Dataset Information

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

ABSTRACT: Antibody-dependent cellular cytotoxicity (ADCC) is promoted through interaction between the Fc region of immunoglobulin G1 (IgG1) and Fc? receptor IIIa (Fc?RIIIa), 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 Fc?RIIIa (sFc?RIIIa) in complex with IgG1-Fc. Our simulation highlights increased conformational fluctuation of the N-glycan at Asn162 of sFc?RIIIa 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 sFc?RIIIa 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 sFc?RIIIa without Fc core fucosylation. Our findings offer a structural foundation for designing and developing therapeutic antibodies with improved ADCC activity.

SUBMITTER: Sakae Y

PROVIDER: S-EPMC5653758 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Sakae Yoshitake Y Satoh Tadashi T Yagi Hirokazu H Yanaka Saeko S Yamaguchi Takumi T Isoda Yuya Y Iida Shigeru S Okamoto Yuko Y Kato Koichi K

Scientific reports 20171023 1

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 for ...[more]

PMID: 29062024

Similar Datasets

Project description:Glycosylation of the immunoglobulin G (IgG)-Fc tail is required for binding to Fc-gamma receptors (Fc?Rs) and complement-component C1q. A variety of IgG1-glycoforms is detected in human sera. Several groups have found global or antigen-specific skewing of IgG glycosylation, for example in autoimmune diseases, viral infections, and alloimmune reactions. The IgG glycoprofiles seem to correlate with disease outcome. Additionally, IgG-glycan composition contributes significantly to Ig-based therapies, as for example IVIg in autoimmune diseases and therapeutic antibodies for cancer treatment. The effect of the different glycan modifications, especially of fucosylation, has been studied before. However, the contribution of the 20 individual IgG glycoforms, in which the combined effect of all 4 modifications, to the IgG function has never been investigated. Here, we combined six glyco-engineering methods to generate all 20 major human IgG1-glycoforms and screened their functional capacity for Fc?R and complement activity. Bisection had no effect on Fc?R or C1q-binding, and sialylation had no- or little effect on Fc?R binding. We confirmed that hypo-fucosylation of IgG1 increased binding to Fc?RIIIa and Fc?RIIIb by ~17-fold, but in addition we showed that this effect could be further increased to ~40-fold for Fc?RIIIa upon simultaneous hypo-fucosylation and hyper-galactosylation, resulting in enhanced NK cell-mediated antibody-dependent cellular cytotoxicity. Moreover, elevated galactosylation and sialylation significantly increased (independent of fucosylation) C1q-binding, downstream complement deposition, and cytotoxicity. In conclusion, fucosylation and galactosylation are primary mediators of functional changes in IgG for Fc?R- and complement-mediated effector functions, respectively, with galactose having an auxiliary role for Fc?RIII-mediated functions. This knowledge could be used not only for glycan profiling of clinically important (antigen-specific) IgG but also to optimize therapeutic antibody applications.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure