title: Systematic discovery of new recognition peptides mediating protein interaction networks.
abstract: Many aspects of cell signalling, trafficking, and targeting are governed by interactions between globular protein domains and short peptide segments. These domains often bind multiple peptides that share a common sequence pattern, or "linear motif" (e.g., SH3 binding to PxxP). Many domains are known, though comparatively few linear motifs have been discovered. Their short length (three to eight residues), and the fact that they often reside in disordered regions in proteins makes them difficult to detect through sequence comparison or experiment. Nevertheless, each new motif provides critical molecular details of how interaction networks are constructed, and can explain how one protein is able to bind to very different partners. Here we show that binding motifs can be detected using data from genome-scale interaction studies, and thus avoid the normally slow discovery process. Our approach based on motif over-representation in non-homologous sequences, rediscovers known motifs and predicts dozens of others. Direct binding experiments reveal that two predicted motifs are indeed protein-binding modules: a DxxDxxxD protein phosphatase 1 binding motif with a KD of 22 microM and a VxxxRxYS motif that binds Translin with a KD of 43 microM. We estimate that there are dozens or even hundreds of linear motifs yet to be discovered that will give molecular insight into protein networks and greatly illuminate cellular processes.
authors.affiliation: European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Victor
authors.initials: V
authors.lastname: Neduva
authors.forename: Rune
authors.initials: R
authors.lastname: Linding
authors.forename: Isabelle
authors.initials: I
authors.lastname: Su-Angrand
authors.forename: Alexander
authors.initials: A
authors.lastname: Stark
authors.forename: Federico
authors.initials: F
authors.lastname: de Masi
authors.forename: Toby J
authors.initials: TJ
authors.lastname: Gibson
authors.forename: Joe
authors.initials: J
authors.lastname: Lewis
authors.forename: Luis
authors.initials: L
authors.lastname: Serrano
authors.forename: Robert B
authors.initials: RB
authors.lastname: Russell
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016678:Genome / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D010455:Peptides; D011506:Proteins