Structural evolution of Fcα/μR-mediated antibody recognition

The Fc alpha-mu receptor (Fcα/μR) is an ancient Fc-receptor sharing common ancestry with the polymeric Ig receptor (pIgR) and binding polymeric IgM and IgA ligands. In several vertebrate lineages, including birds, Fcα/μR may serve as the sole IgM and IgA Fc receptor; yet its evolution and ligand-recognition mechanisms across vertebrates remain poorly understood. Here, we identify FCAMR expression in duck (Anas platyrhynchos, ap) lymphoid tissues and demonstrate that recombinantly expressed apFcα/μR ectodomain binds apIgM and apIgA ligands. apFcα/μR affinity was ~10-fold higher for apIgM versus apIgA and ~10-fold higher than mouse (mm) Fcα/μR. Cryo-EM structures of apFcα/μR in complex with pentameric apIgM (3.27 Å) and tetrameric apIgA (3.57 Å) showed three Ig-like domains (D1-D3) bound asymmetrically with 1:1 stoichiometry. Comparisons to avian pIgR, which contains four Ig-like domains (D1-D4), revealed overlapping contacts between apFcα/μR-D1 and pIgR-D1. apFcα/μR D2-D3 engaged sites similar to pIgR D3-D4, yet formed distinct contact networks. Parallel analysis of a mmFcα/μR–mmIgM structure (4.13 Å) revealed mmFcα/μR′s single Ig-domain bound analogous to apFcα/μR-D1 and to mammalian pIgR-D1, whereas downstream ectodomain regions were not observed. Collectively, the data elucidate PIGR-family mechanisms across vertebrates, providing a foundation for delineating common and divergent functions.