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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; (2022) Cryomicroscopy reveals the structural basis for a flexible hinge motion in the immunoglobulin M pentamer. Nature Communications , 13 (1) , Article 6314. 10.1038/s41467-022-34090-2. Green open access

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Abstract

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.

Type: Article
Title: Cryomicroscopy reveals the structural basis for a flexible hinge motion in the immunoglobulin M pentamer
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41467-022-34090-2
Publisher version: https://doi.org/10.1038/s41467-022-34090-2
Language: English
Additional information: © 2022 Springer Nature Limited. This article is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).
Keywords: Humans, Immunoglobulin M, Immunoglobulin Fc Fragments, Immunoglobulin A, Immunoglobulin G, Immunoglobulin Fab Fragments
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10158425
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