Structure–function of the multifunctional Ca2+/calmodulin-dependent protein kinase II

Ca²⁺/calmodulin (CaM)-dependent protein kinase (CaMKII) is a ubiquitous mediator of Ca²⁺-linked signalling that phosphorylates a wide range of substrates to co-ordinate and regulate Ca²⁺-mediated alterations in cellular function. The transmission of information by the kinase from extracellular stimuli and the intracellular Ca²⁺ rise is not passive. Rather, its multimeric structure and autoregulation enable this enzyme to participate actively in the sensitivity, timing and location of its action. CaMKII can: (i) be activated in a Ca²⁺-spike frequency-dependent manner; (ii) become independent of its initial Ca²⁺/CaM activators; and (iii) undergo a ‘molecular switch-like’ behaviour, which is crucial for certain forms of learning and memory. CaMKII is derived from a family of four homologous but distinct genes, with over 30 alternatively spliced isoforms described at present. These isoforms possess diverse developmental and anatomical expression patterns, as well as subcellular localization. Six independent catalytic/autoregulatory domains are connected by a narrow stalk-like appendage to each hexameric ring within the dodecameric structure. Ca²⁺/CaM binding activates the enzyme by disinhibiting the autoregulatory domain; this process initiates an intra-holoenzyme autophosphorylation reaction that induces complex changes in the enzyme's sensitivity to Ca²⁺/CaM, including the generation of Ca²⁺/CaM-independent (autonomous) activity and marked increase in affinity for CaM. The role of CaMKII in Ca²⁺ signal transduction is shaped by its autoregulation, isoenzymic type and subcellular localization. The molecular determinants and mechanisms producing these processes are discussed as they relate to the structure—function of this multifunctional protein kinase.