PDZ Domain Binding Selectivity Is Optimized Across the Mouse Proteome
2007
Stiffler, Michael A. | Chen, Jiunn R. | Grantcharova, Viara P. | Lei, Ying | Fuchs, Daniel | Allen, John E. | Zaslavskaia, Lioudmila A. | MacBeath, Gavin
PDZ domains have long been thought to cluster into discrete functional classes defined by their peptide-binding preferences. We used protein microarrays and quantitative fluorescence polarization to characterize the binding selectivity of 157 mouse PDZ domains with respect to 217 genome-encoded peptides. We then trained a multidomain selectivity model to predict PDZ domain-peptide interactions across the mouse proteome with an accuracy that exceeds many large-scale, experimental investigations of protein-protein interactions. Contrary to the current paradigm, PDZ domains do not fall into discrete classes; instead, they are evenly distributed throughout selectivity space, which suggests that they have been optimized across the proteome to minimize cross-reactivity. We predict that focusing on families of interaction domains, which facilitates the integration of experimentation and modeling, will play an increasingly important role in future investigations of protein function.
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