Human immunoglobulin E flexes between acutely bent and extended conformations

Nyssa Drinkwater; Benjamin P Cossins; Anthony H Keeble; Michael Wright; Katharine Cain; Hanna Hailu; Amanda Oxbrow; Jean Delgado; Lindsay K Shuttleworth; Michael W-P Kao; James M McDonnell; Andrew J Beavil; Alistair J Henry; Brian J Sutton

doi:10.1038/nsmb.2795

Human immunoglobulin E flexes between acutely bent and extended conformations

Nyssa Drinkwater, Benjamin P Cossins, Anthony H Keeble, Michael Wright, Katharine Cain, Hanna Hailu, Amanda Oxbrow, Jean Delgado, Lindsay K Shuttleworth, Michael W-P Kao, James M McDonnell, Andrew J Beavil, Alistair J Henry, Brian J Sutton

UCB Pharma Ltd
1] Randall Division of Cell and Molecular Biophysics, King's College London, London, UK. [2] Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK.

Research output: Contribution to journal › Article › peer-review

54 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	397-404
Number of pages	8
Journal	NATURE STRUCTURAL AND MOLECULAR BIOLOGY
Volume	21
Issue number	4
Early online date	16 Mar 2014
DOIs	https://doi.org/10.1038/nsmb.2795
Publication status	Published - Apr 2014

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Drinkwater, N., Cossins, B. P., Keeble, A. H., Wright, M., Cain, K., Hailu, H., Oxbrow, A., Delgado, J., Shuttleworth, L. K., Kao, M. W.-P., McDonnell, J. M., Beavil, A. J., Henry, A. J., & Sutton, B. J. (2014). Human immunoglobulin E flexes between acutely bent and extended conformations. NATURE STRUCTURAL AND MOLECULAR BIOLOGY, 21(4), 397-404. https://doi.org/10.1038/nsmb.2795

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abstract = "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 F{\"o}rster 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.",

author = "Nyssa Drinkwater and Cossins, {Benjamin P} and Keeble, {Anthony H} and Michael Wright and Katharine Cain and Hanna Hailu and Amanda Oxbrow and Jean Delgado and Shuttleworth, {Lindsay K} and Kao, {Michael W-P} and McDonnell, {James M} and Beavil, {Andrew J} and Henry, {Alistair J} and Sutton, {Brian J}",

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AU - Drinkwater, Nyssa

AU - Cossins, Benjamin P

AU - Keeble, Anthony H

AU - Wright, Michael

AU - Cain, Katharine

AU - Hailu, Hanna

AU - Oxbrow, Amanda

AU - Delgado, Jean

AU - Shuttleworth, Lindsay K

AU - Kao, Michael W-P

AU - McDonnell, James M

AU - Beavil, Andrew J

AU - Henry, Alistair J

AU - Sutton, Brian J

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AB - 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.

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Human immunoglobulin E flexes between acutely bent and extended conformations

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