Abstract
Neuronal CaMKII holoenzymes (α and β 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 β isoform). CaMKIIα and β 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 inter-holoenzyme interactions associated with distinct functional properties. The extended state of CaMKIIβ 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 β isoform for both basal and excitotoxicity-induced clusters, both in vitro and in neurons.
Original language | English (US) |
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Article number | 110168 |
Journal | Cell Reports |
Volume | 37 |
Issue number | 13 |
DOIs | |
State | Published - Dec 28 2021 |
Externally published | Yes |
Keywords
- CaMKII
- activation
- autophosphorylation
- cell signaling
- clustering
- electron microscopy
- holoenzyme
- intrinsic disorder
- structure
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology