Conformational effects of N-glycan core fucosylation of immunoglobulin G Fc region on its interaction with Fcγ receptor IIIa

• Published in: Scientific reports Vol. 7; no. 1; pp. 13780 - 10
• Main Authors: Sakae, Yoshitake, Satoh, Tadashi, Yagi, Hirokazu, Yanaka, Saeko, Yamaguchi, Takumi, Isoda, Yuya, Iida, Shigeru, Okamoto, Yuko, Kato, Koichi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.10.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/535/1266; 631/57/2266; Amino acids; Crystallography, X-Ray; Cytotoxicity; Fucose; Fucose - chemistry; Glycoproteins; Glycosylation; Humanities and Social Sciences; Humans; Immunoglobulin Fc Fragments - chemistry; Immunoglobulin Fc Fragments - metabolism; Immunoglobulin G; Immunoglobulin G - chemistry; Immunoglobulin G - metabolism; Immunoglobulins; Molecular Dynamics Simulation; multidisciplinary; N-glycans; Polysaccharides; Polysaccharides - chemistry; Protein Conformation; Receptors, IgG - chemistry; Receptors, IgG - metabolism; Science; Science (multidisciplinary)
• DOI: 10.1038/s41598-017-13845-8
• ISSN: 2045-2322

Antibody-dependent cellular cytotoxicity (ADCC) is promoted through interaction between the Fc region of immunoglobulin G1 (IgG1) and Fcγ receptor IIIa (FcγRIIIa), depending on N -glycosylation of these glycoproteins. In particular, core fucosylation of IgG1-Fc N -glycans negatively affects this interaction and thereby compromises ADCC activity. To address the mechanisms of this effect, we performed replica-exchange molecular dynamics simulations based on crystallographic analysis of a soluble form of FcγRIIIa (sFcγRIIIa) in complex with IgG1-Fc. Our simulation highlights increased conformational fluctuation of the N -glycan at Asn162 of sFcγRIIIa upon fucosylation of IgG1-Fc, consistent with crystallographic data giving no interpretable electron density for this N -glycan, except for the innermost part. The fucose residue disrupts optimum intermolecular carbohydrate-carbohydrate interactions, rendering this sFcγRIIIa glycan distal from the Fc glycan. Moreover, our simulation demonstrates that core fucosylation of IgG1-Fc affects conformational dynamics and rearrangements of surrounding amino acid residues, typified by Tyr296 of IgG1-Fc, which was more extensively involved in the interaction with sFcγRIIIa without Fc core fucosylation. Our findings offer a structural foundation for designing and developing therapeutic antibodies with improved ADCC activity.