期刊
MOLECULAR SYSTEMS BIOLOGY
卷 7, 期 -, 页码 -出版社
WILEY
DOI: 10.1038/msb.2011.18
关键词
binding specificity; peptide recognition domains; PDZ; phage display; residue correlations
资金
- Swiss National Science Foundation (SNSF)
- European Molecular Biology Organization (EMBO)
- Canadian Institutes of Health Research [MOP-84324]
- Canada Foundation for Innovation (CFI)
- Canadian Cancer Society Research Institute (CCSRI)
- Heart and Stroke Foundation
- Cystic Fibrosis Foundation
- Ontario Genomics Institute
- Novartis
- Natural Sciences and Engineering Research Council (NSERC)
- Ontario Research Fund (ORF)
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. Molecular Systems Biology 7: 484; published online 26 April 2011; doi:10.1038/msb.2011.18
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