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Publication Abstract from PubMed

Immunoglobulin E (IgE) is the antibody that plays a central role in the mechanisms of allergic diseases such as asthma. Interactions with its receptors, FcepsilonRI on mast cells and CD23 on B cells, are mediated by the Fc region, a dimer of the Cepsilon2, Cepsilon3 and Cepsilon4 domains. A sub-fragment lacking the Cepsilon2 domains, Fcepsilon3-4, also binds to both receptors, although receptor binding almost exclusively involves the Cepsilon3 domains. This domain also contains the N-linked glycosylation site conserved in other isotypes. We report here the crystal structures of IgE-Fc and Fcepsilon3-4 at the highest resolutions yet determined, 1.75A and 2.0A 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 Fcepsilon3-4 structures, shows that the Cepsilon3 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 Cepsilon3 domain. A simplified method for comparing the quaternary structures of the Cepsilon3 domains in free and receptor-bound IgE-Fc structures is presented, which clearly delineates the FcepsilonRI and CD23 bound states. Importantly, differential scanning fluorimetric analysis of IgE-Fc and Fcepsilon3-4 identifies Cepsilon3 as the domain most susceptible to thermally-induced unfolding, and responsible for the characteristically low melting temperature of IgE.

Thermal sensitivity and flexibility of the Cepsilon3 domains in immunoglobulin E.,Dore KA, Davies AM, Drinkwater N, Beavil AJ, McDonnell JM, Sutton BJ Biochim Biophys Acta. 2017 Nov;1865(11 Pt A):1336-1347. doi:, 10.1016/j.bbapap.2017.08.005. Epub 2017 Aug 24. PMID:28844738^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.