title: Phospho-Pon Binding-Mediated Fine-Tuning of Plk1 Activity.
abstract: In Drosophila neuroblasts (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.
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai 200040, China.
authors.forename: Kang
authors.initials: K
authors.lastname: Zhu
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai 200040, China.
authors.forename: Zelin
authors.initials: Z
authors.lastname: Shan
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai 200040, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai 200040, China; Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Systems Biology for Medicine, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China. Electronic address: wywen@fudan.edu.cn.
authors.forename: Wenyu
authors.initials: W
authors.lastname: Wen
mesh_terms: D000818:Animals; D001665:Binding Sites; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000378:metabolism; D004330:Drosophila / Q000378:metabolism; D029721:Drosophila Proteins / Q000737:chemistry* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D010766:Phosphorylation; D011485:Protein Binding; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D016203:CDC2 Protein Kinase; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C115164:PON protein, Drosophila