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Human Vitamin K Epoxide Reductase as a Target of Its Redox Protein

Human vitamin K epoxide reductase (hVKORC1) enzymatic activity requires an initial activation by a specific redox protein, a less studied step in the hVKORC1 vital cycle. Significant steric conditions must be met by enzymes, being that to adapt their configurations is mandatory for hVKORC1 activatio...

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Autores principales: Ledoux, Julie, Stolyarchuk, Maxim, Bachelier, Enki, Trouvé, Alain, Tchertanov, Luba
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998853/
https://www.ncbi.nlm.nih.gov/pubmed/35409257
http://dx.doi.org/10.3390/ijms23073899
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author Ledoux, Julie
Stolyarchuk, Maxim
Bachelier, Enki
Trouvé, Alain
Tchertanov, Luba
author_facet Ledoux, Julie
Stolyarchuk, Maxim
Bachelier, Enki
Trouvé, Alain
Tchertanov, Luba
author_sort Ledoux, Julie
collection PubMed
description Human vitamin K epoxide reductase (hVKORC1) enzymatic activity requires an initial activation by a specific redox protein, a less studied step in the hVKORC1 vital cycle. Significant steric conditions must be met by enzymes, being that to adapt their configurations is mandatory for hVKORC1 activation. We studied, by molecular dynamics (MD) simulations, the folding and conformational plasticity of hVKORC1 in its inactive (fully oxidised) state using available structures, crystallographic and from de novo modelling. According to the obtained results, hVKORC1 is a modular protein composed of the stable transmembrane domain (TMD) and intrinsically disordered luminal (L) loop, possessing the great plasticity/adaptability required to perform various steps of the activation process. The docking (HADDOCK) of Protein Disulfide Isomerase (PDI) onto different hVKORC1 conformations clearly indicated that the most interpretable solutions were found on the target closed L-loop form, a prevalent conformation of hVKORC1’s oxidised state. We also suggest that the cleaved L-loop is an appropriate entity to study hVKORC1 recognition/activation by its redox protein. Additionally, the application of hVKORC1 (membrane protein) in aqueous solution is likely to prove to be very useful in practice in either in silico studies or in vitro experiments.
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spelling pubmed-89988532022-04-12 Human Vitamin K Epoxide Reductase as a Target of Its Redox Protein Ledoux, Julie Stolyarchuk, Maxim Bachelier, Enki Trouvé, Alain Tchertanov, Luba Int J Mol Sci Article Human vitamin K epoxide reductase (hVKORC1) enzymatic activity requires an initial activation by a specific redox protein, a less studied step in the hVKORC1 vital cycle. Significant steric conditions must be met by enzymes, being that to adapt their configurations is mandatory for hVKORC1 activation. We studied, by molecular dynamics (MD) simulations, the folding and conformational plasticity of hVKORC1 in its inactive (fully oxidised) state using available structures, crystallographic and from de novo modelling. According to the obtained results, hVKORC1 is a modular protein composed of the stable transmembrane domain (TMD) and intrinsically disordered luminal (L) loop, possessing the great plasticity/adaptability required to perform various steps of the activation process. The docking (HADDOCK) of Protein Disulfide Isomerase (PDI) onto different hVKORC1 conformations clearly indicated that the most interpretable solutions were found on the target closed L-loop form, a prevalent conformation of hVKORC1’s oxidised state. We also suggest that the cleaved L-loop is an appropriate entity to study hVKORC1 recognition/activation by its redox protein. Additionally, the application of hVKORC1 (membrane protein) in aqueous solution is likely to prove to be very useful in practice in either in silico studies or in vitro experiments. MDPI 2022-03-31 /pmc/articles/PMC8998853/ /pubmed/35409257 http://dx.doi.org/10.3390/ijms23073899 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ledoux, Julie
Stolyarchuk, Maxim
Bachelier, Enki
Trouvé, Alain
Tchertanov, Luba
Human Vitamin K Epoxide Reductase as a Target of Its Redox Protein
title Human Vitamin K Epoxide Reductase as a Target of Its Redox Protein
title_full Human Vitamin K Epoxide Reductase as a Target of Its Redox Protein
title_fullStr Human Vitamin K Epoxide Reductase as a Target of Its Redox Protein
title_full_unstemmed Human Vitamin K Epoxide Reductase as a Target of Its Redox Protein
title_short Human Vitamin K Epoxide Reductase as a Target of Its Redox Protein
title_sort human vitamin k epoxide reductase as a target of its redox protein
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998853/
https://www.ncbi.nlm.nih.gov/pubmed/35409257
http://dx.doi.org/10.3390/ijms23073899
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