Mechanism of zinc-mediated inhibition of caspase-9
Mechanism of zinc-mediated inhibition of caspase-9
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DOI：
10.1002/pro.2090
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发表时间：
2012-07-01
期刊：
影响因子：
8
通讯作者：
Hardy, Jeanne A.
中科院分区：
文献类型：
--
作者：
Huber, Kristen L.;Hardy, Jeanne A.
锌介导的抑制与整体半胱天冬酶调节有关，锌介导的抑制的缓解对小分子和天然诱导的半胱天冬酶活化都至关重要。caspase-9作为一个启动子，调节凋亡caspase级联反应的上游阶段，使其成为一个关键的控制点。在这里，我们确定了两个不同的锌结合位点的caspase-9。第一个位点由H237、C239和C287组成，包括活性位点二联体，主要负责锌介导的抑制。C272处的第二个结合位点远离活性位点。考虑到这两个区域的氨基酸保守性，这些位点似乎存在于胱天蛋白酶家族中，这强调了锌介导的这类酶调节的重要性。
Zinc-mediated inhibition is implicated in global caspase regulation, with relief of zinc-mediated inhibition central to both small-molecule and natively induced caspase activation. As an initiator, caspase-9 regulates the upstream stages of the apoptotic caspase cascade, making it a critical control point. Here we identify two distinct zinc-binding sites on caspase-9. The first site, composed of H237, C239, and C287, includes the active site dyad and is primarily responsible for zinc-mediated inhibition. The second binding site at C272 is distal from the active site. Given the amino-acid conservation in both regions, these sites appear to be present across the caspase family underscoring the importance of zinc-mediated regulation of this class of enzymes.