Glycans influence IgE and IgG recognition by rodent IgG-Fc receptors.

Immunoglobulin E (IgE) drives allergic responses. The IgE-Fc (Fcε) receptor FcεRI plays a critical role in transducing IgE signaling; nevertheless, certain IgG-Fc (Fcγ) receptor (FcγR) can also bind IgE in murine models. Here, we characterize FcγR interactions with IgE and IgG in mice and rats, and report cryoelectron microscopy structures of rat FcγRIV-Fcε, mouse FcγRIV-Fcγ2b, and rat FcγRIIB-Fcε complexes. Together with biochemical analyses, we reveal N-linked glycans as critical determinants of affinity and isotype specificity. Specifically, rat FcγRIV exhibits preferential binding to IgE over IgG, while mouse FcγRIV shows the opposite preference. A unique glycan-glycan interaction involving Asn179 in rat FcγRIV underlies its high-affinity IgE binding, whereas the absence of this glycosylation site in rat FcγRIIB results in attenuated IgE recognition. In contrast, only hypoglycosylated mouse FcγRIV at the equivalent position engages strongly with fucosylated IgG2b. Together, these results provide insights into species-specific IgE- and IgG-mediated immune responses.