Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
Exp Cell Res. 2012 Jul 1;318(11):1213-20. doi: 10.1016/j.yexcr.2012.02.013. Epub 2012 Feb 28.
Key structural and catalytic features are conserved across the entire family of cysteine-dependent aspartate-specific proteases (caspases). Of the caspases involved in apoptosis signal transduction, the initiator caspases-2, -8 and -9 are activated at multi-protein activation platforms, and activation is thought to involve homo-dimerisation of the monomeric zymogens. Caspase-9, the essential initiator caspase required for apoptosis signalling through the mitochondrial pathway, is activated on the apoptosome complex, and failure to activate caspase-9 has profound pathophysiological consequences. Here, we review the pertinent literature on which the currently prevalent understanding of caspase-9 activation is based, extend this view by insight obtained from recent structural and kinetic studies on caspase-9 signalling, and describe an emerging model for the regulation of caspase-9 activation and activity that arise from the complexity of multi-protein interactions at the apoptosome. This integrated view allows us to postulate and to discuss functional consequences for caspase-9 activation and apoptosis execution that may take centre stage in future experimental cell research on apoptosis signalling.
关键的结构和催化特征在整个半胱氨酸依赖的天冬氨酸特异性蛋白酶（胱天蛋白酶）家族中都得到了保守。在参与细胞凋亡信号转导的胱天蛋白酶中，起始胱天蛋白酶-2、-8 和 -9 在多蛋白激活平台上被激活，并且激活被认为涉及单体酶原的同二聚化。胱天蛋白酶-9 是通过线粒体途径进行细胞凋亡信号所必需的起始胱天蛋白酶，它在凋亡小体复合物上被激活，而不能激活胱天蛋白酶-9 会产生深远的病理生理后果。在这里，我们回顾了目前流行的关于胱天蛋白酶-9 激活的理解所依据的相关文献，通过对胱天蛋白酶-9 信号转导的最新结构和动力学研究获得的见解扩展了这一观点，并描述了一个新兴的模型，用于调节凋亡小体上的多蛋白相互作用的复杂性而产生的胱天蛋白酶-9 激活和活性。这种综合观点使我们能够假设并讨论胱天蛋白酶-9 激活和细胞凋亡执行的功能后果，这些后果可能在未来关于细胞凋亡信号的实验细胞研究中占据中心地位。
