CaMKII domain structure and activation. (A) Each CaMKII monomer contains a catalytic kinase domain (blue), a regulatory domain involved (yellow), and an association domain (white). Dimerization of monomeric subunits is mediated via the association domains, followed by oligomerization to form a holoenzyme consisting of 2 stacked hexameric rings (not shown). The sequence of the regulatory domain containing 2 redox-active methionine residues (Met281/Met282) (red) and Thr287 (black) are indicated. (B) In the resting state, the kinase activity of CaMKII is autoinhibited by an interaction between its catalytic and regulatory domains. Binding of calcium/calmodulin (Ca²⁺/CaM) (green) to the regulatory domain causes disassociation and transient activation of the catalytic domain. Autophosphorylation at Thr-287 or oxidation at Met281/Met282 prevents autoinhibition and causes sustained activation of CaMKII that is independent of calcium/calmodulin binding. Adapted with permission from Scott et al.³⁹