title: The Ki-67 and RepoMan mitotic phosphatases assemble via an identical, yet novel mechanism.
abstract: Ki-67 and RepoMan have key roles during mitotic exit. Previously, we showed that Ki-67 organizes the mitotic chromosome periphery and recruits protein phosphatase 1 (PP1) to chromatin at anaphase onset, in a similar manner as RepoMan (Booth et al., 2014). Here we show how Ki-67 and RepoMan form mitotic exit phosphatases by recruiting PP1, how they distinguish between distinct PP1 isoforms and how the assembly of these two holoenzymes are dynamically regulated by Aurora B kinase during mitosis. Unexpectedly, our data also reveal that Ki-67 and RepoMan bind PP1 using an identical, yet novel mechanism, interacting with a PP1 pocket that is engaged only by these two PP1 regulators. These findings not only show how two distinct mitotic exit phosphatases are recruited to their substrates, but also provide immediate opportunities for the design of novel cancer therapeutics that selectively target the Ki-67:PP1 and RepoMan:PP1 holoenzymes.
authors: Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, United States.
authors: Ganesan Senthil
authors: GS
authors: Kumar
authors: College of Health and Life Science, Research Institute for Environment, Health and Society, Brunel University London, Uxbridge, United Kingdom.
authors: Ezgi
authors: E
authors: Gokhan
authors: Laboratory of Biosignaling and Therapeutics, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors: Sofie
authors: S
authors: De Munter
authors: Laboratory of Biosignaling and Therapeutics, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors: Mathieu
authors: M
authors: Bollen
authors: College of Health and Life Science, Research Institute for Environment, Health and Society, Brunel University London, Uxbridge, United Kingdom.
authors: Paola
authors: 0000-0002-0000-2271
authors: P
authors: Vagnarelli
authors: Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, United States.
authors: Wolfgang
authors: W
authors: Peti
authors: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, United States.
authors: Rebecca
authors: 0000-0002-4645-1232
authors: R
authors: Page
mesh_terms: D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D019394:Ki-67 Antigen / Q000737:chemistry / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D055503:Protein Multimerization; D054645:Protein Phosphatase 1 / Q000737:chemistry / Q000378:metabolism*
chemical_list: C509224:CDCA2 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019394:Ki-67 Antigen; D009687:Nuclear Proteins; D054645:Protein Phosphatase 1
keywords: E. coli; Ki-67; RepoMan; biophysics; cancer; cancer biology; cell cycle; chicken; human; protein phosphatase 1 (PP1); structural biology