Substrate-selective and Calcium-independent Activation of CaMKII by α-Actinin

Protein-protein interactions are thought to modulate the efficiency and specificity of Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) signaling in specific subcellular compartments. Here we show that the F-actin-binding protein alpha-actinin targets CaMKII alpha to F-actin in cells by binding to the CaMKII regulatory domain, mimicking CaM. The interaction with alpha-actinin is blocked by CaMKII autophosphorylation at Thr-306, but not by autophosphorylation at Thr-305, whereas autophosphorylation at either site blocks Ca2+/CaM binding. The binding of alpha-actinin to CaMKII is Ca2+-independent and activates the phosphorylation of a subset of substrates in vitro. In intact cells, alpha-actinin selectively stabilizes CaMKII association with GluN2B-containing glutamate receptors and enhances phosphorylation of Ser-1303 in GluN2B, but inhibits CaMKII phosphorylation of Ser-831 in glutamate receptor GluA1 subunits by competing for activation by Ca2+/CaM. These data show that Ca2+-independent binding of alpha-actinin to CaMKII differentially modulates the phosphorylation of physiological targets that play key roles in long-term synaptic plasticity.