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TitleChimeric Immunoglobulin and human Immunoglobulin M structures provide insights on joining-chain independent assembly and function.
Journal, issue, pagesBiorxiv, Year 2025
Publish dateJun 20, 2025 (structure data deposition date)
AuthorsMengfan Lyu / Beth M Stadtmueller /
PubMed AbstractPolymeric (p) immunoglobulins (Igs) play critical roles in vertebrate immunity. IgM is the evolutionarily oldest pIg and functions both in circulation and in the mucosa. pIgM typically comprises ...Polymeric (p) immunoglobulins (Igs) play critical roles in vertebrate immunity. IgM is the evolutionarily oldest pIg and functions both in circulation and in the mucosa. pIgM typically comprises between four and six IgM monomers and up to one joining chain (JC), which in mammals facilitates pIg assembly and promotes delivery to mucosal secretions. Bony fish (teleosts) lack JC and assemble tetrameric IgM whereas humans can express JC-containing pentamers and JC-free hexamers. Here we report cryo-electron microscopy structures of two JC-free chimeric IgM, comprising bony fish and human sequences, and the structure of human hexameric IgM. Chimeric IgM structures adopted unique pentameric geometry distinct from both human and fish pIgM whereas the human hexameric IgM structure adopted hexagonal geometry similar to JC-containing pentameric IgM, albeit with structural differences in center of the molecule. Together results provide new insights on how IgM heavy chain motifs contribute to JC-free pIgM assembly and reveal plasticity of this process, which can be manipulated to create pIg structures not observed in nature. Moreover, we found that antigen-targeting chimeric IgM could neutralize toxin cytotoxicity, indicating potential to engineer uniquely structured pIgs to prevent or treat disease.
External linksBiorxiv / PubMed:40791433 / PubMed Central
MethodsEM (single particle)
Resolution3.9 - 3.92 Å
Structure data

PDB-9p6u:
Cryo-EM structure of chimeric immunoglobulin M comprising bony fish and human sequences, hFcm-tFcm-chi3
Method: ELECTRON MICROSCOPY / Resolution: 3.9 Å

PDB-9p6v:
Cryo-EM structure of chimeric immunoglobulin M comprising bony fish and human sequences, hFcm-tFcm-chi4
Method: ELECTRON MICROSCOPY / Resolution: 3.92 Å

Source
  • homo sapiens (human)
  • oncorhynchus mykiss (rainbow trout)
KeywordsIMMUNE SYSTEM / immunoglobulin M / fragment crystallization

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