Phospho-Pon Binding-Mediated Fine-Tuning of Plk1 Activity.
Phospho-Pon Binding-Mediated Fine-Tuning of Plk1 Activity.
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DOI：
10.1016/j.str.2016.04.012
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发表时间：
2016-07
期刊：
影响因子：
5.7
通讯作者：
K. Zhu;Z. Shan;Lu Zhang;W. Wen
中科院分区：
文献类型：
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作者：
K. Zhu;Z. Shan;Lu Zhang;W. Wen
在果蝇神经母细胞（NBs）中，细胞命运决定因子Numb的不对称定位和分离受其适配体Partner of Numb （Pon）和细胞周期激酶Polo的调控。Polo磷酸化Pon定位域，从而导致其与Numb一起基底分布，尽管其机制尚不清楚。在这里，我们发现Cdk1磷酸化Pon的Thr63位点，从而为polo样激酶1 （Plk1）的Polo-box结构域（PBD）创建一个对接位点。Plk1 PBD/phospho-Pon复合物的晶体结构揭示了两个phospho-Pon结合的PBD结合形成二聚体的二聚体。我们提供的证据表明，phospho-Pon结合诱导的PBD二聚化减轻了Plk1的自身抑制。此外，我们证明Pon的启动Cdk1磷酸化对于顺序Plk1磷酸化是重要的。我们的研究结果不仅提供了磷酸化蛋白结合如何激活Plk1的结构见解，而且表明与不同磷酸化蛋白的结合可能介导Plk1活性的微调。
InDrosophilaneuroblasts (NBs), the asymmetrical localization and segregation of the cell-fate determinant Numb are regulated by its adaptor Partner of Numb (Pon) and the cell-cycle kinase Polo. Polo phosphorylates the Pon localization domain, thus leading to its basal distribution together with Numb, albeit through an unclear mechanism. Here, we find that Cdk1 phosphorylates Pon at Thr63, thus creating a docking site for the Polo-box domain (PBD) of Polo-like kinase 1 (Plk1). The crystal structure of the Plk1 PBD/phospho-Pon complex reveals that two phospho-Pon bound PBDs associate to form a dimer of dimers. We provide evidence that phospho-Pon binding-induced PBD dimerization relieves the autoinhibition of Plk1. Moreover, we demonstrate that the priming Cdk1 phosphorylation of Pon is important for sequential Plk1 phosphorylation. Our results not only provide structural insight into how phosphoprotein binding activates Plk1 but also suggest that binding to different phosphoproteins might mediate the fine-tuning of Plk1 activity.