Protein-protein and protein-lipid interactions of pore-forming BCL-2 family proteins in apoptosis initiation.
Protein-protein and protein-lipid interactions of pore-forming BCL-2 family proteins in apoptosis initiation.
复制标题
细胞凋亡起始中成孔BCL-2家族蛋白的蛋白-蛋白和蛋白-脂质相互作用。
DOI：
10.1042/bst20220323
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发表时间：
2022-06-30
影响因子：
3.9
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中科院分区：
文献类型：
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细胞凋亡是一种常见的细胞死亡程序，对人类健康和疾病具有重要意义。细胞凋亡的信号在很大程度上是通过蛋白质之间的相互作用来驱动的。BCL-2家族蛋白在蛋白质-蛋白质相互作用中作为线粒体孔化的关键调节因子发挥作用，线粒体孔化是通过释放细胞色素c来启动细胞凋亡的过程，这一过程激活了导致细胞破坏的凋亡caspase级联反应。BCL-2致孔蛋白BAK和Bax是线粒体穿孔的关键执行者。我们回顾了通过X射线结晶学和核磁共振波谱研究确定的蛋白质-蛋白质和蛋白质-脂相互作用调节BAK和Bax凋亡功能的知识状况。BAK和BAX是休眠的球状α-螺旋蛋白，参与与其他致死bcl2家族蛋白的蛋白-蛋白相互作用，将它们转化为活性的、部分未折叠的蛋白，使其二聚化，与线粒体膜结合并通透。我们将高分辨结构中观察到的蛋白质-蛋白质相互作用与AlphaFold在硅胶中观察到的蛋白质-蛋白质相互作用进行比较，结合实验和硅胶方法进行预测，以描绘bcl2家族蛋白质新的蛋白质-蛋白质相互作用复合体的结构基础。
Apoptosis is a common cell death program that is important in human health and disease. Signaling in apoptosis is largely driven through protein–protein interactions. The BCL-2 family proteins function in protein–protein interactions as key regulators of mitochondrial poration, the process that initiates apoptosis through the release of cytochrome c, which activates the apoptotic caspase cascade leading to cellular demolition. The BCL-2 pore-forming proteins BAK and BAX are the key executors of mitochondrial poration. We review the state of knowledge of protein–protein and protein–lipid interactions governing the apoptotic function of BAK and BAX, as determined through X-ray crystallography and NMR spectroscopy studies. BAK and BAX are dormant, globular α-helical proteins that participate in protein–protein interactions with other pro-death BCL-2 family proteins, transforming them into active, partially unfolded proteins that dimerize and associate with and permeabilize mitochondrial membranes. We compare the protein–protein interactions observed in high-resolution structures with those derived in silico by AlphaFold, making predictions based on combining experimental and in silico approaches to delineate the structural basis for novel protein–protein interaction complexes of BCL-2 family proteins.