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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
Ying Lei,1
Daniel Fuchs,1
John E. Allen,1
Lioudmila A. Zaslavskaia,1
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.
Present address: Merrimack Pharmaceuticals, 1 Kendall Square, Building 700, Cambridge, MA 02139, USA.
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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