Neuronal Ca2+/Calmodulin-Dependent Protein Kinase II: The Role of Structure and Autoregulation in Cellular Function

Abstract

▪ Abstract  Highly enriched in brain tissue and present throughout the body, Ca2+/calmodulin-dependent protein kinase II (CaMKII) is central to the coordination and execution of Ca2+ signal transduction. The substrates phosphorylated by CaMKII are implicated in homeostatic regulation of the cell, as well as in activity-dependent changes in neuronal function that appear to underlie complex cognitive and behavioral responses, including learning and memory. The architecture of CaMKII holoenzymes is unique in nature. The kinase functional domains (12 per holoenzyme) are attached by stalklike appendages to a gear-shaped core, grouped into two clusters of six. Each subunit contains a catalytic, an autoregulatory, and an association domain. Ca2+/calmodulin (CaM) binding disinhibits the autoregulatory domain, allowing autophosphorylation and complex changes in the enzyme’s sensitivity to Ca2+/CaM, including the generation of Ca2+/CaM-independent activity, CaM trapping, and CaM capping. These processes confer a type of molecular memory to the autoregulation and activity of CaMKII. Its function is intimately shaped by its multimeric structure, autoregulation, isozymic type, and subcellular localization; these features and processes are discussed as they relate to known and potential cellular functions of this multifunctional protein kinase.