title: Systematic identification of phosphorylation-mediated protein interaction switches.
abstract: Proteomics techniques can identify thousands of phosphorylation sites in a single experiment, the majority of which are new and lack precise information about function or molecular mechanism. Here we present a fast method to predict potential phosphorylation switches by mapping phosphorylation sites to protein-protein interactions of known structure and analysing the properties of the protein interface. We predict 1024 sites that could potentially enable or disable particular interactions. We tested a selection of these switches and showed that phosphomimetic mutations indeed affect interactions. We estimate that there are likely thousands of phosphorylation mediated switches yet to be uncovered, even among existing phosphorylation datasets. The results suggest that phosphorylation sites on globular, as distinct from disordered, parts of the proteome frequently function as switches, which might be one of the ancient roles for kinase phosphorylation.
authors.affiliation: CellNetworks, Bioquant, University of Heidelberg, Im Neuenheimer Feld 267, Heidelberg, Germany.|Biochemie Zentrum Heidelberg (BZH), Im Neuenheimer Feld 328, Heidelberg, Germany.
authors.forename: Matthew J
authors.identifier: 0000-0003-4583-9814
authors.initials: MJ
authors.lastname: Betts
authors.affiliation: CellNetworks, Bioquant, University of Heidelberg, Im Neuenheimer Feld 267, Heidelberg, Germany.|Biochemie Zentrum Heidelberg (BZH), Im Neuenheimer Feld 328, Heidelberg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Wichmann
authors.affiliation: CellNetworks, Bioquant, University of Heidelberg, Im Neuenheimer Feld 267, Heidelberg, Germany.|Biochemie Zentrum Heidelberg (BZH), Im Neuenheimer Feld 328, Heidelberg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Utz
authors.affiliation: CellNetworks, Bioquant, University of Heidelberg, Im Neuenheimer Feld 267, Heidelberg, Germany.|Biochemie Zentrum Heidelberg (BZH), Im Neuenheimer Feld 328, Heidelberg, Germany.
authors.forename: Timon
authors.initials: T
authors.lastname: Andre
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada.
authors.forename: Evangelia
authors.identifier: 0000-0002-8294-2995
authors.initials: E
authors.lastname: Petsalaki
authors.affiliation: European Molecular Biology Laboratory, Meyerhofstrasse 1, Heidelberg, Germany.
authors.forename: Pablo
authors.initials: P
authors.lastname: Minguez
authors.affiliation: European Molecular Biology Laboratory, Meyerhofstrasse 1, Heidelberg, Germany.
authors.forename: Luca
authors.initials: L
authors.lastname: Parca
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada.|Donnelly Centre and Departments of Molecular Genetics and Computer Science, University of Toronto, Toronto, Ontario, Canada.|Center for Cancer Systems Biology, Dana-Farber Cancer Institute, One Jimmy Fund Way, Boston, Massachusetts, United States.|Canadian Institute for Advanced Research, Toronto, Ontario, Canada.
authors.forename: Frederick P
authors.initials: FP
authors.lastname: Roth
authors.affiliation: European Molecular Biology Laboratory, Meyerhofstrasse 1, Heidelberg, Germany.
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Gavin
authors.affiliation: European Molecular Biology Laboratory, Meyerhofstrasse 1, Heidelberg, Germany.
authors.forename: Peer
authors.initials: P
authors.lastname: Bork
authors.affiliation: CellNetworks, Bioquant, University of Heidelberg, Im Neuenheimer Feld 267, Heidelberg, Germany.|Biochemie Zentrum Heidelberg (BZH), Im Neuenheimer Feld 328, Heidelberg, Germany.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Russell
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D008956:Models, Chemical; D008958:Models, Molecular; D010766:Phosphorylation; D010770:Phosphotransferases / Q000737:chemistry* / Q000648:ultrastructure; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping / Q000379:methods*; D020543:Proteome / Q000737:chemistry* / Q000648:ultrastructure; D020539:Sequence Analysis, Protein / Q000379:methods*; D013329:Structure-Activity Relationship
chemical_list: D020543:Proteome; D010770:Phosphotransferases