The human anti-apoptotic proteins cIAP1 and cIAP2 bind but do not inhibit caspases
The human anti-apoptotic proteins cIAP1 and cIAP2 bind but do not inhibit caspases
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DOI：
10.1074/jbc.m510863200
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发表时间：
2006-02-10
影响因子：
4.8
通讯作者：
Salvesen, GS
中科院分区：
文献类型：
--
作者：
Eckelman, BP;Salvesen, GS
CIAP(细胞凋亡抑制蛋白)1和2在受体细胞中异位表达时能够调节细胞的凋亡，可能在体内也是如此。以前的工作表明，这至少部分是由于这些蛋白质中包含的三个杆状病毒IAP重复(BIR)结构域中的两个介导了对caspase的直接抑制。为了支持这一点，我们证明了两个CIAP的BIR结构域2和3能够与caspase-7和-9结合。然而，我们证明这两个BIR结构域都不能抑制caspase，因为在X连锁的IAP中针对caspase抑制的区域发生了关键的取代，IAP是一种紧密结合的caspase抑制剂。通过用XIAP残基取代这些关键残基，可以将CIAP BIR结构域转化为紧密结合的caspase抑制剂。因此，cIAP维持着适合直接抑制caspase的蛋白质支架，但失去或从未获得过特定的caspase抑制相互作用位点。因此，尽管CIAP BIR的结合功能可能对它们的生理功能很重要，但抑制caspase并不重要。
cIAPs (cellular inhibitor of apoptosis proteins) 1 and 2 are able to regulate apoptosis when ectopically expressed in recipient cells and probably also in vivo. Previous work suggested that this is at least partially due to direct caspase inhibition, mediated by two of the three baculovirus IAP repeat (BIR) domains that are contained in these proteins. In support of this we show that the BIR domains 2 and 3 of the two cIAPs are able to bind caspases-7 and -9. However, we demonstrate that neither of these BIR domains is able to inhibit caspases because of critical substitutions in the regions that target caspase inhibition in the X-linked IAP, a tight binding caspase inhibitor. The cIAP BIR domains can be converted to tight binding caspase inhibitors by substituting these critical residues with XIAP residues. Thus, cIAPs maintain protein scaffolds suitable for direct caspase inhibition but have lost or never acquired specific caspase inhibitory interaction sites. Consequently, although the binding function of the cIAP BIRs may be important for their physiologic function, caspase inhibition is not.