The importance of being proline: the interaction of proline-rich motifs insignaling proteins with their cognate domains

A common focus among molecular and cellular biologists is the identificatio n of proteins that interact with each other. Yeast two-hybrid, cDNA express ion library screening, and coimmunoprecipitation experiments are powerful m ethods for identifying novel proteins that bind to one's favorite protein f or the purpose of learning more regarding its cellular function, These same techniques, coupled with truncation and mutagenesis experiments, have been used to define the region of interaction between pairs of proteins. One co nclusion from this work is that many interactions occur over short regions, often less than 10 amino acids in length within one protein. For example, mapping studies and 3-dimensional analyses of antigen-antibody interactions have revealed that epitopes are typically 4-7 residues long (1), Other exa mples include protein-interaction modules, such as Src homology (SH) 2 and 3 domains, phosphotyrosine binding domains (PTB), postsynaptic density/disc -large/ZO1 (PDZ) domains, WW domains, Eps15 homology (EH) domains, and 14-3 -3 proteins that typically recognize linear regions of 3-9 amino acids. Eac h of these domains has been the subject of recent reviews published elsewhe re (2-7), Among the primary structures of many ligands for protein-protein interactions, the amino acid proline is critical. In particular, SH3, WW, a nd several new protein-interaction domains prefer ligand sequences that are proline-rich, In addition, even though ligands for EH domains and 14-3-3 d omains are not proline-rich, they do include a single proline residue, This review highlights the analysis of those protein-protein interactions that involve proline residues, the biochemistry of proline, and current drug dis covery efforts based on proline peptidomimetics.