The research was funded by National Institutes of Health grants F32AG066536 (to O.R.B.), P30NS048154 (UCD neuroscience center grant), R01NS081248 and R01NS118786 (to K.U.B.), and R35GM124779 and R01EY030987 (to S.L.R.).
Neuronal CaMKII holoenzymes (a and b isoforms) enable molecular signal computation underlying learning and memory but also mediate excitotoxic neuronal death. Here, we provide a comparative analysis of these signaling devices, using single-particle electron microscopy (EM) in combination with biochemical and live cell imaging studies. In the basal state, both isoforms assemble mainly as 12-mers (but also 14-mers and even 16-mers for the b isoform). CaMKIIa and b isoforms adopt an ensemble of extended activatable states (with average radius of 12.6 versus 16.8 nm, respectively), characterized by multiple transient intra- and interholoenzyme interactions associated with distinct functional properties. The extended state of CaMKIIb allows direct resolution of intra-holoenzyme kinase domain dimers. These dimers could enable cooperative activation by calmodulin, which is observed for both isoforms. High-order CaMKII clustering mediated by inter- holoenzyme kinase domain dimerization is reduced for the b isoform for both basal and excitotoxicity induced clusters, both in vitro and in neurons.
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Buonarati, O. R., Miller, A. P., Coultrap, S. J., Bayer, K. U., & Reichow, S. L. (2021). Conserved and divergent features of neuronal CaMKII holoenzyme structure, function, and high-order assembly. Cell Biology (2021)