Structure of the CaMKIIδ/Calmodulin Complex Reveals the Molecular Mechanism of CaMKII Kinase Activation

Abstract

Author SummaryCaMKII enzymes transmit calcium ion (Ca2+) signals released inside the cell by regulating signal transduction pathways through phosphorylation: Ca2+ first binds to the small regulatory protein CaM; this Ca2+/CaM complex then binds to and activates the kinase, which phosphorylates other proteins in the cell. Since CaMKs remain active long after rapid Ca2+ pulses have dropped they function as molecular switches that turn on or off crucial cell functions in response to Ca2+ levels. The multifunctional CaMKII forms of this enzyme – of which there are four in human – are important in many processes including signaling in neurons and controlling of the heart rate. They are particularly abundant in the brain where they probably play a role in memory. CaMKII forms an exceptionally large, dodecameric complex. Here, we describe the crystal structure of this complex for each of the four human CaMKII catalytic domains in their autoinhibited states, a complex of CaMKII with Ca2+/CaM, as well as the structure of the oligomerization domain (the part of the protein that mediates complex formation) in its physiological dodecameric state and in a tetradecameric state. Detailed comparison of this large body of structural data together with biophysical studies has allowed us to better understand the structural mechanisms of CaMKII activation by CaM and to explain many of the complex regulatory features of these essential enzymes.