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A range of C?3-C?4 interdomain angles in IgE Fc accommodate binding to its receptor CD23.

ABSTRACT: The antibody IgE plays a central role in allergic disease, functioning principally through two cell-surface receptors: Fc?RI and CD23. Fc?RI on mast cells and basophils mediates the immediate hypersensitivity response, whilst the interaction of IgE with CD23 on B cells regulates IgE production. Crystal structures of the lectin-like `head' domain of CD23 alone and bound to a subfragment of IgE consisting of the dimer of C?3 and C?4 domains (Fc?3-4) have recently been determined, revealing flexibility in the IgE-binding site of CD23. Here, a new crystal form of the CD23-Fc?3-4 complex with different molecular-packing constraints is reported, which together with the earlier results demonstrates that conformational variability at the interface extends additionally to the IgE Fc and the quaternary structure of its domains.

SUBMITTER: Dhaliwal B

PROVIDER: S-EPMC3944690 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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A range of Cℇ3-Cℇ4 interdomain angles in IgE Fc accommodate binding to its receptor CD23.

Dhaliwal Balvinder B Pang Marie O Y MO Yuan Daopeng D Beavil Andrew J AJ Sutton Brian J BJ

Acta crystallographica. Section F, Structural biology communications 20140220 Pt 3

The antibody IgE plays a central role in allergic disease, functioning principally through two cell-surface receptors: FcℇRI and CD23. FcℇRI on mast cells and basophils mediates the immediate hypersensitivity response, whilst the interaction of IgE with CD23 on B cells regulates IgE production. Crystal structures of the lectin-like `head' domain of CD23 alone and bound to a subfragment of IgE consisting of the dimer of Cℇ3 and Cℇ4 domains (Fcℇ3-4) have recently been determined, revealing flexibi ...[more]

PMID: 24598915

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Mapping of the CD23 binding site on immunoglobulin E (IgE) and allosteric control of the IgE-Fc epsilonRI interaction.

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IgE binds asymmetrically to its B cell receptor CD23.

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Critical and direct involvement of the CD23 stalk region in IgE binding.

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CD23 is a glycan-binding receptor in some mammalian species.

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Project description:CD23, the low affinity receptor for immunoglobulin E (IgE), has been proposed to play a critical role in the regulation of IgE production, based on altered IgE levels in CD23-deficient mice and transgenic mouse models, as well as in mouse strains with mutations in the CD23 gene, e.g. 129 substrains. Here, we have investigated a mouse line termed LxT1 that expresses reduced CD23 surface levels on B cells, and its influence on natural IgE production. Extensive phenotypic analysis showed that CD23 surface expression was reduced in LxT1 compared to the control, without affecting B cell development in general. This CD23(low) surface level in LxT1 mice is not as a result of reduced CD23 mRNA expression levels or intracellular accumulation, but linked to a recessive locus, a 129-derived region spanning 28 Mb on chromosome 8, which includes the CD23 gene. Sequence analysis confirmed five mutations within the CD23 coding region in LxT1 mice, the same as those present in New Zealand Black (NZB) and 129 mice. However, this CD23(low) phenotype was not observed in all 129 substrains despite carrying these same CD23 mutations in the coding region. Moreover, serum IgE levels in LxT1 mice are as low as those in the C57BL/6 (B6) strain, and much lower than those in 129 substrains. These data indicate that the CD23 surface level and serum IgE level are uncoupled and that neither is directly regulated by the mutations within the CD23 coding region. This study suggests that caution should be taken when interpreting the immunological data derived from mice with different genetic background, especially if the gene of interest is thought to influence CD23 surface expression or serum IgE level.

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Soluble CD23 controls IgE synthesis and homeostasis in human B cells.

Project description:CD23, the low-affinity receptor for IgE, exists in membrane and soluble forms. Soluble CD23 (sCD23) fragments are released from membrane (m)CD23 by the endogenous metalloprotease a disintegrin and metalloprotease 10. When purified tonsil B cells are incubated with IL-4 and anti-CD40 to induce class switching to IgE in vitro, mCD23 is upregulated, and sCD23 accumulates in the medium prior to IgE synthesis. We have uncoupled the effects of mCD23 cleavage and accumulation of sCD23 on IgE synthesis in this system. We show that small interfering RNA inhibition of CD23 synthesis or inhibition of mCD23 cleavage by an a disintegrin and metalloprotease 10 inhibitor, GI254023X, suppresses IL-4 and anti-CD40-stimulated IgE synthesis. Addition of a recombinant trimeric sCD23 enhances IgE synthesis in this system. This occurs even when endogenous mCD23 is protected from cleavage by GI254023X, indicating that IgE synthesis is positively controlled by sCD23. We show that recombinant trimeric sCD23 binds to cells coexpressing mIgE and mCD21 and caps these proteins on the B cell membrane. Upregulation of IgE by sCD23 occurs after class-switch recombination, and its effects are isotype-specific. These results suggest that mIgE and mCD21 cooperate in the sCD23-mediated positive regulation of IgE synthesis on cells committed to IgE synthesis. Feedback regulation may occur when the concentration of secreted IgE becomes great enough to allow binding to mCD23, thus preventing further release of sCD23. We interpret these results with the aid of a model for the upregulation of IgE by sCD23.

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