TOWARDS PREDICTION OF COGNATE COMPLEXES BETWEEN THE WW DOMAIN AND PROLINE-RICH LIGANDS

The UW domain is a structured protein module found in a wide range of regulatory, cytoskeletal, and signaling molecules, Its ligands contain proline-rich sequences, some of which show a core consensus of XPPXY that is critical for binding, In order !to gain a better understanding of the molecular and biological functions of WW domains, we decided t o predict their cognate ligands by searching databases for proteins co ntaining the XPPXY consensus, Using several axioms that take into acco unt evolutionary conservation and functional similarity, we have ident ified four groups of proteins representing candidate ligands that sign al through known or unknown WW domains, These include viral Gag protei ns, sodium channels, interleukin receptors, and a subgroup of serine/t hreonine kinases, In addition, we proposed that dystrophin and beta-dy stroglycan bind through the WW-XPPXY link and that interference with t his interaction could result in muscular dystrophy. Our study provides guidelines for experiments to probe the molecular and biological func tions of the WW domain-ligand connection, Should these predictions be proven empirically, the results may have important ramifications for b asic research and medicine.