Crystal Structure of Fcγ Receptor I and Its Implication in High Affinity γ-Immunoglobulin Binding

Lu, Jinghua; Ellsworth, Jeff L.; Hamacher, Nels; Oak, Si Won; Sun, Peter D.

doi:10.1074/jbc.m111.257550

Cited by 82 publications

(123 citation statements)

References 44 publications

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“…The importance of the FG loop to high-affinity receptor-IgG binding was demonstrated in previous mutational work (26). Placement of the FG loop of FcγRI into FcγRIII resulted in a 15-fold increase in IgG binding affinity, and the mutant FcγRIII bound to IgG only fivefold weaker than FcγRI.…”

Section: Significancementioning

confidence: 95%

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

Chu

Zou

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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 IgG 1 . FcγRI binds to the Fc in a similar mode as the low-affinity FcγRII and FcγRIII receptors. In addition to many conserved contacts, FcγRI 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 FcγRI 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 loopglycan interaction resulted in an ∼20-to 30-fold decrease in FcγRI affinity to all three subclasses of IgGs. Furthermore, deglycosylation of IgG 1 resulted in a 40-fold loss in FcγRI binding, demonstrating involvement of the receptor FG loop in glycan recognition. These results highlight a unique glycan recognition in FcγRI function and open potential therapeutic avenues based on antibody glycan engineering or small molecular glycan mimics to target FcγRI for certain autoimmune diseases.CD64 | FcgRI | IgG recognition | crystal structure | glycan recognition I gGs and pentraxins are circulating immune components that directly recognize pathogens. On formation of immune complexes or opsonization, they activate cellular response through Fc receptors (FcRs) (1, 2). The FcRs for IgGs include FcγRI (CD64); FcγRII (CD32) with A, B, and C isoforms; and FcγRIII (CD16) with two isoforms (3). Most of these are activating receptors either containing an intracellular immunoreceptor tyrosine-based activation motif or associated with an FcR common γ chain (4). FcγRIIB is an inhibitory receptor that contains an intracellular immunoreceptor tyrosine-based inhibitory motif. FcγRIIIB does not have a cytosolic domain and is anchored to the plasma membrane through glycosylphosphatidylinositol linkage. The binding affinity to IgG ranges from 10 −8 M for FcγRI to 10 −5-10 −7 M for FcγRII and III (3).FcγRI plays an important role in the protection against bacterial infections, but also exacerbates certain autoimmune diseases (5). Owing to its high-affinity antibody binding, FcγRI is important in antibody therapy as well (6, 7). To date, the structure of the ligand-bound high-affinity receptor has not been determined, however. Consequently, the mechanism of its highaffinity antibody recognition remains to be elucidated. The role of glycan in antibody function has been a subject of intense study. Differential glycosylation of Fc, notably fucosylated Fc, is...

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Section: Significancementioning

confidence: 95%

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

Chu

Zou

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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173

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“…Structural studies of the interaction of the human IgG1 Ab Fc region with its various cellular receptors [FcgRI (27,28), FcgRIIa (29,30), FcgRIIb (31), and FcgRIIIa (32,33)], in combination with biosensor studies, defined the atomic basis of the 1:1 interactions of single FcR ectodomains with an IgG1-Fc (34,35). However, the physiological interaction of IgG immune complexes (ICs) and FcgR requires avid binding of the complex through the display of multiple Fc regions of "near-neighbor" IgGs to engage and cluster multiple FcgRs on the cell surface (36).…”

mentioning

confidence: 99%

Dimeric FcγR Ectodomains as Probes of the Fc Receptor Function of Anti-Influenza Virus IgG

Wines

Vanderven

Esparon

et al. 2016

The Journal of Immunology

130

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Ab-dependent cellular cytotoxicity, phagocytosis, and Ag presentation are key mechanisms of action of Abs arising in vaccine or naturally acquired immunity, as well of therapeutic mAbs. Cells expressing the low-affinity FcγRs (FcγRII or CD32 and FcγRIII or CD16) are activated for these functions when receptors are aggregated following the binding of IgG-opsonized targets. Despite the diversity of the Fc receptor proteins, IgG ligands, and potential responding cell types, the induction of all FcγR-mediated responses by opsonized targets requires the presentation of multiple Fc regions in close proximity to each other. We demonstrated that such “near-neighbor” Fc regions can be detected using defined recombinant soluble (rs) dimeric low-affinity ectodomains (rsFcγR) that have an absolute binding requirement for the simultaneous engagement of two IgG Fc regions. Like cell surface–expressed FcγRs, the binding of dimeric rsFcγR ectodomains to Ab immune complexes was affected by Ab subclass, presentation, opsonization density, Fc fucosylation, or mutation. The activation of an NK cell line and primary NK cells by human IgG-opsonized influenza A hemagglutinin correlated with dimeric rsFcγRIIIa binding activity but not with Ab titer. Furthermore, the dimeric rsFcγR binding assay sensitively detected greater Fc receptor activity to pandemic H1N1 hemagglutinin after the swine influenza pandemic of 2009 in pooled human polyclonal IgG. Thus these dimeric rsFcγR ectodomains are validated, defined probes that should prove valuable in measuring the immune-activating capacity of IgG Abs elicited by infection or vaccination or experimentally derived IgG and its variants.

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“…The crystal structure of the N-terminal region of Fc␥RIa was reported recently (22). We note that the NG sites 1, 2, and 3 are upstream of the Fc-binding region, whereas the other NG sites were downstream of it (Fig.…”

Section: Mutation Of Fc-binding Region In Fc␥ria Did Not Affect the Ementioning

confidence: 99%

“…Next, we examined the crystal structure of Fc␥RIa (PDB code 3RJD) (22). The interaction between the D1 and D2 fragments in the crystal is well defined; however, the D3 fragment is interacting with a nearby image of the protein in the crystal packing as visualized in the crystal supercell.…”

Section: Methodsmentioning

confidence: 99%

The Interaction of N-Glycans in Fcγ Receptor I α-Chain with Escherichia coli K1 Outer Membrane Protein A for Entry into Macrophages

Krishnan

Liu

Abrol

et al. 2014

Journal of Biological Chemistry

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Background: Escherichia coli OmpA interacts with Fc␥RI ␣-chain (Fc␥RIa) to invade macrophages. Results: Lack of three N-glycans in Fc␥RIa prevents E. coli invasion of macrophages and the onset of meningitis. Conclusion: OmpA binding to Fc␥RIa via N-glycans is crucial in the pathogenesis of E. coli meningitis. Significance: Targeting OmpA and Fc␥RIa interface may be a therapy for E. coli-induced meningitis.

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Crystal Structure of Fcγ Receptor I and Its Implication in High Affinity γ-Immunoglobulin Binding

Cited by 82 publications

References 44 publications

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

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

Dimeric FcγR Ectodomains as Probes of the Fc Receptor Function of Anti-Influenza Virus IgG

The Interaction of N-Glycans in Fcγ Receptor I α-Chain with Escherichia coli K1 Outer Membrane Protein A for Entry into Macrophages

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