Substrate-selective and calcium-independent activation of CaMKII by α-actinin.

Jalan-Sakrikar N, Bartlett RK, Baucum AJ, Colbran RJ
J Biol Chem. 2012 287 (19): 15275-83

PMID: 22427672 · PMCID: PMC3346149 · DOI:10.1074/jbc.M112.351817

Protein-protein interactions are thought to modulate the efficiency and specificity of Ca(2+)/calmodulin (CaM)-dependent protein kinase II (CaMKII) signaling in specific subcellular compartments. Here we show that the F-actin-binding protein α-actinin targets CaMKIIα to F-actin in cells by binding to the CaMKII regulatory domain, mimicking CaM. The interaction with α-actinin is blocked by CaMKII autophosphorylation at Thr-306, but not by autophosphorylation at Thr-305, whereas autophosphorylation at either site blocks Ca(2+)/CaM binding. The binding of α-actinin to CaMKII is Ca(2+)-independent and activates the phosphorylation of a subset of substrates in vitro. In intact cells, α-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 Ca(2+)/CaM. These data show that Ca(2+)-independent binding of α-actinin to CaMKII differentially modulates the phosphorylation of physiological targets that play key roles in long-term synaptic plasticity.

MeSH Terms (25)

Actinin Actins Amino Acid Sequence Animals Binding Sites Calcium Calcium-Calmodulin-Dependent Protein Kinase Type 2 Enzyme Activation HEK293 Cells Humans Immunoblotting Mice Microscopy, Fluorescence Models, Molecular Molecular Sequence Data Mutation Phosphorylation Prosencephalon Protein Binding Protein Structure, Tertiary Receptors, N-Methyl-D-Aspartate Sequence Homology, Amino Acid Serine Substrate Specificity Threonine

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