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

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 bioche...

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Autores principales: Buonarati, Olivia R., Miller, Adam P., Coultrap, Steven J., Bayer, K. Ulrich, Reichow, Steve L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8985225/
https://www.ncbi.nlm.nih.gov/pubmed/34965414
http://dx.doi.org/10.1016/j.celrep.2021.110168
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author Buonarati, Olivia R.
Miller, Adam P.
Coultrap, Steven J.
Bayer, K. Ulrich
Reichow, Steve L.
author_facet Buonarati, Olivia R.
Miller, Adam P.
Coultrap, Steven J.
Bayer, K. Ulrich
Reichow, Steve L.
author_sort Buonarati, Olivia R.
collection PubMed
description 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.
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spelling pubmed-89852252022-04-06 Conserved and divergent features of neuronal CaMKII holoenzyme structure, function, and high-order assembly Buonarati, Olivia R. Miller, Adam P. Coultrap, Steven J. Bayer, K. Ulrich Reichow, Steve L. Cell Rep Article 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. 2021-12-28 /pmc/articles/PMC8985225/ /pubmed/34965414 http://dx.doi.org/10.1016/j.celrep.2021.110168 Text en https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Buonarati, Olivia R.
Miller, Adam P.
Coultrap, Steven J.
Bayer, K. Ulrich
Reichow, Steve L.
Conserved and divergent features of neuronal CaMKII holoenzyme structure, function, and high-order assembly
title Conserved and divergent features of neuronal CaMKII holoenzyme structure, function, and high-order assembly
title_full Conserved and divergent features of neuronal CaMKII holoenzyme structure, function, and high-order assembly
title_fullStr Conserved and divergent features of neuronal CaMKII holoenzyme structure, function, and high-order assembly
title_full_unstemmed Conserved and divergent features of neuronal CaMKII holoenzyme structure, function, and high-order assembly
title_short Conserved and divergent features of neuronal CaMKII holoenzyme structure, function, and high-order assembly
title_sort conserved and divergent features of neuronal camkii holoenzyme structure, function, and high-order assembly
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8985225/
https://www.ncbi.nlm.nih.gov/pubmed/34965414
http://dx.doi.org/10.1016/j.celrep.2021.110168
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