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Restricted motion of the conserved immunoglobulin G1 N-glycan is essential for efficient Fc?RIIIa binding.

ABSTRACT: Immunoglobulin G1 (IgG1)-based therapies are widespread, and many function through interactions with low-affinity Fc ? receptors (Fc?R). N-glycosylation of the IgG1 Fc domain is required for Fc?R binding, though it is unclear why. Structures of the Fc?R:Fc complex fail to explain this because the Fc?R polypeptide does not bind the N-glycan. Here we identify a link between motion of the N-glycan and Fc:Fc?RIIIa affinity that explains the N-glycan requirement. Fc F241 and F243 mutations decreased the N-glycan/polypeptide interaction and increased N-glycan mobility. The affinity of the Fc mutants for Fc?RIIIa was directly proportional to the degree of glycan restriction (R(2) = 0.82). The IgG1 Fc K246F mutation stabilized the N-glycan and enhanced affinity for Fc?RIIIa. Allosteric modulation of a protein/protein interaction represents a previously undescribed role for N-glycans in biology. Conserved features suggesting a similar N-glycan/aromatic interaction were also found in IgD, IgE, and IgM, but not IgA.

SUBMITTER: Subedi GP

PROVIDER: S-EPMC4192013 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Restricted motion of the conserved immunoglobulin G1 N-glycan is essential for efficient FcγRIIIa binding.

Subedi Ganesh P GP Hanson Quinlin M QM Barb Adam W AW

Structure (London, England : 1993) 20140904 10

Immunoglobulin G1 (IgG1)-based therapies are widespread, and many function through interactions with low-affinity Fc γ receptors (FcγR). N-glycosylation of the IgG1 Fc domain is required for FcγR binding, though it is unclear why. Structures of the FcγR:Fc complex fail to explain this because the FcγR polypeptide does not bind the N-glycan. Here we identify a link between motion of the N-glycan and Fc:FcγRIIIa affinity that explains the N-glycan requirement. Fc F241 and F243 mutations decreased ...[more]

PMID: 25199692

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Project description:Chronic HIV-infection modulates the expression of Fc gamma receptors (Fc?Rs) on immune cells and their antibody-dependent effector function capability. Given the increasingly recognized importance of antibody-dependent cellular cytotoxicity (ADCC) in HIV-specific immunity, we investigated the cellular distribution of Fc?RIIIa on cytotoxic lymphocytes-natural killer cells and CD8+ T cells-and the effect of the Fc?RIIIa-F158V variant on ADCC capacity in HIV-infected individuals (n = 23) and healthy controls (n = 23). Study participants were matched for F158V genotypes, carried two copies of the FCGR3A gene and were negative for Fc?RIIb expression on NK cells. The distribution of CD56dimFc?RIIIabright and CD56negFc?RIIIabright NK cell subsets, but not Fc?RIIIa surface expression, differed significantly between HIV-1 negative and HIV-1 positive donors. NK cell-mediated ADCC responses negatively correlated with the proportion of the immunoregulatory CD56brightFc?RIIIadim/neg cells and were lower in the HIV-1 positive group. Intriguingly, the Fc?RIIIa-F158V variant differentially affected the NK-mediated ADCC responses for HIV-1 negative and HIV-1 positive donors. Healthy donors bearing at least one 158V allele had higher ADCC responses compared to those homozygous for the 158F allele (48.1 vs. 34.1%), whereas the opposite was observed for the HIV-infected group (26.4 vs. 34.6%), although not statistically significantly different. Furthermore, Fc?RIIIa+CD8bright and Fc?RIIIa+CD8dim T cell subsets were observed in both HIV-1 negative and HIV-1 positive donors, with median proportions that were significantly higher in HIV-1 positive donors compared to healthy controls (15.7 vs. 8.3%; P = 0.016 and 18.2 vs. 14.1%; P = 0.038, respectively). Using an HIV-1-specific GranToxiLux assay, we demonstrate that CD8+ T cells mediate ADCC through the delivery of granzyme B, which was overall lower compared to that of autologous NK cells. In conclusion, our findings demonstrate that in the presence of an HIV-1 infection, the cellular distribution of Fc?RIIIa is altered and that the functional consequence of Fc?RIIIa variant is affected. Importantly, it underscores the need to characterize Fc?R expression, cellular distribution and functional consequences of Fc?R genetic variants within a specific environment or disease state.

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Restricted motion of the conserved immunoglobulin G1 N-glycan is essential for efficient Fc?RIIIa binding.

Publications

Restricted motion of the conserved immunoglobulin G1 N-glycan is essential for efficient FcγRIIIa binding.

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