Structural analysis and stochastic modelling suggest a mechanism for calmodulin trapping by CaMKII.

Activation of CaMKII by calmodulin and the subsequent maintenance of constitutive activity through autophosphorylation at threonine residue 286 (Thr286) are thought to play a major role in synaptic plasticity. One of the effects of autophosphorylation at Thr286 is to increase the apparent affinity o...

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Autores principales:	Melanie I Stefan, David P Marshall, Nicolas Le Novère
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c676672893514c33ac5c353a48cd6373
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spelling	oai:doaj.org-article:c676672893514c33ac5c353a48cd63732021-11-18T07:29:59ZStructural analysis and stochastic modelling suggest a mechanism for calmodulin trapping by CaMKII.1932-620310.1371/journal.pone.0029406https://doaj.org/article/c676672893514c33ac5c353a48cd63732012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22279535/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Activation of CaMKII by calmodulin and the subsequent maintenance of constitutive activity through autophosphorylation at threonine residue 286 (Thr286) are thought to play a major role in synaptic plasticity. One of the effects of autophosphorylation at Thr286 is to increase the apparent affinity of CaMKII for calmodulin, a phenomenon known as "calmodulin trapping". It has previously been suggested that two binding sites for calmodulin exist on CaMKII, with high and low affinities, respectively. We built structural models of calmodulin bound to both of these sites. Molecular dynamics simulation showed that while binding of calmodulin to the supposed low-affinity binding site on CaMKII is compatible with closing (and hence, inactivation) of the kinase, and could even favour it, binding to the high-affinity site is not. Stochastic simulations of a biochemical model showed that the existence of two such binding sites, one of them accessible only in the active, open conformation, would be sufficient to explain calmodulin trapping by CaMKII. We can explain the effect of CaMKII autophosphorylation at Thr286 on calmodulin trapping: It stabilises the active state and therefore makes the high-affinity binding site accessible. Crucially, a model with only one binding site where calmodulin binding and CaMKII inactivation are strictly mutually exclusive cannot reproduce calmodulin trapping. One of the predictions of our study is that calmodulin binding in itself is not sufficient for CaMKII activation, although high-affinity binding of calmodulin is.Melanie I StefanDavid P MarshallNicolas Le NovèrePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 1, p e29406 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Melanie I Stefan David P Marshall Nicolas Le Novère Structural analysis and stochastic modelling suggest a mechanism for calmodulin trapping by CaMKII.
description	Activation of CaMKII by calmodulin and the subsequent maintenance of constitutive activity through autophosphorylation at threonine residue 286 (Thr286) are thought to play a major role in synaptic plasticity. One of the effects of autophosphorylation at Thr286 is to increase the apparent affinity of CaMKII for calmodulin, a phenomenon known as "calmodulin trapping". It has previously been suggested that two binding sites for calmodulin exist on CaMKII, with high and low affinities, respectively. We built structural models of calmodulin bound to both of these sites. Molecular dynamics simulation showed that while binding of calmodulin to the supposed low-affinity binding site on CaMKII is compatible with closing (and hence, inactivation) of the kinase, and could even favour it, binding to the high-affinity site is not. Stochastic simulations of a biochemical model showed that the existence of two such binding sites, one of them accessible only in the active, open conformation, would be sufficient to explain calmodulin trapping by CaMKII. We can explain the effect of CaMKII autophosphorylation at Thr286 on calmodulin trapping: It stabilises the active state and therefore makes the high-affinity binding site accessible. Crucially, a model with only one binding site where calmodulin binding and CaMKII inactivation are strictly mutually exclusive cannot reproduce calmodulin trapping. One of the predictions of our study is that calmodulin binding in itself is not sufficient for CaMKII activation, although high-affinity binding of calmodulin is.
format	article
author	Melanie I Stefan David P Marshall Nicolas Le Novère
author_facet	Melanie I Stefan David P Marshall Nicolas Le Novère
author_sort	Melanie I Stefan
title	Structural analysis and stochastic modelling suggest a mechanism for calmodulin trapping by CaMKII.
title_short	Structural analysis and stochastic modelling suggest a mechanism for calmodulin trapping by CaMKII.
title_full	Structural analysis and stochastic modelling suggest a mechanism for calmodulin trapping by CaMKII.
title_fullStr	Structural analysis and stochastic modelling suggest a mechanism for calmodulin trapping by CaMKII.
title_full_unstemmed	Structural analysis and stochastic modelling suggest a mechanism for calmodulin trapping by CaMKII.
title_sort	structural analysis and stochastic modelling suggest a mechanism for calmodulin trapping by camkii.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/c676672893514c33ac5c353a48cd6373
work_keys_str_mv	AT melanieistefan structuralanalysisandstochasticmodellingsuggestamechanismforcalmodulintrappingbycamkii AT davidpmarshall structuralanalysisandstochasticmodellingsuggestamechanismforcalmodulintrappingbycamkii AT nicolaslenovere structuralanalysisandstochasticmodellingsuggestamechanismforcalmodulintrappingbycamkii
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Structural analysis and stochastic modelling suggest a mechanism for calmodulin trapping by CaMKII.

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