7ytd
Cryo-EM structure of four human FcmR bound to IgM-Fc/J
Structural highlights
FunctionFCMR_HUMAN High-affinity Fc receptor for immunoglobulin M (IgM), both secreted and membrane-bound IgM (PubMed:19858324, PubMed:22675200, PubMed:36949194, PubMed:37095205). Primarily regulates IgM transport and homeostasis. In lymphoid cells, enables exocytosis of membrane-bound IgM on the plasma membrane as well as endocytosis of IgM-antigen complexes toward lysosomes for degradation. In mucosal epithelium, mediates retrotranscytosis of antigen-IgM complexes across mucosal M cells toward antigen-presenting cells in mucosal lymphoid tissues (PubMed:21908732, PubMed:28230186). Triggers costimulatory signaling and mediates most of IgM effector functions involved in B cell development and primary immune response to infection. Likely limits tonic IgM BCR signaling to self-antigens for proper negative selection of autoreactive B cells in the bone marrow and for the maintenance of regulatory B cell pool in peripheral lymphoid organs. Mediates antibody responses to T cell-dependent and T cell-independent antigens and promotes induction of an efficient neutralizing IgG response. Engages in cross-talk with antigen-receptor signaling via the non-canonical NF-kappa-B, MAP kinases and calcium signaling pathways (PubMed:19858324, PubMed:22675200, PubMed:25601920, PubMed:30840890).[1] [2] [3] [4] [5] [6] [7] [8] Publication Abstract from PubMedImmunoglobulin M (IgM) is the first antibody to emerge during embryonic development and the humoral immune response(1). IgM can exist in several distinct forms, including monomeric, membrane-bound IgM within the B cell receptor (BCR) complex, pentameric and hexameric IgM in serum and secretory IgM on the mucosal surface. FcmuR, the only IgM-specific receptor in mammals, recognizes different forms of IgM to regulate diverse immune responses(2-5). However, the underlying molecular mechanisms remain unknown. Here we delineate the structural basis of the FcmuR-IgM interaction by crystallography and cryo-electron microscopy. We show that two FcmuR molecules interact with a Fcmu-Cmu4 dimer, suggesting that FcmuR can bind to membrane-bound IgM with a 2:1 stoichiometry. Further analyses reveal that FcmuR-binding sites are accessible in the context of IgM BCR. By contrast, pentameric IgM can recruit four FcmuR molecules to bind on the same side and thereby facilitate the formation of an FcmuR oligomer. One of these FcmuR molecules occupies the binding site of the secretory component. Nevertheless, four FcmuR molecules bind to the other side of secretory component-containing secretory IgM, consistent with the function of FcmuR in the retrotransport of secretory IgM. These results reveal intricate mechanisms of IgM perception by FcmuR. Immunoglobulin M perception by FcmuR.,Li Y, Shen H, Zhang R, Ji C, Wang Y, Su C, Xiao J Nature. 2023 Mar;615(7954):907-912. doi: 10.1038/s41586-023-05835-w. Epub 2023 , Mar 22. PMID:36949194[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
