Biological Sciences, Sunnybrook Research Institute, Toronto, ON, Canada.
Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
Cell Death Differ. 2018 Jan;25(1):65-80. doi: 10.1038/cdd.2017.186. Epub 2017 Nov 17.
The BCL-2 family of proteins controls cell death primarily by direct binding interactions that regulate mitochondrial outer membrane permeabilization (MOMP) leading to the irreversible release of intermembrane space proteins, subsequent caspase activation and apoptosis. The affinities and relative abundance of the BCL-2 family proteins dictate the predominate interactions between anti-apoptotic and pro-apoptotic BCL-2 family proteins that regulate MOMP. We highlight the core mechanisms of BCL-2 family regulation of MOMP with an emphasis on how the interactions between the BCL-2 family proteins govern cell fate. We address the critical importance of both the concentration and affinities of BCL-2 family proteins and show how differences in either can greatly change the outcome. Further, we explain the importance of using full-length BCL-2 family proteins (versus truncated versions or peptides) to parse out the core mechanisms of MOMP regulation by the BCL-2 family. Finally, we discuss how post-translational modifications and differing intracellular localizations alter the mechanisms of apoptosis regulation by BCL-2 family proteins. Successful therapeutic intervention of MOMP regulation in human disease requires an understanding of the factors that mediate the major binding interactions between BCL-2 family proteins in cells.
BCL-2 家族蛋白主要通过直接结合相互作用来控制细胞死亡，这些相互作用调节线粒体外膜通透性（MOMP），导致膜间空间蛋白的不可逆释放，随后半胱天冬酶激活和细胞凋亡。BCL-2 家族蛋白的亲和力和相对丰度决定了抗凋亡和促凋亡 BCL-2 家族蛋白之间主要相互作用，从而调节 MOMP。我们重点介绍了 BCL-2 家族调控 MOMP 的核心机制，强调了 BCL-2 家族蛋白相互作用如何控制细胞命运。我们探讨了 BCL-2 家族蛋白浓度和亲和力的重要性，并表明两者的差异如何极大地改变结果。此外，我们解释了使用全长 BCL-2 家族蛋白（而非截短版本或肽）来解析 BCL-2 家族调控 MOMP 的核心机制的重要性。最后，我们讨论了翻译后修饰和不同的细胞内定位如何改变 BCL-2 家族蛋白调控细胞凋亡的机制。成功干预人类疾病中 MOMP 的调控需要了解调节细胞中 BCL-2 家族蛋白主要结合相互作用的因素。
