Dynamic coupling between the SH2 and SH3 domains of c-Src and hck underlies their inactivation by C-terminal tyrosine phosphorylation

The effect of C-terminal tyrosine phosphorylation on molecular motions in t he Src kinases Hck and c-Src is investigated by molecular dynamics simulati ons. The SH2 and SH3 domains of the inactive kinases are seen to be tightly coupled by the connector between them, impeding activation. Dephosphorylat ion of the tail reduces the coupling between the SH2 and SH3 domains in the simulations, as does replacement of connector residues with glycine. A mut ational analysis of c-Src expressed in Schizosaccharomyces pombe demonstrat es that replacement of residues in the SH2-SH3 connector with glycine activ ates c-Src. The SH2-SH3 connector appears to be an inducible "snap lock" th at clamps the SH2 and SH3 domains upon tail phosphorylation, but which allo ws flexibility when the tail is released.