title: Expanding the PP2A Interactome by Defining a B56-Specific SLiM.
abstract: Specific interactions between proteins govern essential physiological processes including signaling. Many enzymes, especially the family of serine/threonine phosphatases (PSPs: PP1, PP2A, and PP2B/calcineurin/CN), recruit substrates and regulatory proteins by binding short linear motifs (SLiMs), short sequences found within intrinsically disordered regions that mediate specific protein-protein interactions. While tremendous progress had been made in identifying where and how SLiMs bind PSPs, especially PP1 and CN, essentially nothing is known about how SLiMs bind PP2A, a validated cancer drug target. Here we describe three structures of a PP2A-SLiM interaction (B56:pS-RepoMan, B56:pS-BubR1, and B56:pSpS-BubR1), show that this PP2A-specific SLiM is defined as LSPIxE, and then use these data to discover scores of likely PP2A regulators and substrates. Together, these data provide a powerful approach not only for dissecting PP2A interaction networks in cells but also for targeting PP2A diseases, such as cancer.
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
authors.forename: Xinru
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
authors.forename: Rakhi
authors.initials: R
authors.lastname: Bajaj
authors.affiliation: Laboratory of Biosignaling & Therapeutics, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bollen
authors.affiliation: Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, RI 02912, USA; Department Chemistry, Brown University, Providence, RI 02912, USA.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Peti
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA. Electronic address: rebecca_page@brown.edu.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Page
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D054648:Protein Phosphatase 2 / Q000737:chemistry* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012694:Serine / Q000378:metabolism
chemical_list: C509224:CDCA2 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C525690:PPP2R5A protein, human; D012694:Serine; C584277:BUB1 protein, human; D017346:Protein Serine-Threonine Kinases; D054648:Protein Phosphatase 2
keywords: B56; BubR1; NMR spectroscopy; PP2A; RepoMan; X-ray crystallography; mitosis; phosphorylation; small linear motif (SLiM)