Molecular mechanism of activation-triggered subunit exchange in Ca2+/calmodulin-dependent protein kinase II

Activation triggers the exchange of subunits in Ca2+/calmodulin-dependent protein kinase II (CaMKII), an oligomeric enzyme that is critical for learning, memory, and cardiac function. The mechanism by which subunit exchange occurs remains elusive. We show that the human CaMKII holoenzyme exists in dodecameric and tetradecameric forms, and that the calmodulin (CaM)-binding element of CaMKII can bind to the hub of the holoenzyme and destabilize it to release dimers. The structures of CaMKII from two distantly diverged organisms suggest that the CaM-binding element of activated CaMKII acts as a wedge by docking at intersubunit interfaces in the hub. This converts the hub into a spiral form that can release or gain CaMKII dimers. Our data reveal a three-way competition for the CaM-binding element, whereby phosphorylation biases it towards the hub interface, away from the kinase domain and calmodulin, thus unlocking the ability of activated CaMKII holoenzymes to exchange dimers with unactivated ones. How does memory outlast the lifetime of the molecules that encode it? One enzyme that is found in neurons and has been suggested to help long-term memories to form is called CaMKII. Each CaMKII assembly is typically composed of 12 to 14 protein subunits associated in a ring and can exist in either an “unactivated” or “activated” state. In 2014, researchers showed that CaMKII assemblies can exchange subunits with each other. Importantly, an active CaMKII can mix with an unactivated CaMKII and share its activation state. CaMKII may use this mechanism to spread information to the next generation of proteins – thereby allowing activation to outlast the lifespan of the initially activated proteins. However the molecular mechanism that underlies this process was not clear. Now, Bhattacharyya et al. – including some of the researchers involved in the 2014 work – address two questions about this mechanism. How do subunits exchange between CaMKII assemblies? And how does the activation of CaMKII initiate subunit exchange? A closed-ring hub ties the subunits of CaMKII together, similar to the organization of the segments in an orange. To undergo subunit exchange, the hub must open up to release and accept subunits. Bhattacharyya et al. have now uncovered an intrinsic flexibility in the hub that is triggered by a short peptide segment in CaMKII. This segment, which is exposed in activated CaMKII but not in the unactivated form, can crack open the hub ring by binding between t