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Structure of Fc?RI in complex with Fc reveals the importance of glycan recognition for high-affinity IgG binding.

ABSTRACT: Fc gamma receptor I (Fc?RI) contributes to protective immunity against bacterial infections, but exacerbates certain autoimmune diseases. The sole high-affinity IgG receptor, Fc?RI plays a significant role in immunotherapy. To elucidate the molecular mechanism of its high-affinity IgG binding, we determined the crystal structure of the extracellular domains of human Fc?RI in complex with the Fc domain of human IgG1. Fc?RI binds to the Fc in a similar mode as the low-affinity Fc?RII and Fc?RIII receptors. In addition to many conserved contacts, Fc?RI forms additional hydrogen bonds and salt bridges with the lower hinge region of Fc. Unique to the high-affinity receptor-Fc complex, however, is the conformation of the receptor D2 domain FG loop, which enables a charged KHR motif to interact with proximal carbohydrate units of the Fc glycans. Both the length and the charge of the Fc?RI FG loop are well conserved among mammalian species. Ala and Glu mutations of the FG loop KHR residues showed significant contributions of His-174 and Arg-175 to antibody binding, and the loss of the FG loop-glycan interaction resulted in an ? 20- to 30-fold decrease in Fc?RI affinity to all three subclasses of IgGs. Furthermore, deglycosylation of IgG1 resulted in a 40-fold loss in Fc?RI binding, demonstrating involvement of the receptor FG loop in glycan recognition. These results highlight a unique glycan recognition in Fc?RI function and open potential therapeutic avenues based on antibody glycan engineering or small molecular glycan mimics to target Fc?RI for certain autoimmune diseases.

SUBMITTER: Lu J

PROVIDER: S-EPMC4311811 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Structure of FcγRI in complex with Fc reveals the importance of glycan recognition for high-affinity IgG binding.

Lu Jinghua J Chu Jonathan J Zou Zhongcheng Z Hamacher Nels B NB Rixon Mark W MW Sun Peter D PD

Proceedings of the National Academy of Sciences of the United States of America 20150105 3

Fc gamma receptor I (FcγRI) contributes to protective immunity against bacterial infections, but exacerbates certain autoimmune diseases. The sole high-affinity IgG receptor, FcγRI plays a significant role in immunotherapy. To elucidate the molecular mechanism of its high-affinity IgG binding, we determined the crystal structure of the extracellular domains of human FcγRI in complex with the Fc domain of human IgG1. FcγRI binds to the Fc in a similar mode as the low-affinity FcγRII and FcγRIII r ...[more]

PMID: 25561553

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Project description:The neonatal Fc receptor (FcRn) is a key membrane protein that plays an integral role in serum immunoglobulin (IgG) recycling, which extends the half-life of antibody. In addition, FcRn is known to traffic antigen-bound immunoglobulins (Ag-IgGs), and to interact with immune complexes to facilitate the antigen cross-presentation of peptides derived from the immune complexes in antigen-presenting cells (APCs). Studies on the IgG-FcRn molecular interactions have primarily focused on the Fc region, and only recently have shown the potential impact of the antigen-binding fragment physiochemical properties on FcRn binding. However, the effect of the antigen physiochemical properties on IgG structure as it relates to Ag-IgG-FcRn binding is not well understood. Here we used an IgG-peptide antigen complex as a model system to investigate the structural effects of the antigen's physiochemical properties on the IgG structure, and the subsequent effects of Ag-IgG-FcRn interactions. We used hydroxyl radical footprinting-mass spectrometry to investigate the structural impact on an IgG upon antigen binding, and observed that the physicochemical properties of the antigen differentially induce conformational changes in the IgG FcRn binding region. The extent of these structural changes directly correlates to the magnitude of the affinity differences between the Ag-IgG complexes and FcRn. Moreover, the antigen's physicochemical properties differentially induce structural differences within the Ag-IgG-FcRn ternary complex. We also provide electron microscopy data that shows corroborating Fab-FcRn interactions, and confirms the hypothesis of potential 2:1 FcRn:IgG binding stoichiometry. These data demonstrate antigen-induced Fc structural rearrangements affect both the affinity toward FcRn and the trimeric antigen-IgG-FcRn complex, providing novel molecular insights in the first steps toward understanding interactions of FcRn-containing large(r)-sized immune complex.

Dataset Information

Structure of Fc?RI in complex with Fc reveals the importance of glycan recognition for high-affinity IgG binding.

Publications

Structure of FcγRI in complex with Fc reveals the importance of glycan recognition for high-affinity IgG binding.

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