title: Centromeric binding and activity of Protein Phosphatase 4.
abstract: The cell division cycle requires tight coupling between protein phosphorylation and dephosphorylation. However, understanding the cell cycle roles of multimeric protein phosphatases has been limited by the lack of knowledge of how their diverse regulatory subunits target highly conserved catalytic subunits to their sites of action. Phosphoprotein phosphatase 4 (PP4) has been recently shown to participate in the regulation of cell cycle progression. We now find that the EVH1 domain of the regulatory subunit 3 of Drosophila PP4, Falafel (Flfl), directly interacts with the centromeric protein C (CENP-C). Unlike other EVH1 domains that interact with proline-rich ligands, the crystal structure of the Flfl amino-terminal EVH1 domain bound to a CENP-C peptide reveals a new target-recognition mode for the phosphatase subunit. We also show that binding of Flfl to CENP-C is required to bring PP4 activity to centromeres to maintain CENP-C and attached core kinetochore proteins at chromosomes during mitosis.
authors.affiliation: Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Lipinszki
authors.affiliation: Macromolecular Structure and Function Laboratory, Cancer Research UK, London Research Institute, London WC2A 3LY, UK.
authors.forename: Stephane
authors.initials: S
authors.lastname: Lefevre
authors.affiliation: Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Savoian
authors.affiliation: Macromolecular Structure and Function Laboratory, Cancer Research UK, London Research Institute, London WC2A 3LY, UK.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Singleton
authors.affiliation: Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Glover
authors.affiliation: Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
authors.forename: Marcin R
authors.initials: MR
authors.lastname: Przewloka
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002453:Cell Cycle / Q000502:physiology*; D002478:Cells, Cultured; D002503:Centromere / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D003461:Crystallography; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000502:physiology; D024202:Electrophoretic Mobility Shift Assay; D007091:Image Processing, Computer-Assisted; D013058:Mass Spectrometry; D018613:Microscopy, Confocal; D016297:Mutagenesis, Site-Directed; D010749:Phosphoprotein Phosphatases / Q000737:chemistry* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D034622:RNA Interference
chemical_list: C581136:CENP-C protein, Drosophila; D002868:Chromosomal Proteins, Non-Histone; D029721:Drosophila Proteins; D010749:Phosphoprotein Phosphatases; C080406:protein phosphatase 4