title: Evolutionarily conserved bias of amino-acid usage refines the definition of PDZ-binding motif.
abstract: BACKGROUND
  The interactions between PDZ (PSD-95, Dlg, ZO-1) domains and PDZ-binding motifs play central roles in signal transductions within cells. Proteins with PDZ domains bind to PDZ-binding motifs almost exclusively when the motifs are located at the carboxyl (C-) terminal ends of their binding partners. However, it remains little explored whether PDZ-binding motifs show any preferential location at the C-terminal ends of proteins, at genome-level.
  
  
  RESULTS
  Here, we examined the distribution of the type-I (x-x-S/T-x-I/L/V) or type-II (x-x-V-x-I/V) PDZ-binding motifs in proteins encoded in the genomes of five different species (human, mouse, zebrafish, fruit fly and nematode). We first established that these PDZ-binding motifs are indeed preferentially present at their C-terminal ends. Moreover, we found specific amino acid (AA) bias for the 'x' positions in the motifs at the C-terminal ends. In general, hydrophilic AAs were favored. Our genomics-based findings confirm and largely extend the results of previous interaction-based studies, allowing us to propose refined consensus sequences for all of the examined PDZ-binding motifs. An ontological analysis revealed that the refined motifs are functionally relevant since a large fraction of the proteins bearing the motif appear to be involved in signal transduction. Furthermore, co-precipitation experiments confirmed two new protein interactions predicted by our genomics-based approach. Finally, we show that influenza virus pathogenicity can be correlated with PDZ-binding motif, with high-virulence viral proteins bearing a refined PDZ-binding motif.
  
  
  CONCLUSIONS
  Our refined definition of PDZ-binding motifs should provide important clues for identifying functional PDZ-binding motifs and proteins involved in signal transduction.
authors.affiliation: Laboratory for Memory and Learning, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan. takahiko@brain.riken.jp
authors.forename: Takahiko
authors.initials: T
authors.lastname: Chimura
authors.forename: Thomas
authors.initials: T
authors.lastname: Launey
authors.forename: Masao
authors.initials: M
authors.lastname: Ito
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D019143:Evolution, Molecular; D023281:Genomics; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D054731:PDZ Domains; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013045:Species Specificity; D013379:Substrate Specificity
chemical_list: D000596:Amino Acids; D011506:Proteins