Restricted Motion of the Conserved Immunoglobulin G1 N-Glycan Is Essential for Efficient FcγRIIIa Binding
Open accessAbstract
Immunoglobulin G1 (IgG1)-based therapies are widespread, and many function through interactions with low-affinity Fc γ receptors (FcγR). N-glycosylation of the IgG1 Fc domain is required for FcγR binding, though it is unclear why. Structures of the FcγR:Fc complex fail to explain this because the FcγR polypeptide does not bind the N-glycan. Here we identify a link between motion of the N-glycan and Fc:FcγRIIIa affinity that explains the N-glycan requirement. Fc F241 and F243 mutations decreased the N-glycan/polypeptide interaction and increased N-glycan mobility. The affinity of the Fc mutants for FcγRIIIa was directly proportional to the degree of glycan restriction (R(2) = 0.82). The IgG1 Fc K246F mutation stabilized the N-glycan and enhanced affinity for FcγRIIIa. Allosteric modulation of a protein/protein interaction represents a previously undescribed role for N-glycans in biology. Conserved features suggesting a similar N-glycan/aromatic interaction were also found in IgD, IgE, and IgM, but not IgA.
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- Barb AW Prestegard JH 2011 NMR analysis demonstrates immunoglobulin G N-glycans are accessible and dynamic Nat Chem Biol 7 147 153 21258329 PMC3074608
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“location of the Asn-297–attached glycan within the Fc (21, 22).”
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“It is now evident that nucleocytoplasmic glycosylation functionally characterizes many proteins according to an allosteric mechanism [76].”
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- Authors
- Subedi, G. P., Hanson, Q. M., & Barb, A. W.
- Affiliations
- Iowa State University (US)
- Corresponding author
- Barb, Adam W.
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 22
- Issue
- 10
- Pages
- 1478-1488
- ISSN
- 0969-2126 (ISSN-L)
- PMC
- PMC4192013
- OpenAlex
- W2010670539
- Cited by
- 81
- References
- 52
- Citations by year
- 2026: 7 · 2025: 2 · 2024: 7 · 2023: 2 · 2022: 9 · 2021: 4 · 2020: 7 · 2019: 8 · 2018: 11 · 2017: 10 · 2016: 7 · 2015: 6 · 2014: 1
- FWCI
- 6.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Structure (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Roy J. Carver Charitable Trust
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- N-glycosylation, FcγRIIIa, glycan-protein interactions, allosteric modulation, protein-protein interaction, antibody isotypes
- MeSH terms
- Acetylglucosamine, Humans, Immunoglobulin D, Immunoglobulin E, Immunoglobulin G, Immunoglobulin M, Immunoglobulin Fc Fragments, Models, Molecular, Mutation, Magnetic Resonance Spectroscopy, Polysaccharides, Protein Binding, Protein Conformation, Receptors, IgG, Protein Folding
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