Immunoglobulin M (IgM) is a crucial player in the early phases of our immune response and happens to be one of five immunoglobulins found in our bodies. Its functions vary considerably, as it takes the shape of an in-membrane IgM monomer within B-cell receptor (BCR) complexes, converts into IgM pentamers and hexamers released into our serum, and operates as secretory IgM on our mucosal surfaces, combining a secretory component. Insightful research by the State Key Laboratory for Protein and Plant Gene Research at the Peking University School of Life Sciences shed light on how IgM pentamer is assembled and transferred within the mucosal layers. Intriguingly, the studies showed that IgM forms pentamers in a non-uniform model. It also revealed the structural foundation of the assembly process, facilitated by the J chain, and its interaction with the mucosal transport receptor pIgR.
The Significance of FcμR in IgM Recognition
Fc receptors, on the other hand, are pivotal receptors in the human immune system, recognized by their unique ability to bind to the Fc region of immunoglobulins. FcμR, also known as Toso or Faim3, is the only receptor specific to IgM in mammals and is mainly found on the surfaces of B cells and other immune cells. This receptor can bind to different forms of IgM, thereby playing a significant role in B-cell development, homeostatic regulation of the immune system, antigen presentation, and the disease process, as manifested by the high expression of FcμR on the surface of B cells in patients with chronic lymphocytic leukemia. While the importance of FcμR cannot be undermined, the molecular mechanism by which it functions remained unclear until March 23, 2023, when significant findings were published in the journal Nature, elucidating the molecular mechanism for FcμR's recognition of different forms of IgM. Due to high glycosylation, the extracellular domain of FcμR consists of an immunoglobulin-like structure (D1 structure domain) and a highly disordered inner region (Stalk region). To understand the mechanism by which FcμR recognizes IgM, a composite of recombinant FcμR-D1 structure domain and the IgM-Cμ4 structure domain was assembled. This structure suggested that two FcμR-D1s bind to each side of an IgM-Cμ4 dimer.
Fig 1. Crystal structure of the FcμR-D1:Fcμ-Cμ4 complex.1
Unveiling the Molecular Mechanism of IgM Perception by FcμR
Further studies using cryo-electron microscopy clarified the structure of the IgM pentamer core and the FcμR extracellular domain complexes, suggesting a 4:1 binding ratio on the same side of the IgM pentamer. This asymmetry could play a role in initiating downstream signals by inducing the formation of FcμR tetramers. Notably, among the four FcμR binding sites, the high-affinity R1 site coincided with the binding site of the D1 structure domain of IgM components secreted. Observations suggested that FcμR could bind to the reverse side of secretory IgM in the presence of its secretory component. An intricate analysis revealed that the J chain induces asymmetry in different ways on either side of the IgM plane. However, regardless of the side, a maximum of four FcμR molecules can bind to the IgM pentamer. The functional correlations of these findings were reinforced using FcμR mutants, protein interaction tests, confocal fluorescence microscopy, and flow cytometry. This extensive research successfully demystified the intricate molecular mechanism of how FcμR specifically perceives different forms of IgM, thereby laying a solid foundation for grasping the biological function of IgM in depth.
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Reference
- Li, Yaxin, et al. "Immunoglobulin M perception by FcμR." Nature 615.7954 (2023): 907-912.
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