Crosstalk between the catalytic and regulatory domains allows bidirectional regulation of Src

The catalytic activity of Src family tyrosine kinases is inhibited by intra molecular interactions between the regulatory SH3 and SH2 domains and the c atalytic domain. In the inactive state, the critical alpha C-helix in the c atalytic domain is positioned such that the formation of the Glu 310-Lys 29 5 salt bridge is precluded, Tyr 416 in the activation loop is unphosphoryla ted, and the SH2 and SH3 domains are unavailable for interactions with othe r proteins. We found that phosphorylation of the activation loop or mutatio n of the loop preceding the alpha C-helix activates Src and increases the a ccessibility of the SH3 domain for Ligands. Interaction of the alpha C-heli x with the activation loop is a central component of this regulatory system . Our data suggest a bidirectional regulation mechanism in which the regula tory domains inhibit Src activity, and Src activity controls the availabili ty of the regulatory domains. By this mechanism, Src family kinases can be activated by proteins phosphorylating or changing the conformation of the c atalytic domain. Once active, Src family kinases become less prone to regul ation, implying a positive feedback loop on their activity.