要的细胞内结构蛋白与功能分子,执行细胞凋亡.

Role for The Bcl-2 Family Proteins and BH3 Domain in Apoptosis

Apoptosis action is primarily exerted at the level of mitochondira, in which Bcl-2 family of proteins play an important role in its regulation. Bcl-2 family consists of anti-apoptotic and pro-apoptotic members. The anti-apoptotic members usually exist in the outer mitochondrial membrane and inhibit cell death via interaction with pro-apoptotic counterparts BH3 domain. Pro-apoptotic members are commonly localize in the cytoplasm. A series of events occured, such as typical Bax conformational change, BAD and Bik phosphorylation as well as Bid and Bim proteolysis in response to several death stimuli. As a result, these pro-apoptotic proteins directly integrate to the outer mitochondrial membranes. Finally, mitochondrial permeability transition pore is opened, by followed the release of apoptogenic factors from the mitochondrial intermembrane space, including cytochrome c, apoptosis inducing factor(AIF) and Smac, then the activation of downstream caspases and execution of cell death.