Fc gamma RI FG-loop functions as a pH sensitive switch for IgG binding and release

Understanding the molecular mechanism underlying the hierarchic binding between Fc gamma Rs and IgG antibodies is critical for therapeutic antibody engineering and Fc gamma R functions. The recent determination of crystal structures of Fc gamma RI-Fc complexes, however, resulted in two controversial mechanisms for the high affinity receptor binding to IgG. Here, we describe high resolution structures of a bovine FG-loop variant of Fc gamma RI in complex with the Fc fragment of IgG(1) crystallized in three different conditions at neutral pH, confirming the characteristic FG loop-Fc interaction is critical to the high affinity immunoglobulin binding. We showed that the Fc gamma RI D2-domain FG-loop functioned as a pH-sensing switch for IgG binding. Further live cell imaging of Fc gamma RI-mediated internalization of immune complexes showed a pH sensitive temporal-spatial antibody-antigen uptake and release. Taken together, we demonstrate that the structures of Fc gamma RI-Fc crystallized at neutral and acidic pH, respectively, represent the high and low affinity binding states of the receptor for IgG uptake and release. These results support a role for Fc gamma RI in antigen delivery, highlight the importance of Fc glycan in antibody binding to the high affinity receptor and provide new insights to future antibody engineering.