Structural and evolutionary insights into FcαμR recognition of polymeric immunoglobulins

Polymeric immunoglobulins (pIgs) are central to adaptive immunity in jawed vertebrates. FcR is a bispecific pIg receptor that recognizes both IgM and IgA, but the molecular basis has been unclear. Here we determine cryo-EM structures of mammalian FcR bound to IgM or IgA and show that FcR engages each ligand in a 1:1 stoichiometry, with higher affinity for IgM. The FcR-binding site overlaps with those of pIgR, and also with the preferred FcR-binding site on IgM, yet distinct features distinguish FcR from both pIgR and FcR. Functionally, FcR efficiently internalizes both IgM and IgA through a pathway independent of the di-leucine motif. Structures of amphibian pIgR and FcR bound to IgM further shed light on the evolutionary diversification of the FcR/pIgR family. Together, these findings define the structural basis of FcR-mediated pIg recognition and provide a framework for understanding the evolution of pIg receptors.