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The structure of the IgE Cɛ2 domain and its role in stabilizing the complex with its high-affinity receptor FcɛRIα

Nature Structural Biology volume 8, pages 437–441 (2001)Cite this article

Abstract

The stability of the complex between IgE and its high-affinity receptor, FcɛRI, on mast cells is a critical factor in the allergic response. The long half-life of the complex of IgE bound to this receptor in situ (∼2 weeks, compared with only hours for the comparable IgG complex) contributes to the permanent sensitization of these cells and, hence, to the immediate response to allergens. Here we show that the second constant domain of IgE, Cɛ2, which takes the place of the flexible hinge in IgG, contributes to this long half-life. When the Cɛ2 domain is deleted from the IgE Fc fragment, leaving only the Cɛ3 and Cɛ4 domains (Cɛ3–4 fragment), the rate of dissociation from the receptor is increased by greater than 1 order of magnitude. We report the structure of the Cɛ2 domain by heteronuclear NMR spectroscopy and show by chemical shift perturbation that it interacts with FcɛRIα. By sedimentation equilibrium we show that the Cɛ2 domain binds to the Cɛ3–4 fragment of IgE. These interactions of Cɛ2 with both FcɛRIα and Cɛ3–4 provide a structural explanation for the exceptionally slow dissociation of the IgE–FcɛRIα complex.

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Figure 1: The Cɛ2 domain affects IgE binding to the high affinity receptor FcɛRIα.
Figure 2: Analytical ultracentrifugation of Cɛ2 in complex with Cɛ3–4.
Figure 3: The solution structure of Cɛ2 and interaction surface with FcɛRIα.
Figure 4: The overall architecture of Cɛ2–4 complexed with FcɛRIα.

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Acknowledgements

We are grateful to M. Werner for some of the pulse sequences used. Awards from the NIH, Pharmacia Allergy Research Foundation Fellowship, MRC and BBSRC (UK), The Wellcome Trust and National Asthma Campaign (UK) supported this work.

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Author notes

  1. James M. McDonnell

    Present address: Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK

  2. Alistair J. Henry

    Present address: Celltech Chiroscience plc, 216 Bath Road, Slough, UK

Authors and Affiliations

  1. The Rockefeller University, 1230 York Avenue, New York, 10021-6399, New York, USA

    James M. McDonnell & David Cowburn

  2. The Randall Centre for Molecular Mechanisms of Cell Function, King's College London, New Hunt's House, Guy's Campus, London, SE1 1UL, UK

    Rosaleen Calvert, Rebecca L. Beavil, Andrew J. Beavil, Alistair J. Henry, Brian J. Sutton & Hannah J. Gould

  3. New York Structural Biology Center, c/o Box 163, 1230 York Avenue, New York, 10021-6399, New York, USA

    David Cowburn

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Correspondence to Hannah J. Gould or David Cowburn.

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McDonnell, J., Calvert, R., Beavil, R. et al. The structure of the IgE Cɛ2 domain and its role in stabilizing the complex with its high-affinity receptor FcɛRIα. Nat Struct Mol Biol 8, 437–441 (2001). https://doi.org/10.1038/87603

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