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Structural basis of pH-dependent antibody binding by the neonatal Fc receptor

Vaughn, Daniel E. and Bjorkman, Pamela J. (1998) Structural basis of pH-dependent antibody binding by the neonatal Fc receptor. Structure, 6 (1). pp. 63-73. ISSN 0969-2126. https://resolver.caltech.edu/CaltechAUTHORS:20170406-094812525

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Abstract

Background: The neonatal Fc receptor (FcRn) mediates the transcytosis of maternal immunoglobulin G(IgG) across fetal and/or neonatal tissues for the acquisition of passive immunity. In adults, FcRn is involved in the maintenance of high serum IgG levels. Both processes are mediated by pH-dependent IgG binding to FcRn –FcRn binds to IgG with nanomolar affinity at pH 6, but shows no detectable binding at pH 7.5. At pH 6, FcRn is more thermally stable and the dissociation rate of its light chain is an order of magnitude slower than at pH 8.0. Comparison of the structures of FcRn at pH 6.5 and pH 8 allows an analysis of the structural basis for the receptor's pH-dependent ligand binding and stability. Results: We have determined the structure of FcRn at pH 8 and compared it to a further refined version of the structure at pH 6.5. An extensive ordered carbohydrate structure is observed at both pH values. The two structures are very similar; thus the pH dependence of FcRn stability and affinity for IgG can be attributed to chemical properties of the structures themselves, rather than mechanisms that rely on conformational changes. The pH-dependent properties are mediated by electrostatic interactions involving histidine residues, which are more favorable for the protonated form of histidine that predominates at acidic pH values. Conclusions: No major conformational change is observed between the pH 6.5 and pH 8 structures of FcRn that could account for the differences in affinity for IgG. The pH dependence of IgG binding to FcRn can therefore primarily be attributed to titration of histidine residues on Fc that interact with anionic pockets on the receptor. The FcRn dimer, which is required for high affinity binding of IgG, is itself stabilized at acidic pH by histidine-mediated salt bridges and a sidechain rearrangement that creates a more favorable interaction with an anionic pocket at pH 6.5 relative to pH 8. FcRn dimerization is facilitated by reciprocal interactions in which carbohydrate from one receptor molecule binds to protein residues from the dimer-related receptor molecule to form a ‘carbohydrate handshake’.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/S0969-2126(98)00008-2DOIArticle
http://www.cell.com/structure/fulltext/S0969-2126(98)00008-2PublisherArticle
ORCID:
AuthorORCID
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 1997 Current Biology Ltd. Received: 15 September 1997. Revisions requested: 20 October 1997. Revisions received: 12 November 1997. Accepted: 20 November 1997. We thank Art Chirino for help with data collection, valuable discussions and critical reading of the manuscript, Luis Sénchez for sharing unpublished results, Axel Brünger for providing test versions of his software, Steve Mayo and Leemor Joshua-Tor for the use of computational resources and the CIT crystallographers for advice and helpful discussions. We thank the MacChess staff and operators at CHESS for help with data collection. This work was supported by a Camille and Henry Dreyfuss Teacher Scholar Award (PJB) and a grant from the NIH (AI/GM41239 to PJB).
Funders:
Funding AgencyGrant Number
Camille and Henry Dreyfus FoundationUNSPECIFIED
NIHAI/GM41239
Subject Keywords:histidine titration, ordered carbohydrate, pH-dependent salt bridges
Issue or Number:1
Record Number:CaltechAUTHORS:20170406-094812525
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170406-094812525
Official Citation:Daniel E Vaughn, Pamela J Bjorkman, Structural basis of pH-dependent antibody binding by the neonatal Fc receptor, Structure, Volume 6, Issue 1, 15 January 1998, Pages 63-73, ISSN 0969-2126, http://dx.doi.org/10.1016/S0969-2126(98)00008-2. (http://www.sciencedirect.com/science/article/pii/S0969212698000082)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:75793
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:06 Apr 2017 18:04
Last Modified:03 Oct 2019 16:54

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