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Fibronectin containing alternatively spliced extra domain A interacts at the central and c-terminal domain of Toll-like receptor-4
Extra domain A of cellular fibronectin (FN-EDA) is known to cause insulin resistance, atherosclerosis, tissue fibrosis, ischemic stroke and exaggerated myocardial reperfusion injury through Toll-like receptor 4 (TLR4). However, the FN-EDA-TLR4 interacting site is not well established. Therefore, in-...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9188610/ https://www.ncbi.nlm.nih.gov/pubmed/35690624 http://dx.doi.org/10.1038/s41598-022-13622-2 |
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author | Gupta, Shubhangi Ali, Azeem Pandey, Saurabh Khan, Imran A. Prakash, Prem |
author_facet | Gupta, Shubhangi Ali, Azeem Pandey, Saurabh Khan, Imran A. Prakash, Prem |
author_sort | Gupta, Shubhangi |
collection | PubMed |
description | Extra domain A of cellular fibronectin (FN-EDA) is known to cause insulin resistance, atherosclerosis, tissue fibrosis, ischemic stroke and exaggerated myocardial reperfusion injury through Toll-like receptor 4 (TLR4). However, the FN-EDA-TLR4 interacting site is not well established. Therefore, in-silico approaches have been used to study FN-EDA and TLR4 interactions at the interface. In the present study, molecular docking studies of FN-EDA with TLR4-myeloid differentiation factor 2 (MD2) heterodimer have been performed to unravel the FN-EDA-TLR4 interacting sequence. Furthermore, the modulatory role of FN-EDA adjacent domains FNIII(11) and FNIII(12) on its interaction with TLR4-MD2 was investigated. The results show that FN-EDA interacting sequence “SPEDGIRELF” selectively interacts with TLR4 directly near its central and C-terminal domain region. The regulatory domains, FN type III 11 facilitate and 12 impede the FN-EDA-TLR4 interaction. Furthermore, the molecular dynamic simulation studies confirmed that FN-EDA forms a stable complex with TLR4-MD2 heterodimer. In conclusion, FN-EDA interacts and forms a stable complex through its “SPEDGIRELF” sequence at the central and C-terminal domain region of TLR4. The revelation of FN-EDA and TLR4 interacting sites may help design novel therapeutics for drug discovery research. |
format | Online Article Text |
id | pubmed-9188610 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-91886102022-06-13 Fibronectin containing alternatively spliced extra domain A interacts at the central and c-terminal domain of Toll-like receptor-4 Gupta, Shubhangi Ali, Azeem Pandey, Saurabh Khan, Imran A. Prakash, Prem Sci Rep Article Extra domain A of cellular fibronectin (FN-EDA) is known to cause insulin resistance, atherosclerosis, tissue fibrosis, ischemic stroke and exaggerated myocardial reperfusion injury through Toll-like receptor 4 (TLR4). However, the FN-EDA-TLR4 interacting site is not well established. Therefore, in-silico approaches have been used to study FN-EDA and TLR4 interactions at the interface. In the present study, molecular docking studies of FN-EDA with TLR4-myeloid differentiation factor 2 (MD2) heterodimer have been performed to unravel the FN-EDA-TLR4 interacting sequence. Furthermore, the modulatory role of FN-EDA adjacent domains FNIII(11) and FNIII(12) on its interaction with TLR4-MD2 was investigated. The results show that FN-EDA interacting sequence “SPEDGIRELF” selectively interacts with TLR4 directly near its central and C-terminal domain region. The regulatory domains, FN type III 11 facilitate and 12 impede the FN-EDA-TLR4 interaction. Furthermore, the molecular dynamic simulation studies confirmed that FN-EDA forms a stable complex with TLR4-MD2 heterodimer. In conclusion, FN-EDA interacts and forms a stable complex through its “SPEDGIRELF” sequence at the central and C-terminal domain region of TLR4. The revelation of FN-EDA and TLR4 interacting sites may help design novel therapeutics for drug discovery research. Nature Publishing Group UK 2022-06-11 /pmc/articles/PMC9188610/ /pubmed/35690624 http://dx.doi.org/10.1038/s41598-022-13622-2 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Gupta, Shubhangi Ali, Azeem Pandey, Saurabh Khan, Imran A. Prakash, Prem Fibronectin containing alternatively spliced extra domain A interacts at the central and c-terminal domain of Toll-like receptor-4 |
title | Fibronectin containing alternatively spliced extra domain A interacts at the central and c-terminal domain of Toll-like receptor-4 |
title_full | Fibronectin containing alternatively spliced extra domain A interacts at the central and c-terminal domain of Toll-like receptor-4 |
title_fullStr | Fibronectin containing alternatively spliced extra domain A interacts at the central and c-terminal domain of Toll-like receptor-4 |
title_full_unstemmed | Fibronectin containing alternatively spliced extra domain A interacts at the central and c-terminal domain of Toll-like receptor-4 |
title_short | Fibronectin containing alternatively spliced extra domain A interacts at the central and c-terminal domain of Toll-like receptor-4 |
title_sort | fibronectin containing alternatively spliced extra domain a interacts at the central and c-terminal domain of toll-like receptor-4 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9188610/ https://www.ncbi.nlm.nih.gov/pubmed/35690624 http://dx.doi.org/10.1038/s41598-022-13622-2 |
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