Direct inhibition of caspase 3 is dispensable for the anti-apoptotic activity of XIAP
Direct inhibition of caspase 3 is dispensable for the anti-apoptotic activity of XIAP
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DOI：
10.1093/emboj/20.12.3114
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发表时间：
2001-06-15
期刊：
影响因子：
11.4
通讯作者：
Vaux, DL
中科院分区：
文献类型：
--
作者：
Silke, J;Ekert, PG;Vaux, DL
XIAP 是哺乳动物细胞凋亡蛋白 (IAP) 抑制剂，为了确定抑制 caspase 3 所需的第二杆状病毒 IAP 重复序列 (BIR2) 内的残基，我们筛选了 BIR2 突变体文库，以检测其在粟酒裂殖酵母中抑制 caspase 3 毒性能力的丧失。其中四个突变（预计不会影响 BIR 折叠的结构）聚集在 BIR2 侧翼的 N 末端区域，表明这是与 caspase 3 相互作用的位点。将这些突变引入全长 XIAP 可使 caspase 3 抑制活性降低高达 500 倍，但不会影响其抑制 caspase 9 或与 IAP 拮抗剂 DIABLO 相互作用的能力。此外，这些突变体保留了抑制转染细胞凋亡的全部能力，这表明虽然XIAP能够抑制caspase 3，但这种活性对于XIAP体内细胞凋亡的抑制是可有可无的。
XIAP is a mammalian inhibitor of apoptosis protein (IAP), To determine residues within the second baculoviral IAP repeat (BIR2) required for inhibition of caspase 3, we screened a library of BIR2 mutants for loss of the ability to inhibit caspase 3 toxicity in the yeast Schizosaccharomyces pombe. Four of the mutations, not predicted to affect the structure of the BIR fold, clustered together on the N-terminal region that flanks BIR2, suggesting that this is a site of interaction with caspase 3. Introduction of these mutations into full-length XIAP reduced caspase 3 inhibitory activity up to 500-fold, but did not affect its ability to inhibit caspase 9 or interact with the IAP antagonist DIABLO. Furthermore, these mutants retained full ability to inhibit apoptosis in transfected cells, demonstrating that although XIAP is able to inhibit caspase 3, this activity is dispensable for inhibition of apoptosis by XIAP in vivo.