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Modeling the Ternary Complex TCR-Vβ/CollagenII(261–273)/HLA-DR4 Associated with Rheumatoid Arthritis
BACKGROUND: It is known that genetic predisposition to rheumatoid arthritis (RA) is associated with the MHC class II allele HLA-DR4 and that residues 261–273 of type II collagen (huCollp261) represent an immunodominant T cell epitope restricted by the DR4 molecule. Despite recent advances in charact...
Autores principales: | , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904365/ https://www.ncbi.nlm.nih.gov/pubmed/20644721 http://dx.doi.org/10.1371/journal.pone.0011550 |
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author | De Rosa, Maria Cristina Giardina, Bruno Bianchi, Caterina Carelli Alinovi, Cristiana Pirolli, Davide Ferraccioli, Gianfranco De Santis, Maria Di Sante, Gabriele Ria, Francesco |
author_facet | De Rosa, Maria Cristina Giardina, Bruno Bianchi, Caterina Carelli Alinovi, Cristiana Pirolli, Davide Ferraccioli, Gianfranco De Santis, Maria Di Sante, Gabriele Ria, Francesco |
author_sort | De Rosa, Maria Cristina |
collection | PubMed |
description | BACKGROUND: It is known that genetic predisposition to rheumatoid arthritis (RA) is associated with the MHC class II allele HLA-DR4 and that residues 261–273 of type II collagen (huCollp261) represent an immunodominant T cell epitope restricted by the DR4 molecule. Despite recent advances in characterization of MHC and T cell receptor (TCR) contacts to this epitope, the atomic details of TCR/huCollp261/HLA-DR4 ternary complex are not known. METHODOLOGY/PRINCIPAL FINDINGS: Here we have used computational modeling to get insight into this interaction. A three-dimensional model of the TCR Vβ domain from a DR4(+) patient affected by RA has been derived by homology modeling techniques. Subsequently, the structure of the TCR Vβ domain in complex with huCollp261/HLA-DR4 was obtained from a docking approach in conjunction with a filtering procedure based on biochemical information. The best complex from the docking experiments was then refined by 20 ns of molecular dynamics simulation in explicit water. The predicted model is consistent with available experimental data. Our results indicate that residues 97–101 of CDR3β are critical for recognition of huCollp261/HLA-DR4 by TCR. We also show that TCR contacts on p/MHC surface affect the conformation of the shared epitope expressed by DR alleles associated with RA susceptibility. CONCLUSIONS/SIGNIFICANCE: This work presents a three-dimensional model for the ternary complex TCR-Vβ/collagenII(261–273)/HLA-DR4 associated with rheumatoid arthritis that can provide insights into the molecular mechanisms of self reactivity. |
format | Text |
id | pubmed-2904365 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-29043652010-07-19 Modeling the Ternary Complex TCR-Vβ/CollagenII(261–273)/HLA-DR4 Associated with Rheumatoid Arthritis De Rosa, Maria Cristina Giardina, Bruno Bianchi, Caterina Carelli Alinovi, Cristiana Pirolli, Davide Ferraccioli, Gianfranco De Santis, Maria Di Sante, Gabriele Ria, Francesco PLoS One Research Article BACKGROUND: It is known that genetic predisposition to rheumatoid arthritis (RA) is associated with the MHC class II allele HLA-DR4 and that residues 261–273 of type II collagen (huCollp261) represent an immunodominant T cell epitope restricted by the DR4 molecule. Despite recent advances in characterization of MHC and T cell receptor (TCR) contacts to this epitope, the atomic details of TCR/huCollp261/HLA-DR4 ternary complex are not known. METHODOLOGY/PRINCIPAL FINDINGS: Here we have used computational modeling to get insight into this interaction. A three-dimensional model of the TCR Vβ domain from a DR4(+) patient affected by RA has been derived by homology modeling techniques. Subsequently, the structure of the TCR Vβ domain in complex with huCollp261/HLA-DR4 was obtained from a docking approach in conjunction with a filtering procedure based on biochemical information. The best complex from the docking experiments was then refined by 20 ns of molecular dynamics simulation in explicit water. The predicted model is consistent with available experimental data. Our results indicate that residues 97–101 of CDR3β are critical for recognition of huCollp261/HLA-DR4 by TCR. We also show that TCR contacts on p/MHC surface affect the conformation of the shared epitope expressed by DR alleles associated with RA susceptibility. CONCLUSIONS/SIGNIFICANCE: This work presents a three-dimensional model for the ternary complex TCR-Vβ/collagenII(261–273)/HLA-DR4 associated with rheumatoid arthritis that can provide insights into the molecular mechanisms of self reactivity. Public Library of Science 2010-07-14 /pmc/articles/PMC2904365/ /pubmed/20644721 http://dx.doi.org/10.1371/journal.pone.0011550 Text en De Rosa et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article De Rosa, Maria Cristina Giardina, Bruno Bianchi, Caterina Carelli Alinovi, Cristiana Pirolli, Davide Ferraccioli, Gianfranco De Santis, Maria Di Sante, Gabriele Ria, Francesco Modeling the Ternary Complex TCR-Vβ/CollagenII(261–273)/HLA-DR4 Associated with Rheumatoid Arthritis |
title | Modeling the Ternary Complex TCR-Vβ/CollagenII(261–273)/HLA-DR4 Associated with Rheumatoid Arthritis |
title_full | Modeling the Ternary Complex TCR-Vβ/CollagenII(261–273)/HLA-DR4 Associated with Rheumatoid Arthritis |
title_fullStr | Modeling the Ternary Complex TCR-Vβ/CollagenII(261–273)/HLA-DR4 Associated with Rheumatoid Arthritis |
title_full_unstemmed | Modeling the Ternary Complex TCR-Vβ/CollagenII(261–273)/HLA-DR4 Associated with Rheumatoid Arthritis |
title_short | Modeling the Ternary Complex TCR-Vβ/CollagenII(261–273)/HLA-DR4 Associated with Rheumatoid Arthritis |
title_sort | modeling the ternary complex tcr-vβ/collagenii(261–273)/hla-dr4 associated with rheumatoid arthritis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904365/ https://www.ncbi.nlm.nih.gov/pubmed/20644721 http://dx.doi.org/10.1371/journal.pone.0011550 |
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