Arginine methylation inhibits the binding of proline-rich ligands to Src homology 3, but not WW, domains

Src homology 3 (SH3) and WW domains are known to associate with proline-ric h motifs within their respective ligands. Here we demonstrate that the prop osed adapter protein for Src kinases, Sam68, is a ligand whose proline-rich motifs interact with the SH3 domains of p59(fyn) and phospholipase C gamma -1 as well as with the WW domains of FBP30 and FBP21. These proline-rich mo tifs, in turn, are flanked by RG repeats that represent targets for the typ e I protein arginine N-methyltransferase. The asymmetrical dimethylation of arginine residues within these RG repeats dramatically reduces the binding of the SH3 domains of p59(fyn) and phospholipase C gamma-1, but has no eff ect on their binding to the WW domain of FBP30. These results suggest that protein arginine methylation can selectively modulate certain protein-prote in interactions and that mechanisms exist for the irreversible regulation o f SH3 domain-mediated interactions.