Structural Insights into Neonatal Fc Receptor-based Recycling Mechanisms
Open accessAbstract
We report the three-dimensional structure of human neonatal Fc receptor (FcRn) bound concurrently to its two known ligands. More particularly, we solved the crystal structure of the complex between human FcRn, wild-type human serum albumin (HSA), and a human Fc engineered for improved pharmacokinetics properties (Fc-YTE). The crystal structure of human FcRn bound to wild-type HSA alone is also presented. HSA domain III exhibits an extensive interface of contact with FcRn, whereas domain I plays a lesser role. A molecular explanation for the HSA recycling mechanism is provided with the identification of FcRn His(161) as the only potential direct contributor to the corresponding pH-dependent process. At last, this study also allows an accurate structural definition of residues considered for decades as important to the human IgG/FcRn interaction and reveals Fc His(310) as a significant contributor to pH-dependent binding. Finally, we explain various structural mechanisms by which several Fc mutations (including YTE) result in increased human IgG binding to FcRn. Our study provides an unprecedented relevant understanding of the molecular basis of human Fc interaction with human FcRn.
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The pH dependence of FcRn-IgG binding is likely mediated at least in part via protonation of histidine residues at the CH2-CH3 domain interface of IgG.
“This characteristic is likely mediated, at least in part, via protonation of histidine residues (the only amino acid that changes between pH 5.5 and 7.4) at the CH2–CH3 domain interface of IgG (54–56).”
From Factors Affecting the FcRn-Mediated Transplacental Transfer of Antibodies and Implications for Vaccination in Pregnancy (2017) · cites this paper as [56]
In “Analysis of HSA·FcRn·Fc-YTE Three-dimensional Structure” (page not provided), the paper places Fc His310 at the CH2–CH3 binding interface and suggests it contributes to pH-dependent binding, consistent with the proposed histidine-based mechanism. But it identifies His310 specifically and concludes that Fc His433 does not directly contribute in humans; it does not establish the citing sentence’s broader reference to histidine residues or its parenthetical claim that histidine is the only amino acid that changes between pH 5.5 and 7.4. (LLM, conf=0.84)
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Cites
Chaudhury, C., Mehnaz, S., Robinson, J. M., Hayton, W. L., Pearl, D. K., Roopenian, D. C., & Anderson, C. L. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20021829 · Cited by 640 · see citing works
Robbie, G. J., Criste, R., Dall'Acqua, W. F., Jensen, K., Patel, N. K., Losonsky, G. A., & Griffin, M. P. (2013) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01285-13 · Cited by 366 · see citing works
Self-citationRaghavan, M., Bonagura, V. R., Morrison, S. L., & Bjorkman, P. J. (1995) · Biochemistry · doi:10.1021/bi00045a005 · Cited by 317 · see citing works
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Research works printed but not linked: 2
- Junghans, R. P., and Anderson, C. L. (1996) The protection receptor for IgG catabolism is the 2-microglobulin-containing neonatal intestinal transport receptor. Proc. Natl. Acad. Sci. U.S.A. 93, 5512-5516
- Andersen, J. T., Dalhus, B., Cameron, J., Daba, M. B., Plumridge, A., Evans, L., Brennan, S. O., Gunnarsen, K. S., Bjørås, M., Sleep, D., and Sandlie, I. (2012) Structure-based mutagenesis reveals the albumin-binding site of the neonatal Fc receptor. Nat. Commun. 10.1038/ncomms1607 · DOI
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IgG Fc engineering to modulate antibody effector functions
Wang, X., Mathieu, M., & Brezski, R. J. (2018) · Protein & Cell · doi:10.1007/s13238-017-0473-8 · Cited by 356 · see citing works
Wilcox, C. R., Holder, B., & Jones, C. E. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01294 · Cited by 200 · see citing works
Extending Serum Half-life of Albumin by Engineering Neonatal Fc Receptor (FcRn) Binding
Andersen, J. T., Dalhus, B., Viuff, D., Ravn, B. T., Gunnarsen, K. S., Plumridge, A., Bunting, K., Antunes, F., Williamson, R., Athwal, S., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.549832 · Cited by 167 · see citing works
The Fab region of IgG impairs the internalization pathway of FcRn upon Fc engagement
Brinkhaus, M., Pannecoucke, E., van der Kooi, E. J., Bentlage, A. E. H., Derksen, N. I. L., Andries, J., Balbino, B., Sips, M., Ulrichts, P., Verheesen, P., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33764-1 · Cited by 51 · see citing works
Neonatal Fc receptor – biology and therapeutics
Bussel, J. B., Cines, D. B., & Blumberg, R. S. (2025) · New England Journal of Medicine · doi:10.1056/nejmra2312718 · Cited by 49 · see citing works
- Authors
- Oganesyan, V., Damschroder, M. M., Cook, K. E., Li, Q., Gao, C., Wu, H., & Dall'Acqua, W. F.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-03
- Volume
- 289
- Issue
- 11
- Pages
- 7812-7824
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3953293
- OpenAlex
- W2099381753
- Cited by
- 259
- References
- 3
- Citations by year
- 2026: 17 · 2025: 24 · 2024: 24 · 2023: 15 · 2022: 26 · 2021: 26 · 2020: 25 · 2019: 19 · 2018: 18 · 2017: 19 · 2016: 16 · 2015: 20 · 2014: 9
- FWCI
- 16.69
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- neonatal Fc receptor, human serum albumin, crystal structure, pH-dependent binding
- MeSH terms
- Crystallization, Humans, Hydrogen Bonding, Hydrogen-Ion Concentration, Immunoglobulin G, Immunoglobulin Fc Fragments, Ligands, Models, Molecular, Mutation, Protein Binding, Protein Conformation, Receptors, Fc, Recombinant Proteins, Serum Albumin, Histocompatibility Antigens Class I, Crystallography, X-Ray, HEK293 Cells
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