Cargando…
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...
Autores principales: | , , , , |
---|---|
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 |
_version_ | 1784682325840232448 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8985225 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT buonaratioliviar conservedanddivergentfeaturesofneuronalcamkiiholoenzymestructurefunctionandhighorderassembly AT milleradamp conservedanddivergentfeaturesofneuronalcamkiiholoenzymestructurefunctionandhighorderassembly AT coultrapstevenj conservedanddivergentfeaturesofneuronalcamkiiholoenzymestructurefunctionandhighorderassembly AT bayerkulrich conservedanddivergentfeaturesofneuronalcamkiiholoenzymestructurefunctionandhighorderassembly AT reichowstevel conservedanddivergentfeaturesofneuronalcamkiiholoenzymestructurefunctionandhighorderassembly |