Activation of caspases-8 and-10 by FLIPL
Activation of caspases-8 and-10 by FLIPL
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DOI：
10.1042/bj20040809
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发表时间：
2004-09-01
影响因子：
4.1
通讯作者：
Salvesen, GS
中科院分区：
文献类型：
--
作者：
Boatright, KM;Deis, C;Salvesen, GS
半胱天冬酶激活的第一步是潜伏酶原转变为活性形式。对于引发剂半胱天冬酶，这通过单体酶原在活化复合物处的二聚化而发生。最近的研究表明，FLIPL [FLICE样抑制蛋白，长型; FLICE是FADD（Fas相关死亡结构域蛋白）样白细胞介素-1 β转化酶]，以前被认为仅作为caspase-8激活的抑制剂，在某些情况下可以增强caspase激活。使用体外诱导邻近试验，我们证明了半胱天冬酶-8和-10的激活独立于半胱天冬酶或FLIPL的裂解而发生。FLIPL通过形成具有与胱天蛋白酶-8同源二聚体难以区分的底物特异性和催化活性的异源二聚体酶分子来激活胱天蛋白酶-8。值得注意的是，异二聚体形成的屏障低于同二聚体形成的屏障，表明FLIPL是比胱天蛋白酶-8本身更有效的胱天蛋白酶-8激活剂。
The first step in caspase activation is transition of the latent zymogen to an active form. For the initiator caspases, this occurs through dimerization of monomeric zymogens at an activating complex. Recent studies have suggested that FLIPL [FLICE-like inhibitory protein, long form; FLICE is FADD (Fas-associated death domain protein)-like interleukin-1beta-converting enzyme], previously thought to act solely as an inhibitor of caspase-8 activation, can under certain circumstances function to enhance caspase activation. Using an in vitro induced-proximity assay, we demonstrate that activation of caspases-8 and -10 occurs independently of cleavage of either the caspase or FLIPL. FLIPL activates caspase-8 by forming heterodimeric enzyme molecules with substrate specificity and catalytic activity indistinguishable from those of caspase-8 homodimers. Significantly, the barrier for heterodimer formation is lower than that for homodimer formation, suggesting that FLIPL is a more potent activator of caspase-8 than is caspase-8 itself.