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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| Format: | Article |
| Language: | English |
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MDPI AG
2022-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/7/3899 |
| _version_ | 1797438963989872640 |
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| author | Julie Ledoux Maxim Stolyarchuk Enki Bachelier Alain Trouvé Luba Tchertanov |
| author_facet | Julie Ledoux Maxim Stolyarchuk Enki Bachelier Alain Trouvé Luba Tchertanov |
| author_sort | Julie Ledoux |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-09T11:45:53Z |
| format | Article |
| id | doaj.art-cbd325e72d0d4607b59bee4b40be4642 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T11:45:53Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-cbd325e72d0d4607b59bee4b40be46422023-11-30T23:23:45ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-03-01237389910.3390/ijms23073899Human Vitamin K Epoxide Reductase as a Target of Its Redox ProteinJulie Ledoux0Maxim Stolyarchuk1Enki Bachelier2Alain Trouvé3Luba Tchertanov4Centre Borelli, ENS Paris-Saclay, CNRS, Université Paris-Saclay, 4 Avenue Des Sciences, F-91190 Gif-sur-Yvette, FranceCentre Borelli, ENS Paris-Saclay, CNRS, Université Paris-Saclay, 4 Avenue Des Sciences, F-91190 Gif-sur-Yvette, FranceCentre Borelli, ENS Paris-Saclay, CNRS, Université Paris-Saclay, 4 Avenue Des Sciences, F-91190 Gif-sur-Yvette, FranceCentre Borelli, ENS Paris-Saclay, CNRS, Université Paris-Saclay, 4 Avenue Des Sciences, F-91190 Gif-sur-Yvette, FranceCentre Borelli, ENS Paris-Saclay, CNRS, Université Paris-Saclay, 4 Avenue Des Sciences, F-91190 Gif-sur-Yvette, FranceHuman 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.https://www.mdpi.com/1422-0067/23/7/3899human vitamin K epoxide reductasehVKORC1blood coagulationredox protein targetenzyme activationmodular protein |
| spellingShingle | Julie Ledoux Maxim Stolyarchuk Enki Bachelier Alain Trouvé Luba Tchertanov Human Vitamin K Epoxide Reductase as a Target of Its Redox Protein International Journal of Molecular Sciences human vitamin K epoxide reductase hVKORC1 blood coagulation redox protein target enzyme activation modular 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 | human vitamin K epoxide reductase hVKORC1 blood coagulation redox protein target enzyme activation modular protein |
| url | https://www.mdpi.com/1422-0067/23/7/3899 |
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