Pop Cristina, Timmer John, Sperandio Sabina, Salvesen Guy S
Program in Apoptosis and Cell Death Research, The Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
Mol Cell. 2006 Apr 21;22(2):269-75. doi: 10.1016/j.molcel.2006.03.009.
The apical protease of the human intrinsic apoptotic pathway, caspase-9, is activated in a polymeric activation platform known as the apoptosome. The mechanism has been debated, and two contrasting hypotheses have been suggested. One of these postulates an allosteric activation of monomeric caspase-9; the other postulates a dimer-driven assembly at the surface of the apoptosome--the "induced proximity" model. We show that both Hofmeister salts and a reconstituted mini-apoptosome activate caspase-9 by a second-order process, compatible with a conserved dimer-driven process. Significantly, replacement of the recruitment domain of the apical caspase of the extrinsic apoptotic pathway, caspase-8, by that of caspase-9 allows activation of this hybrid caspase by the apoptosome. Consequently, apical caspases can be activated simply by directing their zymogens to the apoptosome, ruling out the requirement for allosteric activation and supporting an induced proximity dimerization model for apical caspase activation in vivo.
人类内源性凋亡途径的顶端蛋白酶caspase-9在一种称为凋亡小体的聚合激活平台中被激活。其机制一直存在争议，并且已经提出了两种截然不同的假说。其中一种假说是单体caspase-9的别构激活；另一种假说是在凋亡小体表面由二聚体驱动的组装——“诱导邻近”模型。我们发现霍夫迈斯特盐和重组的微型凋亡小体都通过二级过程激活caspase-9，这与保守的二聚体驱动过程一致。值得注意的是，用caspase-9的募集结构域替换外源性凋亡途径的顶端caspase即caspase-8的募集结构域，可使这种杂合caspase被凋亡小体激活。因此，顶端caspases只需将其酶原导向凋亡小体即可被激活，排除了别构激活的必要性，并支持体内顶端caspase激活的诱导邻近二聚化模型。
