Abstract

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.

Details

Title
Conformational effects of N-glycan core fucosylation of immunoglobulin G Fc region on its interaction with Fcγ receptor IIIa
Author
Yoshitake Sakae 1 ; Satoh, Tadashi 2 ; Yagi, Hirokazu 2 ; Yanaka, Saeko 3 ; Yamaguchi, Takumi 4 ; Isoda, Yuya 5 ; Iida, Shigeru 5 ; Okamoto, Yuko 6 ; Kato, Koichi 3 

 Graduate School of Science, Nagoya University, Nagoya, Aichi, Japan 
 Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi, Japan 
 Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi, Japan; Institute for Molecular Science and Okazaki Institute for Integrative Biosciences, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki, Aichi, Japan 
 Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi, Japan; Institute for Molecular Science and Okazaki Institute for Integrative Biosciences, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki, Aichi, Japan; School of Materials Science, Japan Advanced Institute of Science and Technology, 1-1 Asahidai, Nomi, Ishikawa, Japan 
 Research Functions Unit, R&D Division, Kyowa Hakko Kirin Co., Ltd, 3-6-6 Asahi-machi, Machida-shi, Tokyo, Japan 
 Graduate School of Science, Nagoya University, Nagoya, Aichi, Japan; Information Technology Center, Nagoya University, Nagoya, Aichi, Japan; Structural Biology Research Center, Graduate School of Science, Nagoya University, Nagoya, Aichi, Japan; Center for Computational Science, Graduate School of Engineering, Nagoya University, Nagoya, Aichi, Japan; JST-CREST, Nagoya, Aichi, Japan 
Pages
1-10
Publication year
2017
Publication date
Oct 2017
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
1954386583
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.