CaMKII Regulation
The four mammalian CaMKII genes (alpha, beta, gamma, delta) encode more than 30 distinct CaMKII subunits due to extensive mRNA splicing. The N-terminal catalytic and regulatory domains are highly conserved across the subunit variants. CaMKII subunits assemble into dodecameric holoenzymes consisting of a stacked pair of hexameric rings due to homo- or hetero-meric interactions of their C-terminal association domains, which are more variable.
Each CaMKII subunit in the holoenzyme is independently activated by binding calcium/calmodulin. Simultaneous activation of adjacent subunits results in the inter-subunit autophosphorylation at Thr286 within the regulatory domain. Thus, the level of Thr286 autophosphorylation depends on the amplitude, duration and frequency of the changes in intracellular calcium concentrations. Thr286 autophosphorylated subunits retain kinase activity even after dissociation of calcium/calmodulin, serving as an intracellular molecular “memory” of transient calcium signals. In the absence of bound calcium/ calmodulin, CaMKII autophosphorylates at Thr305 or Thr306 in the calmodulin-binding domain, which “desensitizes” the kinase to subsequent calcium signals by blocking the re-binding of calcium/calmodulin. These effects of autophosphorylation are opposed by cellular protein phosphatases. Thus, intracellular signaling via CaMKII depends on the dynamic balance between calcium concentrations, autophosphorylation and dephosphorylation.
Our lab is pursuing structure-function analyses to understand the the molecular mechanisms that control CaMKII activity and subcellular targeting.
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