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Cryomicroscopy reveals the structural basis for a flexible hinge motion in the immunoglobulin M pentamer
Immunoglobulin M (IgM) is the most ancient of the five isotypes of immunoglobulin (Ig) molecules and serves as the first line of defence against pathogens. Here, we use cryo-EM to image the structure of the human full-length IgM pentamer, revealing antigen binding domains flexibly attached to the as...
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/PMC9588798/ https://www.ncbi.nlm.nih.gov/pubmed/36274064 http://dx.doi.org/10.1038/s41467-022-34090-2 |
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author | Chen, Qu Menon, Rajesh Calder, Lesley J. Tolar, Pavel Rosenthal, Peter B. |
author_facet | Chen, Qu Menon, Rajesh Calder, Lesley J. Tolar, Pavel Rosenthal, Peter B. |
author_sort | Chen, Qu |
collection | PubMed |
description | Immunoglobulin M (IgM) is the most ancient of the five isotypes of immunoglobulin (Ig) molecules and serves as the first line of defence against pathogens. Here, we use cryo-EM to image the structure of the human full-length IgM pentamer, revealing antigen binding domains flexibly attached to the asymmetric and rigid core formed by the Cμ4 and Cμ3 constant regions and the J-chain. A hinge is located at the Cμ3/Cμ2 domain interface, allowing Fabs and Cμ2 to pivot as a unit both in-plane and out-of-plane. This motion is different from that observed in IgG and IgA, where the two Fab arms are able to swing independently. A biased orientation of one pair of Fab arms results from asymmetry in the constant domain (Cμ3) at the IgM subunit interacting most extensively with the J-chain. This may influence the multi-valent binding to surface-associated antigens and complement pathway activation. By comparison, the structure of the Fc fragment in the IgM monomer is similar to that of the pentamer, but is more dynamic in the Cμ4 domain. |
format | Online Article Text |
id | pubmed-9588798 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-95887982022-10-25 Cryomicroscopy reveals the structural basis for a flexible hinge motion in the immunoglobulin M pentamer Chen, Qu Menon, Rajesh Calder, Lesley J. Tolar, Pavel Rosenthal, Peter B. Nat Commun Article Immunoglobulin M (IgM) is the most ancient of the five isotypes of immunoglobulin (Ig) molecules and serves as the first line of defence against pathogens. Here, we use cryo-EM to image the structure of the human full-length IgM pentamer, revealing antigen binding domains flexibly attached to the asymmetric and rigid core formed by the Cμ4 and Cμ3 constant regions and the J-chain. A hinge is located at the Cμ3/Cμ2 domain interface, allowing Fabs and Cμ2 to pivot as a unit both in-plane and out-of-plane. This motion is different from that observed in IgG and IgA, where the two Fab arms are able to swing independently. A biased orientation of one pair of Fab arms results from asymmetry in the constant domain (Cμ3) at the IgM subunit interacting most extensively with the J-chain. This may influence the multi-valent binding to surface-associated antigens and complement pathway activation. By comparison, the structure of the Fc fragment in the IgM monomer is similar to that of the pentamer, but is more dynamic in the Cμ4 domain. Nature Publishing Group UK 2022-10-23 /pmc/articles/PMC9588798/ /pubmed/36274064 http://dx.doi.org/10.1038/s41467-022-34090-2 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 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 Chen, Qu Menon, Rajesh Calder, Lesley J. Tolar, Pavel Rosenthal, Peter B. Cryomicroscopy reveals the structural basis for a flexible hinge motion in the immunoglobulin M pentamer |
title | Cryomicroscopy reveals the structural basis for a flexible hinge motion in the immunoglobulin M pentamer |
title_full | Cryomicroscopy reveals the structural basis for a flexible hinge motion in the immunoglobulin M pentamer |
title_fullStr | Cryomicroscopy reveals the structural basis for a flexible hinge motion in the immunoglobulin M pentamer |
title_full_unstemmed | Cryomicroscopy reveals the structural basis for a flexible hinge motion in the immunoglobulin M pentamer |
title_short | Cryomicroscopy reveals the structural basis for a flexible hinge motion in the immunoglobulin M pentamer |
title_sort | cryomicroscopy reveals the structural basis for a flexible hinge motion in the immunoglobulin m pentamer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9588798/ https://www.ncbi.nlm.nih.gov/pubmed/36274064 http://dx.doi.org/10.1038/s41467-022-34090-2 |
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