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-rich motifs within their respective ligands. Here we demonstrate that the proposed adapter protein for Src kinases, Sam68, is a ligand whose proline-rich motifs interact with the SH3 domains of p59(fyn) and phospholipase Cgamma-1 as well as with the WW domains of FBP30 and FBP21. These proline-rich motifs, in turn, are flanked by RG repeats that represent targets for the type 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 Cgamma-1, but has no effect on their binding to the WW domain of FBP30. These results suggest that protein arginine methylation can selectively modulate certain protein-protein interactions and that mechanisms exist for the irreversible regulation of SH3 domain-mediated interactions.
Bedford
M T
MT
Department of Genetics, Harvard Medical School, Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.
Frankel
A
A
Yaffe
M B
MB
Clarke
S
S
Leder
P
P
Richard
S
S
D000595:Amino Acid Sequence; D001120:Arginine / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008745:Methylation; D008780:Methyltransferases; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D011484:Protein-Arginine N-Methyltransferases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D016601:RNA-Binding Proteins / Q000378:metabolism*; D014364:Tryptophan / Q000378:metabolism*; D015003:Yeasts; D018909:src Homology Domains
D002352:Carrier Proteins; C485727:FNBP4 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D016601:RNA-Binding Proteins; D014364:Tryptophan; D001120:Arginine; D008780:Methyltransferases; C077013:PRMT2 protein, human; D011484:Protein-Arginine N-Methyltransferases; D051076:Proto-Oncogene Proteins c-fyn