How J-chain ensures the assembly of immunoglobulin IgM pentamers
Name
44318_2024_Article_317.pdf
Size
6.44 MB
Format
Adobe PDF
Checksum (MD5)
87cf6a1e54c1a73ef8275bb016fd7e3c
Author(s)
Giannone, Chiara
Mess, Xenia
He, Ruiming
Chelazzi, Maria R.
Mayer, Annika
Bakunts, Anush
Nguyen, Tuan
Bushman, Yevheniia
Orsi, Andrea
Gansen, Benedikt
Date Issued
December 4, 2024
Journal
The EMBO Journal
Publisher
Nature Publishing Group UK
Citation
Giannone, Chiara, Mess, Xenia, He, Ruiming, Chelazzi, Maria R., Mayer, Annika et al. 2024. "How J-chain ensures the assembly of immunoglobulin IgM pentamers." The EMBO Journal.
Version
Final published version
Abstract
Polymeric IgM immunoglobulins have high avidity for antigen and complement, and dominate primary antibody responses. They are produced either as assemblies of six µ2L2 subunits (i.e., hexamers), or as pentamers of two µ2L2 subunits and an additional protein termed J-chain (JC), which allows transcytosis across epithelia. The molecular mechanism of IgM assembly with the desired stoichiometry remained unknown. Here, we show in vitro and in cellula that JC outcompetes the sixth IgM subunit during assembly. Before insertion into IgM, JC exists as an ensemble of largely unstructured, protease-sensitive species with heterogeneous, non-native disulfide bonds. The J-chain interacts with the hydrophobic β-sheets selectively exposed by nascent pentamers. Completion of an amyloid-like core triggers JC folding and drives disulfide rearrangements that covalently stabilize JC-containing pentamers. In cells, the quality control factor ERp44 surveys IgM assembly and prevents the secretion of aberrant conformers. This mechanism allows the efficient production of high-avidity IgM for systemic or mucosal immunity.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Terms of Use
Creative Commons Attribution
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1038/s44318-024-00317-9
