Conserved and divergent features of neuronal CaMKII holoenzyme structure, function, and high-order assembly.

Autor:	Buonarati OR; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Miller AP; Department of Chemistry, Portland State University, Portland, OR 97201, USA., Coultrap SJ; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Bayer KU; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address: ulli.bayer@cuanschutz.edu., Reichow SL; Department of Chemistry, Portland State University, Portland, OR 97201, USA. Electronic address: reichow@pdx.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2021 Dec 28; Vol. 37 (13), pp. 110168.
DOI:	10.1016/j.celrep.2021.110168
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests (but wish to disclose that K.U.B. is a co-founder and board member of Neurexis Therapeutics). (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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