Structural studies on the regulation of Ca2+/calmodulin dependent protein kinase II

• CaMKII typically forms a dodecameric assembly.
• Analysis of CaMKII kinase domains reveals both monomeric and dimeric configurations.
• CaMKII holoenzymes exist in an equilibrium between a compact and an extended state.
• The intact CaMKII holoenzyme was crystallized in a compact, autoinhibited state.
• The holoenzyme structure reveals a mode of inhibition in which the CaM binding domain is sequestered.

Ca2+/calmodulin dependent protein kinase II (CaMKII) is a broadly distributed metazoan Ser/Thr protein kinase that is important in neuronal and cardiac signaling. CaMKII forms oligomeric assemblies, typically dodecameric, in which the calcium-responsive kinase domains are organized around a central hub. We review the results of crystallographic analyses of CaMKII, including the recently determined structure of a full-length and autoinhibited form of the holoenzyme. These structures, when combined with other data, allow informed speculation about how CaMKII escapes calcium-dependence when calcium spikes exceed threshold frequencies.