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Publication Abstract from PubMed

Understanding the molecular mechanism underlying the hierarchic binding between FcgammaRs and IgG antibodies is critical for therapeutic antibody engineering and FcgammaR functions. The recent determination of crystal structures of FcgammaRI-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 FcgammaRI 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 FcgammaRI D2-domain FG-loop functioned as a pH-sensing switch for IgG binding. Further live cell imaging of FcgammaRI-mediated internalization of immune complexes showed a pH sensitive temporal-spatial antibody-antigen uptake and release. Taken together, we demonstrate that the structures of FcgammaRI-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 FcgammaRI 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.

FcgammaRI FG-loop functions as a pH sensitive switch for IgG binding and release.,Lu J, Spencer M, Zou Z, Traver M, Brzostowski J, Sun PD Front Immunol. 2023 Feb 6;14:1100499. doi: 10.3389/fimmu.2023.1100499. , eCollection 2023. PMID:36814926^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.