Klebba Joseph E, Buster Daniel W, McLamarrah Tiffany A, Rusan Nasser M, Rogers Gregory C
Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724; and.
National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
Proc Natl Acad Sci U S A. 2015 Feb 17;112(7):E657-66. doi: 10.1073/pnas.1417967112. Epub 2015 Feb 2.
Polo-like kinase 4 (Plk4) is a master regulator of centriole duplication, and its hyperactivity induces centriole amplification. Homodimeric Plk4 has been shown to be ubiquitinated as a result of autophosphorylation, thus promoting its own degradation and preventing centriole amplification. Unlike other Plks, Plk4 contains three rather than two Polo box domains, and the function of its third Polo box (PB3) is unclear. Here, we performed a functional analysis of Plk4's structural domains. Like other Plks, Plk4 possesses a previously unidentified autoinhibitory mechanism mediated by a linker (L1) near the kinase domain. Thus, autoinhibition is a conserved feature of Plks. In the case of Plk4, autoinhibition is relieved after homodimerization and is accomplished by PB3 and by autophosphorylation of L1. In contrast, autophosphorylation of the second linker promotes separation of the Plk4 homodimer. Therefore, autoinhibition delays the multiple consequences of activation until Plk4 dimerizes. These findings reveal a complex mechanism of Plk4 regulation and activation which govern the process of centriole duplication.
Polo样激酶4（Plk4）是中心粒复制的主要调节因子，其过度活跃会导致中心粒扩增。已表明同型二聚体Plk4由于自身磷酸化而被泛素化，从而促进其自身降解并防止中心粒扩增。与其他Plk不同，Plk4含有三个而非两个Polo框结构域，其第三个Polo框（PB3）的功能尚不清楚。在这里，我们对Plk4的结构域进行了功能分析。与其他Plk一样，Plk4具有一种先前未被识别的自抑制机制，该机制由激酶结构域附近的一个连接子（L1）介导。因此，自抑制是Plk的一个保守特征。就Plk4而言，自抑制在同型二聚化后解除，并由PB3和L1的自身磷酸化完成。相反，第二个连接子的自身磷酸化促进Plk4同型二聚体的分离。因此，自抑制会延迟激活的多种后果，直到Plk4二聚化。这些发现揭示了Plk4调节和激活的复杂机制，该机制控制着中心粒复制过程。
