title: A Conserved Motif Provides Binding Specificity to the PP2A-B56 Phosphatase.
abstract: Dynamic protein phosphorylation is a fundamental mechanism regulating biological processes in all organisms. Protein phosphatase 2A (PP2A) is the main source of phosphatase activity in the cell, but the molecular details of substrate recognition are unknown. Here, we report that a conserved surface-exposed pocket on PP2A regulatory B56 subunits binds to a consensus sequence on interacting proteins, which we term the LxxIxE motif. The composition of the motif modulates the affinity for B56, which in turn determines the phosphorylation status of associated substrates. Phosphorylation of amino acid residues within the motif increases B56 binding, allowing integration of kinase and phosphatase activity. We identify conserved LxxIxE motifs in essential proteins throughout the eukaryotic domain of life and in human viruses, suggesting that the motifs are required for basic cellular function. Our study provides a molecular description of PP2A binding specificity with broad implications for understanding signaling in eukaryotes.
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.
authors.forename: Emil Peter Thrane
authors.initials: EPT
authors.lastname: Hertz
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark. Electronic address: thomas.kruse@cpr.ku.dk.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kruse
authors.affiliation: Conway Institute of Biomolecular and Biomedical Sciences, University College Dublin, Dublin 4, Ireland.
authors.forename: Norman E
authors.initials: NE
authors.lastname: Davey
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.
authors.forename: Blanca
authors.initials: B
authors.lastname: López-Méndez
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.
authors.forename: Jón Otti
authors.initials: JO
authors.lastname: Sigurðsson
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Montoya
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.
authors.forename: Jesper V
authors.initials: JV
authors.lastname: Olsen
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark. Electronic address: jakob.nilsson@cpr.ku.dk.
authors.forename: Jakob
authors.initials: J
authors.lastname: Nilsson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019295:Computational Biology; D017124:Conserved Sequence; D030562:Databases, Protein; D000071316:Forkhead Box Protein O3 / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D062105:Molecular Docking Simulation; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D054648:Protein Phosphatase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013379:Substrate Specificity; D014162:Transfection
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D020690:GTPase-Activating Proteins; D011993:Recombinant Fusion Proteins; C115995:mgcRacGAP; C572369:PP2A-B56alpha protein, human; D054648:Protein Phosphatase 2