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Thermal sensitivity and flexibility of the Cε3 domains in immunoglobulin E

DOI: 10.1016/j.bbapap.2017.08.005 DOI Help

Authors: Katy A. Dore (King's College London; Medical Research Council & Asthma UK Centre in Allergic Mechanisms of Asthma) , Anna M. Davies (King's College London; Medical Research Council & Asthma UK Centre in Allergic Mechanisms of Asthma) , Nyssa Drinkwater (King's College London; Medical Research Council & Asthma UK Centre in Allergic Mechanisms of Asthma) , Andrew J. Beavil (King's College London; Medical Research Council & Asthma UK Centre in Allergic Mechanisms of Asthma) , James M. Mcdonnell (King's College London; Medical Research Council & Asthma UK Centre in Allergic Mechanisms of Asthma) , Brian J. Sutton (King's College London; Medical Research Council & Asthma UK Centre in Allergic Mechanisms of Asthma)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biochimica Et Biophysica Acta (bba) - Proteins And Proteomics

State: Published (Approved)
Published: August 2017
Diamond Proposal Number(s): 1220 , 9495

Open Access Open Access

Abstract: 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 domains. 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.

Journal Keywords: Antibody; Immunoglobulin E; Glycosylation; Domain flexibility; Thermal unfolding; Differential scanning fluorimetry

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Added On: 29/08/2017 15:36

Documents:
1-s2.0-S1570963917301851-main.pdf

Discipline Tags:

Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech Allergic Diseases

Technical Tags:

Diffraction Macromolecular Crystallography (MX)