CLARP, a death effector domain-containing protein interacts with caspase-8 and regulates apoptosis
CLARP, a death effector domain-containing protein interacts with caspase-8 and regulates apoptosis
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DOI：
10.1073/pnas.94.20.10717
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发表时间：
1997-09-30
影响因子：
11.1
通讯作者：
Nunez, G
中科院分区：
文献类型：
--
作者：
Inohara, N;Koseki, T;Nunez, G
我们已经确定并表征了一种半胱天冬酶样凋亡调控蛋白--序列分析表明，人BMPs含有两个氨基端死亡效应结构域和一个羧基端半胱天冬酶样结构域，BMPs的结构和氨基酸序列与本研究中鉴定的果蝇蛋白caspase-8、caspase-10和DCP 2相似，但与caspase-8、caspase-10和DCP 2不同，预测参与催化的两个重要残基在CIPTP的半胱天冬酶样结构域中丢失，用荧光底物对半胱天冬酶活性的分析证实CIPTP是无催化活性的，发现CIPTP与半胱天冬酶-8相互作用但不与FADD/MORT-1相互作用，Fas和肿瘤坏死因子受体1信号传导途径的上游死亡效应结构域蛋白，BMPs的表达诱导细胞凋亡，其被病毒性半胱天冬酶抑制剂p35、显性负突变型半胱天冬酶-8和合成半胱天冬酶抑制剂苄氧基羰基-Val-Ala-Asp-（OMe）-氟甲基酮（zVAD-fp 35）阻断。人clarp基因定位于2 q33，因此，clarp是上游caspase-8的调节因子，可能在组织发育和稳态过程中参与细胞凋亡。
We have identified and characterized CLARP, a caspase-like apoptosis-regulatory protein. Sequence analysis revealed that human CLARP contains two amino-terminal death effector domains fused to a carboxyl-terminal caspase-like domain, The structure and amino acid sequence of CLARP resemble those of caspase-8, caspase-10, and DCP2, a Drosophila melanogaster protein identified in this study, Unlike caspase-8, caspase-10, and DCP2, however, two important residues predicted to be involved in catalysis were lost in the caspase-like domain of CLARP, Analysis with fluorogenic substrates for caspase activity confirmed that CLARP is catalytically inactive, CLARP was found to interact with caspase-8 but not with FADD/MORT-1, an upstream death effector domain-containing protein of the Fas and tumor necrosis factor receptor 1 signaling pathway, Expression of CLARP induced apoptosis, which was blocked by the viral caspase inhibitor p35, dominant negative mutant caspase-8, and the synthetic caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-(OMe)-fluoromethylketone (zVAD-fmk). Moreover, CLARP augmented the killing ability of caspase-8 and FADD/MORT-1 in mammalian cells, The human clarp gene maps to 2q33, Thus, CLARP represents a regulator of the upstream caspase-8, which may play a role in apoptosis during tissue development and homeostasis.