Structural evolution of Fcα/μR-mediated antibody recognition

Abstract

The Fc alpha-mu receptor (Fc/R) 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, Fc/R 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 apFc/R ectodomain binds apIgM and apIgA ligands. apFc/R affinity was ~10-fold higher for apIgM versus apIgA and ~10-fold higher than mouse (mm) Fc/R. Cryo-EM structures of apFc/R in complex with pentameric apIgM (3.27 [A]) and tetrameric apIgA (3.57 [A]) 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 apFc/R-D1 and pIgR-D1. apFc/R D2-D3 engaged sites similar to pIgR D3-D4, yet formed distinct contact networks. Parallel analysis of a mmFc/R-mmIgM structure (4.13 [A]) revealed mmFc/R's single Ig-domain bound analogous to apFc/R-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.