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Cocrystal structure of human CaMKII-alpha (CAMK2A)kinase domain and Tiam1 in complex with ATP
Structural highlights
FunctionKCC2A_HUMAN CaM-kinase II (CAMK2) is a prominent kinase in the central nervous system that may function in long-term potentiation and neurotransmitter release. Member of the NMDAR signaling complex in excitatory synapses it may regulate NMDAR-dependent potentiation of the AMPAR and synaptic plasticity (By similarity). Publication Abstract from PubMedCa(2+)/calmodulin-dependent protein kinase II (CaMKII) is a signaling protein required for long-term memory. When activated by Ca(2+)/CaM, it sustains activity even after the Ca(2+) dissipates. In addition to the well-known autophosphorylation-mediated mechanism, interaction with specific binding partners also persistently activates CaMKII. A long-standing model invokes two distinct S and T sites. If an interactor binds at the T-site, then it will preclude autoinhibition and allow substrates to be phosphorylated at the S site. Here, we specifically test this model with X-ray crystallography, molecular dynamics simulations, and biochemistry. Our data are inconsistent with this model. Co-crystal structures of four different activators or substrates show that they all bind to a single continuous site across the kinase domain. We propose a mechanistic model where persistent CaMKII activity is facilitated by high-affinity binding partners that kinetically compete with autoinhibition by the regulatory segment to allow substrate phosphorylation. CaMKII binds both substrates and activators at the active site.,Ozden C, Sloutsky R, Mitsugi T, Santos N, Agnello E, Gaubitz C, Foster J, Lapinskas E, Esposito EA, Saneyoshi T, Kelch BA, Garman SC, Hayashi Y, Stratton MM Cell Rep. 2022 Jul 12;40(2):111064. doi: 10.1016/j.celrep.2022.111064. PMID:35830796[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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