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Cell. October 3, 2003; 115 (1): 83-95.

The molecular basis for phosphodependent substrate targeting and regulation of Plks by the Polo-box domain.

Elia AE , Rellos P , Haire LF , Chao JW , Ivins FJ , Hoepker K , Mohammad D , Cantley LC , Smerdon SJ , Yaffe MB .

Polo-like kinases (Plks) perform crucial functions in cell-cycle progression and multiple stages of mitosis. Plks are characterized by a C-terminal noncatalytic region containing two tandem Polo boxes, termed the Polo-box domain (PBD), which has recently been implicated in phosphodependent substrate targeting. We show that the PBDs of human, Xenopus, and yeast Plks all recognize similar phosphoserine/threonine-containing motifs. The 1.9 A X-ray structure of a human Plk1 PBD-phosphopeptide complex shows that the Polo boxes each comprise beta6alpha structures that associate to form a 12-stranded beta sandwich domain. The phosphopeptide binds along a conserved, positively charged cleft located at the edge of the Polo-box interface. Mutations that specifically disrupt phosphodependent interactions abolish cell-cycle-dependent localization and provide compelling phenotypic evidence that PBD-phospholigand binding is necessary for proper mitotic progression. In addition, phosphopeptide binding to the PBD stimulates kinase activity in full-length Plk1, suggesting a conformational switching mechanism for Plk regulation and a dual functionality for the PBD.

PubMed ID: 14532005
Article link: Cell.
Grant support: GM60594 NIGMS NIH HHS , R01 GM056203 NIGMS NIH HHS

Genes referenced: plk1

Leung, 2003, Pubmed

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