Insights into the regulatory mechanism for caspase-8 activation
Insights into the regulatory mechanism for caspase-8 activation
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DOI：
10.1016/s1097-2765(03)00059-5
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发表时间：
2003-02-01
期刊：
影响因子：
16
通讯作者：
Grütter, MG
中科院分区：
文献类型：
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作者：
Donepudi, M;Mac Sweeney, A;Grütter, MG
在死亡受体诱导的凋亡途径中，胱天蛋白酶-8在特定的切割位点自催化切割自身。为了更好地理解caspase-8激活背后的调控机制，我们比较了活性野生型caspase-8（wtC 8）和一种不可裂解的caspase-8（不可裂解的C8）。我们证明，wtC 8主要存在作为单体和二聚化的浓度和抑制剂结合依赖的方式。二聚体wtC 8的K-D与50 μ M相似，并且当抑制剂结合时降低。不可裂解的C8主要是单体的，但少量的二聚体与wtC 8一样具有活性。抑制剂结合不有利于二聚化，但诱导活性位点重排在不可裂解的C8。我们的研究结果表明，二聚化是caspase-8激活的关键因素。
In the death receptor induced apoptotic pathway, caspase-8 autocatalytically cleaves itself at specific cleavage sites. To better understand the regulatory mechanisms behind caspase-8 activation, we compared active wild-type caspase-8 (wtC8) and an uncleavable form of procaspase-8 (uncleavable C8). We demonstrate that wtC8 predominantly exists as a monomer and dimerizes in a concentration and inhibitor binding-dependent fashion. The K-D for dimeric wtC8 is similar to50 muM and decreases when inhibitor bound. Uncleavable C8 is mainly monomeric, but a small amount that dimerizes is as active as wtC8. Inhibitor binding does not favor dimerization but induces active site rearrangements in uncleavable C8. Our findings suggest that dimerization is the crucial factor for caspase-8 activation.