Structural and evolutionary insights into FcαμR recognition of polymeric immunoglobulins

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