Analogous regulatory sites within the αC-β4 loop regions of ZAP-70 tyrosine kinase and AGC kinases

The precise positioning of the flexible C-helix in the catalytic core is a critical step in the activation of most protein kinases. Consequently, the αC-β4 loop, which anchors the C-helix to the catalytic core, is highly conserved and mediates key structural interactions that serve as a hinge for C-helix movement. While these hinge interactions are conserved across diverse eukaryotic protein kinase structures, some families such as AGC kinases diverge from the canonical hinge interactions. This divergence was recently proposed to facilitate an alternative mode of regulation wherein a conserved C-terminal tail interacts with the αC-β4 loop to position the C-helix. Here we show how interactions between the αC-β4 loop and the N-terminal SH2 domain of ZAP-70 tyrosine kinase are mechanistically and functionally analogous to interactions between the αC-β4 loop and the C-terminal tail of AGC kinases. Such cis regulation of protein kinase activity may be a feature of other eukaryotic protein kinase families as well.