Functional genomics of intracellular peptide recognition domains with combinatorial biology methods.

Phage-displayed peptide libraries have been used to identify specific ligands for peptide-binding domains that mediate intracellular protein-protein interactions. These studies have provided significant insights into the specificities of particular domains. For PDZ domains that recognize C-terminal sequences, the information has proven useful in identifying natural binding partners from genomic databases. For SH3 domains that recognize internal proline-rich motifs, the results of database searches with phage-derived ligands have been compared with the results of yeast-two-hybrid experiments to produce overlap networks that reliably predict natural protein-protein interactions. In addition, libraries of phage-displayed PDZ and SH3 domains have been used to identify the residues responsible for ligand recognition, and also to engineer domains with altered specificities.