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Affimer proteins inhibit immune complex binding to Fc?RIIIa with high specificity through competitive and allosteric modes of action.

ABSTRACT: Protein-protein interactions are essential for the control of cellular functions and are critical for regulation of the immune system. One example is the binding of Fc regions of IgG to the Fc gamma receptors (Fc?Rs). High sequence identity (98%) between the genes encoding Fc?RIIIa (expressed on macrophages and natural killer cells) and Fc?RIIIb (expressed on neutrophils) has prevented the development of monospecific agents against these therapeutic targets. We now report the identification of Fc?RIIIa-specific artificial binding proteins called "Affimer" that block IgG binding and abrogate Fc?RIIIa-mediated downstream effector functions in macrophages, namely TNF release and phagocytosis. Cocrystal structures and molecular dynamics simulations have revealed the structural basis of this specificity for two Affimer proteins: One binds directly to the Fc binding site, whereas the other acts allosterically.

SUBMITTER: Robinson JI

PROVIDER: S-EPMC5776790 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Affimer proteins inhibit immune complex binding to FcγRIIIa with high specificity through competitive and allosteric modes of action.

Robinson James I JI Baxter Euan W EW Owen Robin L RL Thomsen Maren M Tomlinson Darren C DC Waterhouse Mark P MP Win Stephanie J SJ Nettleship Joanne E JE Tiede Christian C Foster Richard J RJ Owens Raymond J RJ Fishwick Colin W G CWG Harris Sarah A SA Goldman Adrian A McPherson Michael J MJ Morgan Ann W AW

Proceedings of the National Academy of Sciences of the United States of America 20171215 1

Protein-protein interactions are essential for the control of cellular functions and are critical for regulation of the immune system. One example is the binding of Fc regions of IgG to the Fc gamma receptors (FcγRs). High sequence identity (98%) between the genes encoding FcγRIIIa (expressed on macrophages and natural killer cells) and FcγRIIIb (expressed on neutrophils) has prevented the development of monospecific agents against these therapeutic targets. We now report the identification of F ...[more]

PMID: 29247053

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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.

Dataset Information

Affimer proteins inhibit immune complex binding to Fc?RIIIa with high specificity through competitive and allosteric modes of action.

Publications

Affimer proteins inhibit immune complex binding to FcγRIIIa with high specificity through competitive and allosteric modes of action.

Similar Datasets

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