NMR STRUCTURE OF THE N-TERMINAL SH3 DOMAIN OF GRB2 AND ITS COMPLEX WITH A PROLINE-RICH PEPTIDE FROM SOS

GRB2 is a small adaptor protein of 217 amino acids comprising one SH2 domain surrounded by two SH3 domains. GRB2 couples receptor tyrosine k inase activation to Ras signalling by interacting, through its SH3 dom ains, to the carboxy-terminal proline-rich regions of the guanine nucl eotide exchange factor Sos. Here we report the synthesis and solution structure of the amino-terminal SH3 domain of GRB2 and of its more sta ble Ser 32 mutant. H-1 NMR analysis of the complex between the Ser-32- GRB2-N-SH3 domain and the proline-rich peptide VPPPVPPRRR, derived fro m h-Sos, shows that relative to the SH3 peptide complexes described fo r P13K, Fyn and Abl, the proline-rich peptide in this complex binds in the opposite orientation.