Boatright Kelly M, Renatus Martin, Scott Fiona L, Sperandio Sabina, Shin Hwain, Pedersen Irene M, Ricci Jean Ehrland, Edris Wade A, Sutherlin Daniel P, Green Douglas R, Salvesen Guy S
The Program in Apoptosis and Cell Death Research, Burnham Institute, 10901 North Torrey Pines Road, University of California, San Diego, La Jolla, CA 92037, USA.
Mol Cell. 2003 Feb;11(2):529-41. doi: 10.1016/s1097-2765(03)00051-0.
Apoptosis is orchestrated by the concerted action of caspases, activated in a minimal two-step proteolytic cascade. Existing data suggests that apical caspases are activated by adaptor-mediated clustering of inactive zymogens. However, the mechanism by which apical caspases achieve catalytic competence in their recruitment/activation complexes remains unresolved. We explain that proximity-induced activation of apical caspases is attributable to dimerization. Internal proteolysis does not activate these apical caspases but is a secondary event resulting in partial stabilization of activated dimers. Activation of caspases-8 and -9 occurs by dimerization that is fully recapitulated in vitro by kosmotropes, salts with the ability to stabilize the structure of proteins. Further, single amino acid substitutions at the dimer interface abrogate the activity of caspases-8 and -9 introduced into recipient mammalian cells. We propose a unified caspase activation hypothesis whereby apical caspases are activated by dimerization of monomeric zymogens.
细胞凋亡是由半胱天冬酶的协同作用精心编排的，这些半胱天冬酶在一个最少两步的蛋白水解级联反应中被激活。现有数据表明，顶端半胱天冬酶是通过衔接蛋白介导的无活性酶原聚集而被激活的。然而，顶端半胱天冬酶在其募集/激活复合物中获得催化活性的机制仍未得到解决。我们解释说，顶端半胱天冬酶的邻近诱导激活归因于二聚化。内部蛋白水解不会激活这些顶端半胱天冬酶，而是一个导致激活二聚体部分稳定的次要事件。半胱天冬酶-8和-9的激活是通过二聚化发生的，在体外，具有稳定蛋白质结构能力的促溶剂盐能完全重现这种二聚化。此外，二聚体界面处的单个氨基酸替换会消除导入受体哺乳动物细胞中的半胱天冬酶-8和-9的活性。我们提出了一个统一的半胱天冬酶激活假说，即顶端半胱天冬酶通过单体酶原的二聚化被激活。
