The structure of the teleost Immunoglobulin M core provides insights on polymeric antibody evolution, assembly, and function
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1.
University of Illinois Urbana-Champaign
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2.
California Institute of Technology
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3.
Takeda (United States)
Abstract
Polymeric (p) immunoglobulins (Igs) serve broad functions during vertebrate immune responses. Typically, pIgs contain between two and six Ig monomers, each with two antigen binding fragments and one fragment crystallization (Fc). In addition, many pIgs assemble with a joining-chain (JC); however, the number of monomers and potential to include JC vary with species and heavy chain class. Here, we report the cryo-electron microscopy structure of IgM from a teleost (t) species, which does not encode JC. The structure reveals four tIgM Fcs linked through eight C-terminal tailpieces (Tps), which adopt a single β-sandwich-like domain (Tp assembly) located between two Fcs. Specifically, two of eight heavy chains fold uniquely, resulting in a structure distinct from mammalian IgM, which typically contains five IgM monomers, one JC and a centrally-located Tp assembly. Together with mutational analysis, structural data indicate that pIgs have evolved a range of assembly mechanisms and structures, each likely to support unique antibody effector functions.
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© The Author(s) 2023. 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/.
Acknowledgement
We thank Kushol Gupta (University of Pennsylvania) for assistance with SEC-MALS data collection and analysis and thank members of the Stadtmueller Laboratory for insightful conversations and suggestions related to this work. (Cryo) Electron microscopy was performed in the Beckman Institute Resource Center for Transmission Electron Microscopy at Caltech. This work was supported by NIH grant 1R01AI165570 and University of Illinois start-up funding to B.M.S, and the Lowell P. Hager Fellowship in Biochemistry to M.L.
Contributions
The study was conceived by B.M.S and M.L.; experiments were conducted by M.L. and A.G.M.; all authors contributed to data analysis and manuscript writing.
Data Availability
The tFcμ tetramer Cryo-EM data generated in this study have been deposited in the EM databank (www.ebi.ac.uk/emdb) with the accession code EMD-40054. The refined coordinates generated in this study have been deposited in the Protein Data Bank (www.rcsb.org) with accession code 8GHZ. Previously published protein structure data used for analysis in this study are available in the Protein Data Bank (www.rcsb.org) under PDB ID: 6KXS24 (human hSIgM-Fc core), 6UE723 (human hSIgA-Fc core), 1MCO43 (human IgG1-Fc). Source data are provided with this paper. The protein sequences used for sequence alignment are available in NCBI database (https://www.ncbi.nlm.nih.gov/) under these accession codes: Oncorhynchus mykiss (trout) IgM secretory form (AAW66974.1), Salmo Salar (salmon) IgM (AAB24064.1), Xenopus laevis (frog) IgM (AAA49774.1), Trachemys scripta elegans (turtle) IgM (AFR90255.1), Gallus gallus (chicken) IgM (P01875), Mus musculus (mouse) IgM (P01872), and Homo sapiens (human) IgM (P01871). All other data are available in the article and its Supplementary files or from the corresponding author upon request. Source data are provided with this paper.
Conflict of Interest
BMS and ML are listed as inventors on a patent application that includes the design, production, and use of chimeric antibodies, some of which include teleost Ig heavy chain motifs. The remaining authors declare no competing interests.
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Additional details
Identifiers
- PMCID
- PMC10663602
Related works
- Is derived from
- https://authors.library.caltech.edu/records/pa78n-zyr70 (URL)
- Is supplemented by
- Dataset: https://static-content.springer.com/esm/art%3A10.1038%2Fs41467-023-43240-z/MediaObjects/41467_2023_43240_MOESM4_ESM.xlsx (URL)
Funding
- National Institutes of Health
- R01AI165570
- University of Illinois Urbana-Champaign