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Organizing structural principles of the IL-17 ligand–receptor axis
The IL-17 family of cytokines and receptors have central roles in host defence against infection and development of inflammatory diseases(1). The compositions and structures of functional IL-17 family ligand–receptor signalling assemblies remain unclear. IL-17E (also known as IL-25) is a key regulat...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9477748/ https://www.ncbi.nlm.nih.gov/pubmed/35863378 http://dx.doi.org/10.1038/s41586-022-05116-y |
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author | Wilson, Steven C. Caveney, Nathanael A. Yen, Michelle Pollmann, Christoph Xiang, Xinyu Jude, Kevin M. Hafer, Maximillian Tsutsumi, Naotaka Piehler, Jacob Garcia, K. Christopher |
author_facet | Wilson, Steven C. Caveney, Nathanael A. Yen, Michelle Pollmann, Christoph Xiang, Xinyu Jude, Kevin M. Hafer, Maximillian Tsutsumi, Naotaka Piehler, Jacob Garcia, K. Christopher |
author_sort | Wilson, Steven C. |
collection | PubMed |
description | The IL-17 family of cytokines and receptors have central roles in host defence against infection and development of inflammatory diseases(1). The compositions and structures of functional IL-17 family ligand–receptor signalling assemblies remain unclear. IL-17E (also known as IL-25) is a key regulator of type 2 immune responses and driver of inflammatory diseases, such as allergic asthma, and requires both IL-17 receptor A (IL-17RA) and IL-17RB to elicit functional responses(2). Here we studied IL-25–IL-17RB binary and IL-25–IL-17RB–IL-17RA ternary complexes using a combination of cryo-electron microscopy, single-molecule imaging and cell-based signalling approaches. The IL-25–IL-17RB–IL-17RA ternary signalling assembly is a C2-symmetric complex in which the IL-25–IL-17RB homodimer is flanked by two ‘wing-like’ IL-17RA co-receptors through a ‘tip-to-tip’ geometry that is the key receptor–receptor interaction required for initiation of signal transduction. IL-25 interacts solely with IL-17RB to allosterically promote the formation of the IL-17RB–IL-17RA tip-to-tip interface. The resulting large separation between the receptors at the membrane-proximal level may reflect proximity constraints imposed by the intracellular domains for signalling. Cryo-electron microscopy structures of IL-17A–IL-17RA and IL-17A–IL-17RA–IL-17RC complexes reveal that this tip-to-tip architecture is a key organizing principle of the IL-17 receptor family. Furthermore, these studies reveal dual actions for IL-17RA sharing among IL-17 cytokine complexes, by either directly engaging IL-17 cytokines or alternatively functioning as a co-receptor. |
format | Online Article Text |
id | pubmed-9477748 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-94777482022-09-17 Organizing structural principles of the IL-17 ligand–receptor axis Wilson, Steven C. Caveney, Nathanael A. Yen, Michelle Pollmann, Christoph Xiang, Xinyu Jude, Kevin M. Hafer, Maximillian Tsutsumi, Naotaka Piehler, Jacob Garcia, K. Christopher Nature Article The IL-17 family of cytokines and receptors have central roles in host defence against infection and development of inflammatory diseases(1). The compositions and structures of functional IL-17 family ligand–receptor signalling assemblies remain unclear. IL-17E (also known as IL-25) is a key regulator of type 2 immune responses and driver of inflammatory diseases, such as allergic asthma, and requires both IL-17 receptor A (IL-17RA) and IL-17RB to elicit functional responses(2). Here we studied IL-25–IL-17RB binary and IL-25–IL-17RB–IL-17RA ternary complexes using a combination of cryo-electron microscopy, single-molecule imaging and cell-based signalling approaches. The IL-25–IL-17RB–IL-17RA ternary signalling assembly is a C2-symmetric complex in which the IL-25–IL-17RB homodimer is flanked by two ‘wing-like’ IL-17RA co-receptors through a ‘tip-to-tip’ geometry that is the key receptor–receptor interaction required for initiation of signal transduction. IL-25 interacts solely with IL-17RB to allosterically promote the formation of the IL-17RB–IL-17RA tip-to-tip interface. The resulting large separation between the receptors at the membrane-proximal level may reflect proximity constraints imposed by the intracellular domains for signalling. Cryo-electron microscopy structures of IL-17A–IL-17RA and IL-17A–IL-17RA–IL-17RC complexes reveal that this tip-to-tip architecture is a key organizing principle of the IL-17 receptor family. Furthermore, these studies reveal dual actions for IL-17RA sharing among IL-17 cytokine complexes, by either directly engaging IL-17 cytokines or alternatively functioning as a co-receptor. Nature Publishing Group UK 2022-07-21 2022 /pmc/articles/PMC9477748/ /pubmed/35863378 http://dx.doi.org/10.1038/s41586-022-05116-y 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 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 Wilson, Steven C. Caveney, Nathanael A. Yen, Michelle Pollmann, Christoph Xiang, Xinyu Jude, Kevin M. Hafer, Maximillian Tsutsumi, Naotaka Piehler, Jacob Garcia, K. Christopher Organizing structural principles of the IL-17 ligand–receptor axis |
title | Organizing structural principles of the IL-17 ligand–receptor axis |
title_full | Organizing structural principles of the IL-17 ligand–receptor axis |
title_fullStr | Organizing structural principles of the IL-17 ligand–receptor axis |
title_full_unstemmed | Organizing structural principles of the IL-17 ligand–receptor axis |
title_short | Organizing structural principles of the IL-17 ligand–receptor axis |
title_sort | organizing structural principles of the il-17 ligand–receptor axis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9477748/ https://www.ncbi.nlm.nih.gov/pubmed/35863378 http://dx.doi.org/10.1038/s41586-022-05116-y |
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