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Structural characterization of GASDALIE Fc bound to the activating Fc receptor Fc?RIIIa.

ABSTRACT: The Fc region of Immunoglobulin G (IgG) initiates inflammatory responses such as antibody-dependent cell-mediated cytotoxicity (ADCC) through binding to activating Fc receptors (Fc?RI, Fc?RIIa, Fc?RIIIa). These receptors are expressed on the surface of immune cells including macrophages, dendritic cells, and natural killer cells. An inhibitory receptor, Fc?RIIb, is expressed on macrophages and other myeloid leukocytes simultaneously with the activating receptor Fc?RIIa, thereby setting a threshold for cell activation. The affinity of IgG Fc for binding activating Fc receptors depends on IgG subclass and the composition of N-linked glycans attached to a conserved asparagine in the Fc CH2 domain. For example, Fc regions with afucosylated glycans bind more tightly to Fc?RIIIa than fucosylated Fc, and afucosylated Fcs exhibit enhanced ADCC activity in vivo and in vitro. Enhanced pro-inflammatory responses have also been seen for Fc regions with amino acid substitutions. GASDALIE Fc is an Fc mutant (G236A/S239D/A330L/I332E) that exhibits a higher affinity for Fc?RIIIa and increased effector functions in vivo compared to wild-type Fc. To explore its altered functions, we compared the affinities of GASDALIE and wild-type Fc for activating and inhibitory Fc?Rs. We also determined the crystal structure of GASDALIE Fc alone and bound to Fc?RIIIa. The overall structure of GASDALIE Fc alone was similar to wild-type Fc structures, however, increased electrostatic interactions in the GASDALIE Fc:Fc?RIIIa interface compared with other Fc:Fc?R structures suggest a mechanism for the increased affinity of GASDALIE Fc for Fc?RIIIa.

SUBMITTER: Ahmed AA

PROVIDER: S-EPMC4769027 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Structural characterization of GASDALIE Fc bound to the activating Fc receptor FcγRIIIa.

Ahmed Alysia A AA Keremane Sravya R SR Vielmetter Jost J Bjorkman Pamela J PJ

Journal of structural biology 20160202 1

The Fc region of Immunoglobulin G (IgG) initiates inflammatory responses such as antibody-dependent cell-mediated cytotoxicity (ADCC) through binding to activating Fc receptors (FcγRI, FcγRIIa, FcγRIIIa). These receptors are expressed on the surface of immune cells including macrophages, dendritic cells, and natural killer cells. An inhibitory receptor, FcγRIIb, is expressed on macrophages and other myeloid leukocytes simultaneously with the activating receptor FcγRIIa, thereby setting a thresho ...[more]

PMID: 26850169

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Dataset Information

Structural characterization of GASDALIE Fc bound to the activating Fc receptor Fc?RIIIa.

Publications

Structural characterization of GASDALIE Fc bound to the activating Fc receptor FcγRIIIa.

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