Met125 is essential for maintaining the structural integrity of calmodulin’s C-terminal domain

Abstract We have used NMR and circular dichroism spectroscopy to investigate the structural and dynamic effects of oxidation on calmodulin (CaM), using peroxide and the Met to Gln oximimetic mutations. CaM is a Ca2+-sensitive regulatory protein that interacts with numerous targets. Due to its high m...

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Autores principales:	Sarah E. D. Nelson, Daniel K. Weber, Robyn T. Rebbeck, Razvan L. Cornea, Gianluigi Veglia, David D. Thomas
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/36f3e28887f142c5b2edc2e310a92fe1
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spelling	oai:doaj.org-article:36f3e28887f142c5b2edc2e310a92fe12021-12-02T16:08:57ZMet125 is essential for maintaining the structural integrity of calmodulin’s C-terminal domain10.1038/s41598-020-78270-w2045-2322https://doaj.org/article/36f3e28887f142c5b2edc2e310a92fe12020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78270-whttps://doaj.org/toc/2045-2322Abstract We have used NMR and circular dichroism spectroscopy to investigate the structural and dynamic effects of oxidation on calmodulin (CaM), using peroxide and the Met to Gln oximimetic mutations. CaM is a Ca2+-sensitive regulatory protein that interacts with numerous targets. Due to its high methionine content, CaM is highly susceptible to oxidation by reactive oxygen species under conditions of cell stress and age-related muscle degeneration. CaM oxidation alters regulation of a host of CaM’s protein targets, emphasizing the importance of understanding the mechanism of CaM oxidation in muscle degeneration and overall physiology. It has been shown that the M125Q CaM mutant can mimic the functional effects of methionine oxidation on CaM’s regulation of the calcium release channel, ryanodine receptor (RyR). We report here that the M125Q mutation causes a localized unfolding of the C-terminal lobe of CaM, preventing the formation of a hydrophobic cluster of residues near the EF-hand Ca2+ binding sites. NMR analysis of CaM oxidation by peroxide offers further insights into the susceptibility of CaM’s Met residues to oxidation and the resulting structural effects. These results further resolve oxidation-driven structural perturbation of CaM, with implications for RyR regulation and the decay of muscle function in aging.Sarah E. D. NelsonDaniel K. WeberRobyn T. RebbeckRazvan L. CorneaGianluigi VegliaDavid D. ThomasNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-11 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sarah E. D. Nelson Daniel K. Weber Robyn T. Rebbeck Razvan L. Cornea Gianluigi Veglia David D. Thomas Met125 is essential for maintaining the structural integrity of calmodulin’s C-terminal domain
description	Abstract We have used NMR and circular dichroism spectroscopy to investigate the structural and dynamic effects of oxidation on calmodulin (CaM), using peroxide and the Met to Gln oximimetic mutations. CaM is a Ca2+-sensitive regulatory protein that interacts with numerous targets. Due to its high methionine content, CaM is highly susceptible to oxidation by reactive oxygen species under conditions of cell stress and age-related muscle degeneration. CaM oxidation alters regulation of a host of CaM’s protein targets, emphasizing the importance of understanding the mechanism of CaM oxidation in muscle degeneration and overall physiology. It has been shown that the M125Q CaM mutant can mimic the functional effects of methionine oxidation on CaM’s regulation of the calcium release channel, ryanodine receptor (RyR). We report here that the M125Q mutation causes a localized unfolding of the C-terminal lobe of CaM, preventing the formation of a hydrophobic cluster of residues near the EF-hand Ca2+ binding sites. NMR analysis of CaM oxidation by peroxide offers further insights into the susceptibility of CaM’s Met residues to oxidation and the resulting structural effects. These results further resolve oxidation-driven structural perturbation of CaM, with implications for RyR regulation and the decay of muscle function in aging.
format	article
author	Sarah E. D. Nelson Daniel K. Weber Robyn T. Rebbeck Razvan L. Cornea Gianluigi Veglia David D. Thomas
author_facet	Sarah E. D. Nelson Daniel K. Weber Robyn T. Rebbeck Razvan L. Cornea Gianluigi Veglia David D. Thomas
author_sort	Sarah E. D. Nelson
title	Met125 is essential for maintaining the structural integrity of calmodulin’s C-terminal domain
title_short	Met125 is essential for maintaining the structural integrity of calmodulin’s C-terminal domain
title_full	Met125 is essential for maintaining the structural integrity of calmodulin’s C-terminal domain
title_fullStr	Met125 is essential for maintaining the structural integrity of calmodulin’s C-terminal domain
title_full_unstemmed	Met125 is essential for maintaining the structural integrity of calmodulin’s C-terminal domain
title_sort	met125 is essential for maintaining the structural integrity of calmodulin’s c-terminal domain
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/36f3e28887f142c5b2edc2e310a92fe1
work_keys_str_mv	AT sarahednelson met125isessentialformaintainingthestructuralintegrityofcalmodulinscterminaldomain AT danielkweber met125isessentialformaintainingthestructuralintegrityofcalmodulinscterminaldomain AT robyntrebbeck met125isessentialformaintainingthestructuralintegrityofcalmodulinscterminaldomain AT razvanlcornea met125isessentialformaintainingthestructuralintegrityofcalmodulinscterminaldomain AT gianluigiveglia met125isessentialformaintainingthestructuralintegrityofcalmodulinscterminaldomain AT daviddthomas met125isessentialformaintainingthestructuralintegrityofcalmodulinscterminaldomain
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Met125 is essential for maintaining the structural integrity of calmodulin’s C-terminal domain

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