Structural basis for Fc receptor recognition of immunoglobulin M

Immunoglobulin Fc receptors are cell surface transmembrane proteins that bind to the Fc constant region of antibodies and play critical roles in regulating immune responses by activation of immune cells, clearance of immune complexes, and regulation of antibody production. FcμR is the IgM antibody isotype-specific Fc receptor involved in the survival and activation of B cells. Here we reveal eight binding sites for the human FcμR immunoglobulin (Ig) domain on the IgM pentamer by cryo-EM. One of the sites overlaps with the binding site for the transcytosis receptor pIgR, but a different mode of FcμR binding explains its antibody isotype specificity. Variation in FcμR binding sites and their occupancy reflects the asymmetry of the IgM pentameric core and the versatility of FcμR binding. The complex explains engagement with polymeric serum IgM and the monomeric IgM B cell receptor.