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Science 20 July 2007:
Vol. 317. no. 5836, pp. 364 - 369
DOI: 10.1126/science.1144592
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Reports

PDZ Domain Binding Selectivity Is Optimized Across the Mouse Proteome

Michael A. Stiffler,1* Jiunn R. Chen,2* Viara P. Grantcharova,1{dagger} Ying Lei,1 Daniel Fuchs,1 John E. Allen,1 Lioudmila A. Zaslavskaia,1{ddagger} Gavin MacBeath1§

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.

1 Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.
2 Department of Molecular and Cellular Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.

* These authors contributed equally to this work.

{dagger} Present address: Merrimack Pharmaceuticals, 1 Kendall Square, Building 700, Cambridge, MA 02139, USA.

{ddagger} Present address: Tepnel Lifecodes Corporation, 550 West Avenue, Stamford, CT 06902, USA.

§ To whom correspondence should be addressed. E-mail: macbeath{at}chemistry.harvard.edu

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