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Cover picture: Regulation of CaMKII by autophosphorylation. Autophosphorylation within the regulatory domain of CaMKII defines several activity states for the kinase. In the absence of Ca2+/CaM and autophosphorylation, CaMKII is inactive. Binding of Ca2+/CaM activates the kinase for substrate phosphorylation, bringing it to 100% of its maximal activity. Binding of two Ca2+/CaMs to adjacent subunits stimulates inter-subunit phosphorylation of Thr286. The off-rate of Ca2+/CaM from pThr286 CaMKII is decreased >1000-fold, resulting in an enzyme that remains at 100% of its maximal Ca2+/CaM-stimulated activity even as calcium falls in the cell. Once Ca2+/CaM dissociates, the enzyme remains active, but at a lower level than with saturating Ca2+/CaM, having between 20 and 80% of its maximal Ca22+/CaM-stimulated activity. The dissociation of Ca2+/CaM also uncovers additional sites in the regulatory domain (Thr305 and Thr306) that rapidly become autophosphorylated. The pThr286/pThr305/ pThr306 CaMKII remains active at 20-80% of maximal activity because of pThr286 but is incapable of binding Ca2+/CaM. Phosphatase activity is required to reset the kinase to its basal state. For details, see the article by Griffith in this issue (pages 8391–8393).