CRYSTAL-STRUCTURE OF THE PI-3-KINASE P85 AMINO-TERMINAL SH2 DOMAIN AND ITS PHOSPHOPEPTIDE COMPLEXES

Crystal structures of the amino-terminal SH2 domain of the p85 alpha s ubunit of phosphatidylinositol (PI) 3-kinase, alone and in complex wit h phosphopeptides bearing pTyr-Met/Val-Xaa-Met motifs, show that phosp hopeptides bind in the two-pronged manner seen in high-affinity Lck an d Src SH2 complexes, with conserved interactions between the domain an d the peptide segment from phosphotyrosine to Met+3. Peptide binding r equires the rearrangement of a tyrosyl side chain in the BG loop to cr eate the hydrophobic Met+3 binding pocket. The structures suggest a me chanism for the biological specificity exhibited by PI3-kinase in its interactions with phosphoprotein partners.