Autoactivation of procaspase-9 by Apaf-1-mediated oligomerization
Autoactivation of procaspase-9 by Apaf-1-mediated oligomerization
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DOI：
10.1016/s1097-2765(00)80095-7
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发表时间：
1998-06-01
期刊：
影响因子：
16
通讯作者：
Alnemri, ES
中科院分区：
文献类型：
--
作者：
Srinivasula, SM;Ahmad, M;Alnemri, ES
在细胞色素c/dATP依赖性途径中，Apaf-1对半胱天冬酶原-9的激活需要蛋白水解裂解以产生成熟的半胱天冬酶分子。为了阐明Apaf-1激活procaspase-9的机制，我们设计了一个使用重组组分的体外Apaf-1-procaspase-9激活系统。在这里，我们表明，Apaf-1 WD-40重复的缺失使Apaf-1组成型活性和能够独立于细胞色素c和dATP的加工半胱天冬酶原-9。Apaf-1介导的procaspase-9的加工通过procaspase-9本身的内在自催化活性发生在Asp-315处。我们提供的证据表明，Apaf-1可以形成寡聚体，并可能通过寡聚其前体分子促进procaspase-9的自激活。一旦激活，caspase-9可以启动涉及下游执行器caspase-3，-6和-7的caspase级联反应。
Activation of procaspase-9 by Apaf-1 in the cytochrome c/dATP-dependent pathway requires proteolytic cleavage to generate the mature caspase molecule. To elucidate the mechanism of activation of procaspase-9 by Apaf-1, we designed an in vitro Apaf-1-procaspase-9 activation system using recombinant components. Here, we show that deletion of the Apaf-1 WD-40 repeats makes Apaf-1 constitutively active and capable of processing procaspase-9 independent of cytochrome c and dATP. Apaf-1-mediated processing of procaspase-9 occurs at Asp-315 by an intrinsic autocatalytic activity of procaspase-9 itself. We provide evidence that Apaf-1 can form oligomers and may facilitate procaspase-9 autoactivation by oligomerizing its precursor molecules. Once activated, caspase-9 can initiate a caspase cascade involving the downstream executioners caspase-3, -6, and -7.