Abstract
PDZ domains constitute one of the largest families of interaction domains and function by binding the C termini of their target proteins1,2. Using Bayesian estimation, we constructed a three-dimensional extension of a position-specific scoring matrix that predicts to which peptides a PDZ domain will bind, given the primary sequences of the PDZ domain and the peptides. The model, which was trained using interaction data from 82 PDZ domains and 93 peptides encoded in the mouse genome3, successfully predicts interactions involving other mouse PDZ domains, as well as PDZ domains from Drosophila melanogaster and, to a lesser extent, PDZ domains from Caenorhabditis elegans. The model also predicts the differential effects of point mutations in peptide ligands on their PDZ domain–binding affinities. Overall, we show that our approach captures, in a single model, the binding selectivity of the PDZ domain family.
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Change history
09 October 2008
In the version of this article initially published, a negative sign was omitted before the expression Punified(a, b) in the text on page 1043, col. 1, line 20 and the color key in Figure 2 was upside down. These errors have been corrected in the HTML and PDF versions of the article. In addition, a sentence was added to the legend of Figure 2 to clarify the significance of positive and negative values of Punified(a, b).
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Acknowledgements
We thank Anna M. Lone for experimental contributions and Eugene I. Shakhnovich for helpful discussions. This work was supported by awards from the Arnold and Mabel Beckman Foundation, the W.M. Keck Foundation and the Camille and Henry Dreyfus Foundation, and by a grant from the US National Institutes of Health (1 RO1 GM072872-01).
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Contributions
J.R.C. conceived and implemented the model. B.H.C. and J.R.C. performed the mouse-related experiments. J.E.A., B.H.C., J.R.C., and M.A.S. performed the D. melanogaster- and C. elegans-related experiments. J.R.C., B.H.C., and G.M. interpreted the data. J.R.C. and G.M. wrote the manuscript, with contributions from B.H.C., J.E.A. and M.A.S. G.M. supervised the research.
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Figures 1–4, Tables 1,2, 4–13, Tutorial, Methods (PDF 643 kb)
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Supplementary Table 3 (XLS 1497 kb)
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Chen, J., Chang, B., Allen, J. et al. Predicting PDZ domain–peptide interactions from primary sequences. Nat Biotechnol 26, 1041–1045 (2008). https://doi.org/10.1038/nbt.1489
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DOI: https://doi.org/10.1038/nbt.1489
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