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Thermal sensitivity and flexibility of the Cε3 domains in immunoglobulin E

Immunoglobulin E (IgE) is the antibody that plays a central role in the mechanisms of allergic diseases such as asthma. Interactions with its receptors, FcεRI on mast cells and CD23 on B cells, are mediated by the Fc region, a dimer of the Cε2, Cε3 and Cε4 domains. A sub-fragment lacking the Cε2 dom...

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Autores principales: Doré, Katy A., Davies, Anna M., Drinkwater, Nyssa, Beavil, Andrew J., McDonnell, James M., Sutton, Brian J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Pub. Co 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652521/
https://www.ncbi.nlm.nih.gov/pubmed/28844738
http://dx.doi.org/10.1016/j.bbapap.2017.08.005
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author Doré, Katy A.
Davies, Anna M.
Drinkwater, Nyssa
Beavil, Andrew J.
McDonnell, James M.
Sutton, Brian J.
author_facet Doré, Katy A.
Davies, Anna M.
Drinkwater, Nyssa
Beavil, Andrew J.
McDonnell, James M.
Sutton, Brian J.
author_sort Doré, Katy A.
collection PubMed
description Immunoglobulin E (IgE) is the antibody that plays a central role in the mechanisms of allergic diseases such as asthma. Interactions with its receptors, FcεRI on mast cells and CD23 on B cells, are mediated by the Fc region, a dimer of the Cε2, Cε3 and Cε4 domains. A sub-fragment lacking the Cε2 domains, Fcε3–4, also binds to both receptors, although receptor binding almost exclusively involves the Cε3 domains. This domain also contains the N-linked glycosylation site conserved in other isotypes. We report here the crystal structures of IgE-Fc and Fcε3–4 at the highest resolutions yet determined, 1.75 Å and 2.0 Å respectively, revealing unprecedented detail regarding the carbohydrate and its interactions with protein domains. Analysis of the crystallographic B-factors of these, together with all earlier IgE-Fc and Fcε3–4 structures, shows that the Cε3 domains exhibit the greatest intrinsic flexibility and quaternary structural variation within IgE-Fc. Intriguingly, both well-ordered carbohydrate and disordered polypeptide can be seen within the same Cε3 domain. A simplified method for comparing the quaternary structures of the Cε3 domains in free and receptor-bound IgE-Fc structures is presented, which clearly delineates the FcεRI and CD23 bound states. Importantly, differential scanning fluorimetric analysis of IgE-Fc and Fcε3–4 identifies Cε3 as the domain most susceptible to thermally-induced unfolding, and responsible for the characteristically low melting temperature of IgE.
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spelling pubmed-56525212017-11-01 Thermal sensitivity and flexibility of the Cε3 domains in immunoglobulin E Doré, Katy A. Davies, Anna M. Drinkwater, Nyssa Beavil, Andrew J. McDonnell, James M. Sutton, Brian J. Biochim Biophys Acta Article Immunoglobulin E (IgE) is the antibody that plays a central role in the mechanisms of allergic diseases such as asthma. Interactions with its receptors, FcεRI on mast cells and CD23 on B cells, are mediated by the Fc region, a dimer of the Cε2, Cε3 and Cε4 domains. A sub-fragment lacking the Cε2 domains, Fcε3–4, also binds to both receptors, although receptor binding almost exclusively involves the Cε3 domains. This domain also contains the N-linked glycosylation site conserved in other isotypes. We report here the crystal structures of IgE-Fc and Fcε3–4 at the highest resolutions yet determined, 1.75 Å and 2.0 Å respectively, revealing unprecedented detail regarding the carbohydrate and its interactions with protein domains. Analysis of the crystallographic B-factors of these, together with all earlier IgE-Fc and Fcε3–4 structures, shows that the Cε3 domains exhibit the greatest intrinsic flexibility and quaternary structural variation within IgE-Fc. Intriguingly, both well-ordered carbohydrate and disordered polypeptide can be seen within the same Cε3 domain. A simplified method for comparing the quaternary structures of the Cε3 domains in free and receptor-bound IgE-Fc structures is presented, which clearly delineates the FcεRI and CD23 bound states. Importantly, differential scanning fluorimetric analysis of IgE-Fc and Fcε3–4 identifies Cε3 as the domain most susceptible to thermally-induced unfolding, and responsible for the characteristically low melting temperature of IgE. Elsevier Pub. Co 2017-11 /pmc/articles/PMC5652521/ /pubmed/28844738 http://dx.doi.org/10.1016/j.bbapap.2017.08.005 Text en © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Doré, Katy A.
Davies, Anna M.
Drinkwater, Nyssa
Beavil, Andrew J.
McDonnell, James M.
Sutton, Brian J.
Thermal sensitivity and flexibility of the Cε3 domains in immunoglobulin E
title Thermal sensitivity and flexibility of the Cε3 domains in immunoglobulin E
title_full Thermal sensitivity and flexibility of the Cε3 domains in immunoglobulin E
title_fullStr Thermal sensitivity and flexibility of the Cε3 domains in immunoglobulin E
title_full_unstemmed Thermal sensitivity and flexibility of the Cε3 domains in immunoglobulin E
title_short Thermal sensitivity and flexibility of the Cε3 domains in immunoglobulin E
title_sort thermal sensitivity and flexibility of the cε3 domains in immunoglobulin e
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652521/
https://www.ncbi.nlm.nih.gov/pubmed/28844738
http://dx.doi.org/10.1016/j.bbapap.2017.08.005
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