Published In

Cell Reports

Document Type

Article

Publication Date

12-2021

Subjects

Electron microscopy

Abstract

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.

Rights

Copyright (c) 2021 The Authors

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

DOI

10.1016/j.celrep.2021.110168

Persistent Identifier

https://archives.pdx.edu/ds/psu/36891

Included in

Chemistry Commons

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