title: Autoinhibition and relief mechanism for Polo-like kinase 4.
abstract: 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.
authors: Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724; and.
authors: Joseph E
authors: JE
authors: Klebba
authors: Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724; and.
authors: Daniel W
authors: DW
authors: Buster
authors: Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724; and.
authors: Tiffany A
authors: TA
authors: McLamarrah
authors: National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
authors: Nasser M
authors: NM
authors: Rusan
authors: Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724; and gcrogers@email.arizona.edu.
authors: Gregory C
authors: GC
authors: Rogers
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D019281:Dimerization; D004330:Drosophila; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D063347:Native Polyacrylamide Gel Electrophoresis; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D053719:Tandem Mass Spectrometry; D054875:Ubiquitination
chemical_list: D017931:DNA Primers; D029721:Drosophila Proteins; D017346:Protein Serine-Threonine Kinases; C522064:Sak protein, Drosophila
keywords: Polo box; Polo-like kinase 4; autoinhibition; centriole; centrosome
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