9uo3

From Proteopedia

Cryo-EM structure of the human IgM-Fc hexamer

Structural highlights

9uo3 is a 12 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.17Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

IGHM_HUMAN Autosomal agammaglobulinemia. The disease is caused by mutations affecting the gene represented in this entry.^[1]

Function

IGHM_HUMAN IgM antibodies play an important role in primary defense mechanisms. They have been shown to be involved in early recognition of external invaders like bacteria and viruses, cellular waste and modified self, as well as in recognition and elimination of precancerous and cancerous lesions. The membrane-bound form is found in the majority of normal B-cells alongside with IgD. Membrane-bound IgM induces the phosphorylation of CD79A and CD79B by the Src family of protein tyrosine kinases. It may cause death of cells by apoptosis. It is also found in soluble form, which represents about 30% of the total serum immunoglobulins where it is found almost exclusively as a homopentamer. After the antigen binds to the B-cell receptor, the secreted form is secreted in large amounts.^[2]

Publication Abstract from PubMed

Polymeric immunoglobulins are essential components of the immune system in jawed vertebrates. While mammalian immunoglobulin M (IgM) typically forms a pentamer linked by the joining chain (J-chain), Xenopus laevis IgX can assemble into a J-chain-independent polymer. Here, we present the cryo-electron microscopy (cryo-EM) structure of IgX, revealing its hexameric configuration. By incorporating the IgX tailpiece into human IgM, we achieved efficient IgM hexamer formation. Truncating IgM's natural tailpiece to a range of 11 to 16 residues also substantially enhanced hexamerization efficiency. Furthermore, introducing a shortened IgM tailpiece to IgG resulted in effective IgG hexamer formation. We further show that the engineered IgM and IgG hexamers targeting CD20 demonstrated robust complement-dependent cytotoxicity (CDC) against several B lymphoma cells. In addition, the IgG-Fc hexamer functioned as a decoy, attenuating CDC in cell cultures. These findings deepen our understanding of polymeric immunoglobulin evolution and introduce innovative strategies for the development of IgM- and IgG-based biologics.

Xenopus IgX informs engineering strategies of IgM and IgG hexamers.,Zhang R, Ji C, Li S, Li N, Gao N, Xiao J Sci Adv. 2025 Nov 7;11(45):eaea3737. doi: 10.1126/sciadv.aea3737. Epub 2025 Nov , 5. PMID:41191733^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Yel L, Minegishi Y, Coustan-Smith E, Buckley RH, Trubel H, Pachman LM, Kitchingman GR, Campana D, Rohrer J, Conley ME. Mutations in the mu heavy-chain gene in patients with agammaglobulinemia. N Engl J Med. 1996 Nov 14;335(20):1486-93. PMID:8890099 doi:http://dx.doi.org/10.1056/NEJM199611143352003
↑ Tisch R, Roifman CM, Hozumi N. Functional differences between immunoglobulins M and D expressed on the surface of an immature B-cell line. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6914-8. PMID:3137579
↑ Zhang R, Ji C, Li S, Li N, Gao N, Xiao J. Xenopus IgX informs engineering strategies of IgM and IgG hexamers. Sci Adv. 2025 Nov 7;11(45):eaea3737. PMID:41191733 doi:10.1126/sciadv.aea3737