After initial activation by Ca2+, the catalytic activity of type II Ca2+/calmodulin-dependent protein kinase rapidly becomes partially independent of Ca2+. The transition is caused by autophosphorylation of a few subunits in the dodecameric holoenzyme, which is composed of varying proportions of two homologous types of subunits, α (50 kd) and β (58-60 kd). We have identified one site in the α subunit (Thr286) and two in the β subunit (Thr287 and Thr382) that are rapidly autophosphorylated. We show that phosphorylation of α-Thr286 and β;-Thr287, which are located immediately adjacent to the calmodulin binding domain, controls Ca2+-independent activity. In contrast, phosphorylation of β-Thr382 is not required to maintain Ca2+ independence. It is absent in the a subunit and is selectively removed from the minor β subunit, apparently by alternative splicing. Regulation of the presence of β-Thr382 in the holoenzyme by both differential gene expression and alternative splicing suggests that it may have an important but highly specialized function.
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