Human immunoglobulin E flexes between acutely bent and extended conformations

IgE molecules associate with the FcɛRIα receptor in an acutely bent conformation where the Cɛ2 domains fold over the Cɛ3-Cɛ4 domains. A new study demonstrates that IgE can exist in an extended conformation with a Cɛ2 domain capable of flipping from side to side, suggesting a level of structural flex...

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Bibliographic Details
Published in:	Nature structural & molecular biology Vol. 21; no. 4; pp. 397 - 404
Main Authors:	Drinkwater, Nyssa, Cossins, Benjamin P, Keeble, Anthony H, Wright, Michael, Cain, Katharine, Hailu, Hanna, Oxbrow, Amanda, Delgado, Jean, Shuttleworth, Lindsay K, Kao, Michael W-P, McDonnell, James M, Beavil, Andrew J, Henry, Alistair J, Sutton, Brian J
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-04-2014 Nature Publishing Group
Subjects:	631/250 631/535/1266 631/57/2272 82 82/1 82/103 Allergens Allergies Analysis B-Lymphocytes - immunology Biochemistry Biological Microscopy Calorimetry Crystallography Crystallography, X-Ray Crystals Energy transfer Fluorescence Resonance Energy Transfer Humans Hypersensitivity - immunology Immunoglobulin E Immunoglobulin E - chemistry Immunoglobulin E - physiology Immunoglobulins Life Sciences Medical research Medicine, Experimental Membrane Biology Molecular biology Physiological aspects Protein Structure Protein Structure, Tertiary Receptors, IgE - chemistry Resonance Structure Surface Plasmon Resonance
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Summary:	IgE molecules associate with the FcɛRIα receptor in an acutely bent conformation where the Cɛ2 domains fold over the Cɛ3-Cɛ4 domains. A new study demonstrates that IgE can exist in an extended conformation with a Cɛ2 domain capable of flipping from side to side, suggesting a level of structural flexibility that could functionally impact allergen recognition. Crystallographic and solution studies have shown that IgE molecules are acutely bent in their Fc region. Crystal structures reveal the Cɛ2 domain pair folded back onto the Cɛ3-Cɛ4 domains, but is the molecule exclusively bent or can the Cɛ2 domains adopt extended conformations and even 'flip' from one side of the molecule to the other? We report the crystal structure of IgE-Fc captured in a fully extended, symmetrical conformation and show by molecular dynamics, calorimetry, stopped-flow kinetic, surface plasmon resonance (SPR) and Förster resonance energy transfer (FRET) analyses that the antibody can indeed adopt such extended conformations in solution. This diversity of conformational states available to IgE-Fc offers a new perspective on IgE function in allergen recognition, as part of the B-cell receptor and as a therapeutic target in allergic disease.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 AUTHOR CONTRIBUTIONS: N.D. and B.C. contributed equally to this work. N.D. performed the crystallography and structure analysis, with J.M.M conducted SPR experiments, and with B.J.S. wrote the manuscript. B.C. undertook the molecular dynamics and contributed to writing. A.H.K. was responsible for the ITC and stopped flow analyses, M.W. generated the aεFab molecule, K.C. performed antibody engineering, H.H expressed the proteins, A.O. purified the proteins, J.D. and L.K.S. collected intramolecular FRET data using reagents made by M.W-P.K. and A.J.H. J.M.M., A.J.H. and A.J.B. contributed to writing, data interpretation and with B.J.S. designed and supervised the research.
ISSN:	1545-9993 1545-9985
DOI:	10.1038/nsmb.2795