title: Optimization of specificity in a cellular protein interaction network by negative selection.
abstract: Most proteins that participate in cellular signalling networks contain modular protein-interaction domains. Multiple versions of such domains are present within a given organism: the yeast proteome, for example, contains 27 different Src homology 3 (SH3) domains. This raises the potential problem of cross-reaction. It is generally thought that isolated domain-ligand pairs lack sufficient information to encode biologically unique interactions, and that specificity is instead encoded by the context in which the interaction pairs are presented. Here we show that an isolated peptide ligand from the yeast protein Pbs2 recognizes its biological partner, the SH3 domain from Sho1, with near-absolute specificity--no other SH3 domain present in the yeast genome cross-reacts with the Pbs2 peptide, in vivo or in vitro. Such high specificity, however, is not observed in a set of non-yeast SH3 domains, and Pbs2 motif variants that cross-react with other SH3 domains confer a fitness defect, indicating that the Pbs2 motif might have been optimized to minimize interaction with competing domains specifically found in yeast. System-wide negative selection is a subtle but powerful evolutionary mechanism to optimize specificity within an interaction network composed of overlapping recognition elements.
authors.affiliation: Program in Biological Sciences, University of California, San Francisco, 600 16th Street, San Francisco, California 94143-2240, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Zarrinpar
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Park
authors.forename: Wendell A
authors.initials: WA
authors.lastname: Lim
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001667:Binding, Competitive; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000737:chemistry* / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding; D020543:Proteome / Q000737:chemistry / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000378:metabolism*; D013045:Species Specificity; D013379:Substrate Specificity; D018909:src Homology Domains
chemical_list: D008024:Ligands; D008565:Membrane Proteins; D020543:Proteome; C459787:SHO1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; C089356:PBS2 protein, S cerevisiae