How thioredoxin dissociates its mixed disulfide.

The dissociation mechanism of the thioredoxin (Trx) mixed disulfide complexes is unknown and has been debated for more than twenty years. Specifically, opposing arguments for the activation of the nucleophilic cysteine as a thiolate during the dissociation of the complex have been put forward. As a...

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Autores principales:	Goedele Roos, Nicolas Foloppe, Koen Van Laer, Lode Wyns, Lennart Nilsson, Paul Geerlings, Joris Messens
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/4f596919d83a42cda0c68aaf17e2fe37
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spelling	oai:doaj.org-article:4f596919d83a42cda0c68aaf17e2fe372021-11-25T05:42:15ZHow thioredoxin dissociates its mixed disulfide.1553-734X1553-735810.1371/journal.pcbi.1000461https://doaj.org/article/4f596919d83a42cda0c68aaf17e2fe372009-08-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19675666/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358The dissociation mechanism of the thioredoxin (Trx) mixed disulfide complexes is unknown and has been debated for more than twenty years. Specifically, opposing arguments for the activation of the nucleophilic cysteine as a thiolate during the dissociation of the complex have been put forward. As a key model, the complex between Trx and its endogenous substrate, arsenate reductase (ArsC), was used. In this structure, a Cys29(Trx)-Cys89(ArsC) intermediate disulfide is formed by the nucleophilic attack of Cys29(Trx) on the exposed Cys82(ArsC)-Cys89(ArsC) in oxidized ArsC. With theoretical reactivity analysis, molecular dynamics simulations, and biochemical complex formation experiments with Cys-mutants, Trx mixed disulfide dissociation was studied. We observed that the conformational changes around the intermediate disulfide bring Cys32(Trx) in contact with Cys29(Trx). Cys32(Trx) is activated for its nucleophilic attack by hydrogen bonds, and Cys32(Trx) is found to be more reactive than Cys82(ArsC). Additionally, Cys32(Trx) directs its nucleophilic attack on the more susceptible Cys29(Trx) and not on Cys89(ArsC). This multidisciplinary approach provides fresh insights into a universal thiol/disulfide exchange reaction mechanism that results in reduced substrate and oxidized Trx.Goedele RoosNicolas FoloppeKoen Van LaerLode WynsLennart NilssonPaul GeerlingsJoris MessensPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 5, Iss 8, p e1000461 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Goedele Roos Nicolas Foloppe Koen Van Laer Lode Wyns Lennart Nilsson Paul Geerlings Joris Messens How thioredoxin dissociates its mixed disulfide.
description	The dissociation mechanism of the thioredoxin (Trx) mixed disulfide complexes is unknown and has been debated for more than twenty years. Specifically, opposing arguments for the activation of the nucleophilic cysteine as a thiolate during the dissociation of the complex have been put forward. As a key model, the complex between Trx and its endogenous substrate, arsenate reductase (ArsC), was used. In this structure, a Cys29(Trx)-Cys89(ArsC) intermediate disulfide is formed by the nucleophilic attack of Cys29(Trx) on the exposed Cys82(ArsC)-Cys89(ArsC) in oxidized ArsC. With theoretical reactivity analysis, molecular dynamics simulations, and biochemical complex formation experiments with Cys-mutants, Trx mixed disulfide dissociation was studied. We observed that the conformational changes around the intermediate disulfide bring Cys32(Trx) in contact with Cys29(Trx). Cys32(Trx) is activated for its nucleophilic attack by hydrogen bonds, and Cys32(Trx) is found to be more reactive than Cys82(ArsC). Additionally, Cys32(Trx) directs its nucleophilic attack on the more susceptible Cys29(Trx) and not on Cys89(ArsC). This multidisciplinary approach provides fresh insights into a universal thiol/disulfide exchange reaction mechanism that results in reduced substrate and oxidized Trx.
format	article
author	Goedele Roos Nicolas Foloppe Koen Van Laer Lode Wyns Lennart Nilsson Paul Geerlings Joris Messens
author_facet	Goedele Roos Nicolas Foloppe Koen Van Laer Lode Wyns Lennart Nilsson Paul Geerlings Joris Messens
author_sort	Goedele Roos
title	How thioredoxin dissociates its mixed disulfide.
title_short	How thioredoxin dissociates its mixed disulfide.
title_full	How thioredoxin dissociates its mixed disulfide.
title_fullStr	How thioredoxin dissociates its mixed disulfide.
title_full_unstemmed	How thioredoxin dissociates its mixed disulfide.
title_sort	how thioredoxin dissociates its mixed disulfide.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/4f596919d83a42cda0c68aaf17e2fe37
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How thioredoxin dissociates its mixed disulfide.

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