title: The multiple-specificity landscape of modular peptide recognition domains.
abstract: Modular protein interaction domains form the building blocks of eukaryotic signaling pathways. Many of them, known as peptide recognition domains, mediate protein interactions by recognizing short, linear amino acid stretches on the surface of their cognate partners with high specificity. Residues in these stretches are usually assumed to contribute independently to binding, which has led to a simplified understanding of protein interactions. Conversely, we observe in large binding peptide data sets that different residue positions display highly significant correlations for many domains in three distinct families (PDZ, SH3 and WW). These correlation patterns reveal a widespread occurrence of multiple binding specificities and give novel structural insights into protein interactions. For example, we predict a new binding mode of PDZ domains and structurally rationalize it for DLG1 PDZ1. We show that multiple specificity more accurately predicts protein interactions and experimentally validate some of the predictions for the human proteins DLG1 and SCRIB. Overall, our results reveal a rich specificity landscape in peptide recognition domains, suggesting new ways of encoding specificity in protein interaction networks.
authors.affiliation: Banting and Best Department of Medical Research, The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Gfeller
authors.forename: Frank
authors.initials: F
authors.lastname: Butty
authors.forename: Marta
authors.initials: M
authors.lastname: Wierzbicka
authors.forename: Erik
authors.initials: E
authors.lastname: Verschueren
authors.forename: Peter
authors.initials: P
authors.lastname: Vanhee
authors.forename: Haiming
authors.initials: H
authors.lastname: Huang
authors.forename: Andreas
authors.initials: A
authors.lastname: Ernst
authors.forename: Nisa
authors.initials: N
authors.lastname: Dar
authors.forename: Igor
authors.initials: I
authors.lastname: Stagljar
authors.forename: Luis
authors.initials: L
authors.lastname: Serrano
authors.forename: Sachdev S
authors.initials: SS
authors.lastname: Sidhu
authors.forename: Gary D
authors.initials: GD
authors.lastname: Bader
authors.forename: Philip M
authors.initials: PM
authors.lastname: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D016000:Cluster Analysis; D000074288:Discs Large Homolog 1 Protein; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D054731:PDZ Domains; D011485:Protein Binding; D025941:Protein Interaction Mapping; D015398:Signal Transduction; D049490:Systems Biology; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C513314:DLG1 protein, human; D000074288:Discs Large Homolog 1 Protein; D008565:Membrane Proteins; C480591:SCRIB protein, human; D025521:Tumor Suppressor Proteins