title: PDZ domain binding selectivity is optimized across the mouse proteome.
abstract: 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.
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Stiffler
authors.forename: Jiunn R
authors.initials: JR
authors.lastname: Chen
authors.forename: Viara P
authors.initials: VP
authors.lastname: Grantcharova
authors.forename: Ying
authors.initials: Y
authors.lastname: Lei
authors.forename: Daniel
authors.initials: D
authors.lastname: Fuchs
authors.forename: John E
authors.initials: JE
authors.lastname: Allen
authors.forename: Lioudmila A
authors.initials: LA
authors.lastname: Zaslavskaia
authors.forename: Gavin
authors.initials: G
authors.lastname: MacBeath
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000818:Animals; D019295:Computational Biology; D003198:Computer Simulation; D005454:Fluorescence Polarization; D051379:Mice; D010455:Peptides / Q000378:metabolism*; D040081:Protein Array Analysis; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020543:Proteome / Q000737:chemistry / Q000378:metabolism*
chemical_list: D010455:Peptides; D020543:Proteome