Mutual inhibition of separase and Cdk1 by two-step complex formation
Mutual inhibition of separase and Cdk1 by two-step complex formation
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DOI：
10.1016/j.molcel.2005.05.022
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发表时间：
2005-07-01
期刊：
影响因子：
16
通讯作者：
Stemmann, O
中科院分区：
文献类型：
--
作者：
Gorr, IH;Boos, D;Stemmann, O
遗传信息的稳定保持需要染色体分离以高精度发生。分裂后期是由环状粘连蛋白被分离酶切割而触发的，分离酶是一种受其抑制剂securin调节的蛋白酶。脊椎动物securin的可分配性强烈表明分离酶调节的额外手段。事实上，姐妹染色单体分离，但不securin降解抑制的组成型活性细胞周期蛋白依赖性激酶1（Cdk1），可以拯救单独通过防止磷酸化的分离酶。我们证明，Cdk1依赖的磷酸化分离酶是不足以抑制。在第二步中，Cdk1通过其调节性细胞周期蛋白B1亚基稳定结合磷酸化分离酶。复合物的形成抑制蛋白酶和激酶的结果，我们表明，脊椎动物分离酶是Cdk1的直接抑制剂。分离酶的这种意想不到的功能是负调控的securin，但独立的分离酶的蛋白水解活性。
Stable maintenance of genetic information requires chromosome segregation to occur with high accuracy. Anaphase is triggered when ring-shaped cohesin is cleaved by separase, a protease regulated by association with its inhibitor securin. Dispensability of vertebrate securin strongly suggests additional means of separase regulation. Indeed, sister chromatid separation but not securin degradation is inhibited by constitutively active cyclin-dependent kinase 1 (Cdk1) and can be rescued solely by preventing phosphorylation of separase. We demonstrate that Cdk1-dependent phosphorylation of separase is not sufficient for inhibition. In a second step, Cdk1 stably binds phosphorylated separase via its regulatory cyclin B1 subunit. Complex formation results in inhibition of both protease and kinase, and we show that vertebrate separase is a direct inhibitor of Cdk1. This unanticipated function of separase is negatively regulated by securin but independent of separase's proteolytic activity.