Long-term potentiation (LTP) a long-lasting enhancement in communication between neurons is considered to be the CCT137690 major cellular mechanism underlying learning and memory. four human CaMKII catalytic domains in their autoinhibited states as well as structures of human CaMKII oligomerization domains in their tetradecameric and physiological dodecameric states. All four autoinhibited human CaMKIIs were monomeric in the determined crystal structures but associated weakly in solution. In the CaMKIIδ/Ca2+/CaM complex the inhibitory region adopted an extended conformation and interacted with an adjacent CCT137690 catalytic domain positioning T287 into the active site of the interacting protomer. Comparisons with autoinhibited CaMKII structures showed that binding of calmodulin leads to the rearrangement of residues in the active site to a conformation suitable for ATP binding and to the closure of the binding groove for the autoinhibitory helix by helix αD. The structural data together with biophysical interaction studies reveals the mechanism of CaMKII activation by calmodulin and explains many of the unique regulatory properties of these two essential signaling molecules. Enhanced version This article can also be viewed as an CCT137690 enhanced version in which the text of the article is integrated with interactive 3-D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the Web plugin are available in Text S1. Author Summary CaMKII 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 CCT137690 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 CCT137690 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 SIGLEC9 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. Introduction Calcium/Calmodulin (Ca2+/CaM)-dependent serine/threonine kinases (CaMKs) constitute a family of 81 proteins in the human proteome that play a central role in cellular signaling by transmitting Ca2+ signals . Kinases in this protein family are activated through binding of Ca2+/CaM to CCT137690 regulatory regions that either flank the catalytic domain or are located in regulatory molecules . Four CaMKII isozymes (α β γ and δ) in addition to about 30 splice variants are expressed in humans. The α and β isoforms are brain specific and together make up approximately 1% of total brain protein in rodents and up to 2% of total protein in their hippocampus . The γ and δ isoforms are expressed in most tissues but in comparison have much lower expression levels  . The unique switch-like properties of CaMKII activation and its extremely high abundance in the brain identified CaMKII as a key regulator of cellular memory and learning . CaMKII is essential for the induction of long-term potentiation (LTP) a long-lasting increase in the efficiency of synaptic transmission between neurons that is believed to be a cellular correlate of memory  . Stimuli that induce LTP lead to autophosphorylation at T286 in CaMKIIα (T287 in the β γ and δ isoforms) thereby resulting in sustained CaMKII activation ; mice expressing the CaMKIIα T286A mutant were severely impaired.