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  • Review Article
  • Published:

Human antibody–Fc receptor interactions illuminated by crystal structures

Nature Reviews Immunology volume 4, pages 89–99 (2004)Cite this article

Key Points

  • The structures of the Fc regions of human IgG, IgE and IgA have been solved, revealing similarities in overall domain arrangements.

  • The extracellular domains of the human IgG Fc receptors FcγRIIa, FcγRIIb, FcγRIIIb, the high affinity IgE FcR FcεRI and the IgA FcR FcαRI have been crystallized and their structures solved to high resolution. FcγRIIa/FcγRIIb, FcγRIII and FcεRI have the same overall heart-shaped structure.

  • The structure of the FcαRI is distinct with a different arrangement of the two extracellular domains to that of the other FcRs. The FcαRI structure more closely resembles those of members of the natural killer cell inhibitory receptor family.

  • High resolution crystal structures are available for the complexes of IgG Fc with FcγRIII, IgE Fc (Cε2, Cε3, Cε4)2 with FcεRI, and IgA Fc with FcαRI.

  • The interaction modes of IgG Fc with FcγR and IgE Fc with FcεRI have common features and a 1:1 receptor:antibody stoichiometry. The membrane proximal domain of each FcR interacts with sites at corresponding positions on the amino-terminal regions of the penultimate constant domains of their immunoglobulin ligands.

  • The FcαRI–IgA interaction differs. The interaction site on IgA occurs at the domain interface between the penultimate and ultimate carboxy-terminal domains of the Fc region, the IgA-binding site on FcαRI is located in the membrane distal domain, and the receptor:antibody stoichiometry (in solution) is 2:1.

  • As many targets for elimination by FcR-mediated effector mechanisms are whole cells, immunoglobulin molecules must simultaneously bridge an antigen molecule on the target cell and an FcR on the effector cell. For IgG and IgE, the interaction sites for FcR at the 'top' of the Fc region indicate that antibody bridging between target and effector cell probably involves some degree of dislocation, such that the Fc region moves out of the plane of the antigen-binding (Fab) arms.

  • As the therapeutic use of antibody continues to increase, detailed understanding of effector function sites will allow antibody function to be tailored for particular applications.

Abstract

Immunoglobulins couple the recognition of invading pathogens with the triggering of potent effector mechanisms for pathogen elimination. Different immunoglobulin classes trigger different effector mechanisms through interaction of immunoglobulin Fc regions with specific Fc receptors (FcRs) on immune cells. Here, we review the structural information that is emerging on three human immunoglobulin classes and their FcRs. New insights are provided, including an understanding of the antibody conformational adjustments that are required to bring effector cell and target cell membranes sufficiently close for efficient killing and signal transduction to occur. The results might also open up new possibilities for the design of therapeutic antibodies.

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Figure 1: The structure of human IgG1, IgE and IgA1.
Figure 2: Comparison of the structures of the carboxy-terminal domains of the Fc regions of human IgG1, IgE and IgA1.
Figure 3: Structures of human Fc receptors (FcRs).
Figure 4: Comparison of the IgG–FcγRIII, IgE–FcεRI and IgA–FcαRI complexes.
Figure 5: Antibody bridging between cells.

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Acknowledgements

We thank P. Parren for critical reading of the manuscript, A. Herr for providing values for buried surface areas in IgA, and the Wellcome Trust and the National Institutes of Health for financial support.

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Authors and Affiliations

  1. Division of Pathology and Neuroscience, University of Dundee Medical School, Ninewells Hospital, Dundee, DD1 9SY, UK

    Jenny M. Woof

  2. Departments of Immunology and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Dennis R. Burton

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  1. Jenny M. Woof
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Correspondence to Jenny M. Woof.

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DATABASES

LocusLink

FcαRI

FcεRI

FcεRII

FcγRI

FcγRII

FcγRIII

GPVI

MAC1

FURTHER INFORMATION

Protein Data Bank

Glossary

IMMUNOGLOBULIN DOMAINS

The essential building blocks of all immunoglobulins, comprising a globular unit of ∼110 amino acids with a predominant β-sheet arrangement that is stabilized by an internal disulphide bond. The β-strands of antibody constant domains are labelled ABCDEFG from the amino-terminus.

IMMUNORECEPTOR TYROSINE-BASED ACTIVATION MOTIFS

(ITAMs). ITAMs consist of two tyrosine-containing Tyr-Xaa-Xaa-Leu boxes interspaced by seven amino acids, crucial for transducing activatory signals. Mutation of either of the tyrosine residues reduces or abrogates signalling. When phosphorylated after receptor crosslinking ITAMs function as sites that promote the activation of cytoplasmic proteins into signalling complexes.

IMMUNORECEPTOR TYROSINE-BASED INHIBITORY MOTIFS

(ITIMs). ITIMs, typically Ile/Val-Xaa-Tyr-Xaa-Xaa-Leu/Val, when phosphorylated after receptor crosslinking, function to negatively regulate cytoplasmic signalling complexes.

LEUKOCYTE RECEPTOR COMPLEX

(LRC). A group of genes that are located adjacent to each other on human chromosome 19q13.4 encoding a family of proteins including natural killer cell inhibitory receptors (KIRs), leukocyte immunoglobulin-like receptors (LIRs, LILRs or ILTs) and FcαRI.

ROSETTE FORMATION

A method of assessing Fc receptor (FcR) interactions, in which the interaction of FcR-expressing cells with erythrocytes coated in erythrocyte-specific antibody is visualized by microscopy. A rosette comprises an FcR-expressing cell bound by three or more erythrocytes. Rosette formation serves as a model of FcR-expressing cell–target-cell interaction

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Woof, J., Burton, D. Human antibody–Fc receptor interactions illuminated by crystal structures. Nat Rev Immunol 4, 89–99 (2004). https://doi.org/10.1038/nri1266

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