Human caspase-7 activity and regulation by its N-terminal peptide
Human caspase-7 activity and regulation by its N-terminal peptide
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DOI：
10.1074/jbc.m305110200
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发表时间：
2003-09-05
影响因子：
4.8
通讯作者：
Salvesen, GS
中科院分区：
文献类型：
--
作者：
Denault, JB;Salvesen, GS
细胞凋亡执行阶段的中心是两个密切相关的半胱天冬酶-3和-7。它们具有共同的底物特异性和结构，但在其各自的N-末端区域的序列上完全不同，包括其N-肽，在酶原活化期间去除的23-28个残基片段。我们表明，N-肽的caspase-7在体外活性蛋白酶的基本激活或性质中没有发挥作用。然而，N-肽在体内改变胱天蛋白酶-7的性质。在异位表达实验中，没有N-肽的胱天蛋白酶-7构建体比具有不可切割肽的构建体更致命。此外，在酶原的有效活化可以在体内发生之前，必须去除胱天蛋白酶-7的N-肽。对N肽的这些不同的要求表明，它用于将胱天蛋白酶-7酶原物理隔离在胞质位置，防止上游激活剂（胱天蛋白酶-8、-9和-10）进入。在酶原的有效转化和激活可以在体内发生之前，N-肽必须首先被去除，可能是通过半胱天冬酶-3。
Central to the execution phase of apoptosis are the two closely related caspase-3 and -7. They share common substrate specificity and structure, but differ completely in the sequence of their respective N-terminal regions including their N-peptides, a 23-28 residue segment that are removed during zymogen activation. We show that the N-peptide of caspase-7 plays no role in the fundamental activation or properties of the active protease in vitro. However, the N-peptide modifies the properties of caspase-7 in vivo. In ectopic expression experiments, caspase-7 constructs with no N-peptide are far more lethal than constructs that have an uncleavable peptide. Moreover, the N-peptide of caspase-7 must be removed before efficient activation of the zymogen can occur in vivo. These disparate requirements for the N-peptide argue that it serves to physically sequester the caspase-7 zymogen in a cytosolic location that prevents access by upstream activators (caspase-8, -9, and -10). The N-peptide must first be removed, probably by caspase-3, before efficient conversion and activation of the zymogen can occur in vivo.