The structure of the teleost Immunoglobulin M core provides insights on polymeric antibody evolution, assembly, and function

Creators: Lyu, Mengfan; Malyutin, Andrey G.; Stadtmueller, Beth M.

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 varies 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 revealed four tIgM Fcs linked through eight C-terminal tailpieces (Tps), which adopt a single β-sandwich-like domain (Tp assembly) located between two Fcs. Remarkably, 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.

Additional Information

The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. 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. Cryogenic electron microscopy was done in the Beckman Institute cryo-EM resource center at California Institute of Technology. This work was supported by NIH grant 1R01AI165570 and University of Illinois start-up funding to B.M.S. AUTHOR 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. Cryo-EM density map has been deposited in the EM databank (www.ebi.ac.uk/emdb) with the accession code EMD-40054 and the refined coordinate has been deposited in the Protein Data Bank (www.rcsb.org) with accession code 8GHZ. Competing Interest Statement. 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.

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