The N-terminal end of the catalytic domain of Src kinase Hck is a conformational switch implicated in long-range allosteric regulation

Signal transduction in cell growth and proliferation involves regulation of kinases through long-range allostery between remote protein regions. Molecular dynamics free energy calculations are used to clarify the coupling between the catalytic domain of Src kinase Hck and its N-terminal end connecting to the regulatory SH2 and SH3 modules. The N-terminal end is stable in the orientation required for the regulatory modules to remain properly bound only in the inactive catalytic domain. In the active catalytic domain, the N-terminal end prefers a different conformation consistent with dissociation of the regulatory modules. The free energy surface shows that the N-terminal end acts as a reversible two-state conformational switch coupling the catalytic domain to the regulatory modules. Structural analogy with insulin receptor kinase and c-Src suggests that such reversible conformational switching in a critical hinge region could be a common mechanism in long-range allosteric regulation of protein kinase activity.