人类 Plk4 在中心体生物发生中单向支架转换的分子基础。
Molecular basis for unidirectional scaffold switching of human Plk4 in centriole biogenesis.
机构信息
1] Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. [2] Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Republic of Korea. [3].
1] Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. [2].
出版信息
Nat Struct Mol Biol. 2014 Aug;21(8):696-703. doi: 10.1038/nsmb.2846. Epub 2014 Jun 29.
Polo-like kinase 4 (Plk4) is a key regulator of centriole duplication, an event critical for the maintenance of genomic integrity. We show that Plk4 relocalizes from the inner Cep192 ring to the outer Cep152 ring as newly recruited Cep152 assembles around the Cep192-encircled daughter centriole. Crystal-structure analyses revealed that Cep192- and Cep152-derived peptides bind the cryptic polo box (CPB) of Plk4 in opposite orientations and in a mutually exclusive manner. The Cep152 peptide bound to the CPB markedly better than did the Cep192 peptide and effectively 'snatched' the CPB away from a preformed CPB-Cep192 peptide complex. A cancer-associated Cep152 mutation impairing the Plk4 interaction induced defects in procentriole assembly and chromosome segregation. Thus, Plk4 is intricately regulated in time and space through ordered interactions with two distinct scaffolds, Cep192 and Cep152, and a failure in this process may lead to human cancer.
丝氨酸/苏氨酸激酶 4（Plk4）是中心体复制的关键调节因子，中心体复制对于维持基因组完整性至关重要。我们发现 Plk4 从内 Cep192 环重新定位到外 Cep152 环，因为新募集的 Cep152 围绕着被 Cep192 环绕的子中心体组装。晶体结构分析显示 Cep192 和 Cep152 衍生肽以相反的方向和相互排斥的方式结合 Plk4 的隐藏 Polo 盒（CPB）。Cep152 肽与 CPB 的结合明显优于 Cep192 肽，并且有效地“抢夺”了 CPB 从预先形成的 CPB-Cep192 肽复合物。一种与癌症相关的 Cep152 突变会损害 Plk4 的相互作用，导致前中心体组装和染色体分离缺陷。因此，Plk4 通过与两个不同支架 Cep192 和 Cep152 的有序相互作用以及与一个失败的过程在时间和空间上受到复杂的调节，而这个过程的失败可能导致人类癌症。
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