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Complement is activated by elevated IgG3 hexameric platforms and deposits C4b onto distinct antibody domains
IgG3 is unique among the IgG subclasses due to its extended hinge, allotypic diversity and enhanced effector functions, including highly efficient pathogen neutralisation and complement activation. It is also underrepresented as an immunotherapeutic candidate, partly due to a lack of structural info...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10328927/ https://www.ncbi.nlm.nih.gov/pubmed/37419978 http://dx.doi.org/10.1038/s41467-023-39788-5 |
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author | Abendstein, Leoni Dijkstra, Douwe J. Tjokrodirijo, Rayman T. N. van Veelen, Peter A. Trouw, Leendert A. Hensbergen, Paul J. Sharp, Thomas H. |
author_facet | Abendstein, Leoni Dijkstra, Douwe J. Tjokrodirijo, Rayman T. N. van Veelen, Peter A. Trouw, Leendert A. Hensbergen, Paul J. Sharp, Thomas H. |
author_sort | Abendstein, Leoni |
collection | PubMed |
description | IgG3 is unique among the IgG subclasses due to its extended hinge, allotypic diversity and enhanced effector functions, including highly efficient pathogen neutralisation and complement activation. It is also underrepresented as an immunotherapeutic candidate, partly due to a lack of structural information. Here, we use cryoEM to solve structures of antigen-bound IgG3 alone and in complex with complement components. These structures reveal a propensity for IgG3-Fab clustering, which is possible due to the IgG3-specific flexible upper hinge region and may maximise pathogen neutralisation by forming high-density antibody arrays. IgG3 forms elevated hexameric Fc platforms that extend above the protein corona to maximise binding to receptors and the complement C1 complex, which here adopts a unique protease conformation that may precede C1 activation. Mass spectrometry reveals that C1 deposits C4b directly onto specific IgG3 residues proximal to the Fab domains. Structural analysis shows this to be caused by the height of the C1-IgG3 complex. Together, these data provide structural insights into the role of the unique IgG3 extended hinge, which will aid the development and design of upcoming immunotherapeutics based on IgG3. |
format | Online Article Text |
id | pubmed-10328927 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-103289272023-07-09 Complement is activated by elevated IgG3 hexameric platforms and deposits C4b onto distinct antibody domains Abendstein, Leoni Dijkstra, Douwe J. Tjokrodirijo, Rayman T. N. van Veelen, Peter A. Trouw, Leendert A. Hensbergen, Paul J. Sharp, Thomas H. Nat Commun Article IgG3 is unique among the IgG subclasses due to its extended hinge, allotypic diversity and enhanced effector functions, including highly efficient pathogen neutralisation and complement activation. It is also underrepresented as an immunotherapeutic candidate, partly due to a lack of structural information. Here, we use cryoEM to solve structures of antigen-bound IgG3 alone and in complex with complement components. These structures reveal a propensity for IgG3-Fab clustering, which is possible due to the IgG3-specific flexible upper hinge region and may maximise pathogen neutralisation by forming high-density antibody arrays. IgG3 forms elevated hexameric Fc platforms that extend above the protein corona to maximise binding to receptors and the complement C1 complex, which here adopts a unique protease conformation that may precede C1 activation. Mass spectrometry reveals that C1 deposits C4b directly onto specific IgG3 residues proximal to the Fab domains. Structural analysis shows this to be caused by the height of the C1-IgG3 complex. Together, these data provide structural insights into the role of the unique IgG3 extended hinge, which will aid the development and design of upcoming immunotherapeutics based on IgG3. Nature Publishing Group UK 2023-07-07 /pmc/articles/PMC10328927/ /pubmed/37419978 http://dx.doi.org/10.1038/s41467-023-39788-5 Text en © The Author(s) 2023 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Abendstein, Leoni Dijkstra, Douwe J. Tjokrodirijo, Rayman T. N. van Veelen, Peter A. Trouw, Leendert A. Hensbergen, Paul J. Sharp, Thomas H. Complement is activated by elevated IgG3 hexameric platforms and deposits C4b onto distinct antibody domains |
title | Complement is activated by elevated IgG3 hexameric platforms and deposits C4b onto distinct antibody domains |
title_full | Complement is activated by elevated IgG3 hexameric platforms and deposits C4b onto distinct antibody domains |
title_fullStr | Complement is activated by elevated IgG3 hexameric platforms and deposits C4b onto distinct antibody domains |
title_full_unstemmed | Complement is activated by elevated IgG3 hexameric platforms and deposits C4b onto distinct antibody domains |
title_short | Complement is activated by elevated IgG3 hexameric platforms and deposits C4b onto distinct antibody domains |
title_sort | complement is activated by elevated igg3 hexameric platforms and deposits c4b onto distinct antibody domains |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10328927/ https://www.ncbi.nlm.nih.gov/pubmed/37419978 http://dx.doi.org/10.1038/s41467-023-39788-5 |
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