Conformational changes in IgE contribute to its uniquely slow dissociation rate from receptor FcIRI

Mary D. Holdom; Anna M. Davies; Joanne E. Nettleship; Sarah C. Bagby; Balvinder Dhaliwal; Enrico Girardi; James Hunt; Hannah J. Gould; Andrew J. Beavil; James M. McDonnell; Ray J. Owens; Brian J. Sutton

doi:10.1038/nsmb.2044

Conformational changes in IgE contribute to its uniquely slow dissociation rate from receptor FcIRI

Mary D. Holdom, Anna M. Davies, Joanne E. Nettleship, Sarah C. Bagby, Balvinder Dhaliwal, Enrico Girardi, James Hunt, Hannah J. Gould, Andrew J. Beavil, James M. McDonnell, Ray J. Owens, Brian J. Sutton

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

Abstract

Among antibody classes, IgE has a uniquely slow dissociation rate from, and high affinity for, its cell surface receptor FcI RI. We show the structural basis for these key determinants of the ability of IgE to mediate allergic hypersensitivity through the 3.4-Ã.-resolution crystal structure of human IgE-Fc (consisting of the CI 2, CI 3 and CI 4 domains) bound to the extracellular domains of the FcI RI Î ± chain. Comparison with the structure of free IgE-Fc (reported here at a resolution of 1.9 Ã.) shows that the antibody, which has a compact, bent structure before receptor engagement, becomes even more acutely bent in the complex. Thermodynamic analysis indicates that the interaction is entropically driven, which explains how the noncontacting CI 2 domains, in place of the flexible hinge region of IgG antibodies, contribute together with the conformational changes to the unique binding properties of IgE. © 2011 Nature America, Inc. All rights reserved.

Original language	English
Pages (from-to)	571-576
Number of pages	5
Journal	Nature Structural and Molecular Biology
Volume	18
Issue number	5
DOIs	https://doi.org/10.1038/nsmb.2044
Publication status	Published - May 2011

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Holdom, M. D., Davies, A. M., Nettleship, J. E., Bagby, S. C., Dhaliwal, B., Girardi, E., Hunt, J., Gould, H. J., Beavil, A. J., McDonnell, J. M., Owens, R. J., & Sutton, B. J. (2011). Conformational changes in IgE contribute to its uniquely slow dissociation rate from receptor FcIRI. Nature Structural and Molecular Biology, 18(5), 571-576. https://doi.org/10.1038/nsmb.2044

@article{b150be464a2b4243a904b966499caa67,

title = "Conformational changes in IgE contribute to its uniquely slow dissociation rate from receptor FcIRI",

abstract = "Among antibody classes, IgE has a uniquely slow dissociation rate from, and high affinity for, its cell surface receptor FcI RI. We show the structural basis for these key determinants of the ability of IgE to mediate allergic hypersensitivity through the 3.4-{\~A}.-resolution crystal structure of human IgE-Fc (consisting of the CI 2, CI 3 and CI 4 domains) bound to the extracellular domains of the FcI RI {\^I} ± chain. Comparison with the structure of free IgE-Fc (reported here at a resolution of 1.9 {\~A}.) shows that the antibody, which has a compact, bent structure before receptor engagement, becomes even more acutely bent in the complex. Thermodynamic analysis indicates that the interaction is entropically driven, which explains how the noncontacting CI 2 domains, in place of the flexible hinge region of IgG antibodies, contribute together with the conformational changes to the unique binding properties of IgE. {\textcopyright} 2011 Nature America, Inc. All rights reserved.",

author = "Holdom, {Mary D.} and Davies, {Anna M.} and Nettleship, {Joanne E.} and Bagby, {Sarah C.} and Balvinder Dhaliwal and Enrico Girardi and James Hunt and Gould, {Hannah J.} and Beavil, {Andrew J.} and McDonnell, {James M.} and Owens, {Ray J.} and Sutton, {Brian J.}",

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year = "2011",

month = may,

doi = "10.1038/nsmb.2044",

language = "English",

volume = "18",

pages = "571--576",

journal = "Nature Structural and Molecular Biology",

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AU - Holdom, Mary D.

AU - Davies, Anna M.

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AU - Dhaliwal, Balvinder

AU - Girardi, Enrico

AU - Hunt, James

AU - Gould, Hannah J.

AU - Beavil, Andrew J.

AU - McDonnell, James M.

AU - Owens, Ray J.

AU - Sutton, Brian J.

N1 - 081320, Wellcome Trust, United Kingdom090532, Wellcome Trust, United KingdomG0001352, Medical Research Council, United KingdomG0200486, Medical Research Council, United KingdomG0200486(63136), Medical Research Council, United KingdomG0501494, Medical Research Council, United KingdomG0501494(76353), Medical Research Council, United KingdomG0601043, Medical Research Council, United KingdomG0701506, Medical Research Council, United KingdomMC_G0900865, Medical Research Council, United Kingdom, Medical Research Council, United Kingdom

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N2 - Among antibody classes, IgE has a uniquely slow dissociation rate from, and high affinity for, its cell surface receptor FcI RI. We show the structural basis for these key determinants of the ability of IgE to mediate allergic hypersensitivity through the 3.4-Ã.-resolution crystal structure of human IgE-Fc (consisting of the CI 2, CI 3 and CI 4 domains) bound to the extracellular domains of the FcI RI Î ± chain. Comparison with the structure of free IgE-Fc (reported here at a resolution of 1.9 Ã.) shows that the antibody, which has a compact, bent structure before receptor engagement, becomes even more acutely bent in the complex. Thermodynamic analysis indicates that the interaction is entropically driven, which explains how the noncontacting CI 2 domains, in place of the flexible hinge region of IgG antibodies, contribute together with the conformational changes to the unique binding properties of IgE. © 2011 Nature America, Inc. All rights reserved.

AB - Among antibody classes, IgE has a uniquely slow dissociation rate from, and high affinity for, its cell surface receptor FcI RI. We show the structural basis for these key determinants of the ability of IgE to mediate allergic hypersensitivity through the 3.4-Ã.-resolution crystal structure of human IgE-Fc (consisting of the CI 2, CI 3 and CI 4 domains) bound to the extracellular domains of the FcI RI Î ± chain. Comparison with the structure of free IgE-Fc (reported here at a resolution of 1.9 Ã.) shows that the antibody, which has a compact, bent structure before receptor engagement, becomes even more acutely bent in the complex. Thermodynamic analysis indicates that the interaction is entropically driven, which explains how the noncontacting CI 2 domains, in place of the flexible hinge region of IgG antibodies, contribute together with the conformational changes to the unique binding properties of IgE. © 2011 Nature America, Inc. All rights reserved.

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DO - 10.1038/nsmb.2044

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SN - 1545-9993

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SP - 571

EP - 576

JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

IS - 5

ER -

Conformational changes in IgE contribute to its uniquely slow dissociation rate from receptor FcIRI

Abstract

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