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Glycine 236 in the Lower Hinge Region of Human IgG1 Differentiates FcγR from Complement Effector Function.

˜The œjournal of immunology/˜The œJournal of immunology(2020)

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摘要
Abs of the IgG isotype mediate effector functions like Ab-dependent cellular cytotoxicity and Ab-dependent cellular phagocytosis by Fc interactions with Fc gamma Rs and complement-dependent cytotoxicity upon IgG-Fc binding to C1q. In this study, we describe the crucial role of the highly conserved dual glycines at position 236-237 in the lower hinge region of human IgG, including the lack of one glycine as found in IgG2. We found several permutations in this region that either silence or largely abrogate Fc gamma R binding and downstream Fc gamma R effector functions, as demonstrated by surface plasmon resonance, Ab-dependent cellular phagocytosis, and Ab-dependent cellular cytotoxicity assays. Although the binding regions of Fc gamma Rs and C1q on the IgG-Fc largely overlap, IgG1 with a deletion of G236 only silences Fc gamma R-mediated effector functions without affecting C1q-binding or activation. Several mutations resulted in only residual Fc gamma RI binding with differing affinities that are either complement competent or silenced. Interestingly, we also found that IgG2, naturally only binding Fc gamma RIIa, gains binding to Fc gamma RI and Fc gamma RIIIa after insertion of G236, highlighting the crucial importance of G236 in IgG for Fc gamma R interaction. These mutants may become invaluable tools for Fc gamma R-related research as well as for therapeutic purposes in which only complement-mediated functions are required without the involvement of Fc gamma R.
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