Crystal structure of IgE bound to its B-cell receptor CD23 reveals a mechanism of reciprocal allosteric inhibition with high affinity receptor FcεRI

The role of IgE in allergic disease mechanisms is performed principally through its interactions with two receptors, Fc epsilon RI on mast cells and basophils, and CD23 (Fc epsilon RII) on B cells. The former mediates allergic hypersensitivity, the latter regulates IgE levels, and both receptors, also expressed on antigen-presenting cells, contribute to allergen uptake and presentation to the immune system. We have solved the crystal structure of the soluble lectin-like "head" domain of CD23 (derCD23) bound to a subfragment of IgE-Fc consisting of the dimer of C epsilon 3 and C epsilon 4 domains (Fc epsilon 3-4). One CD23 head binds to each heavy chain at the interface between the two domains, explaining the known 2:1 stoichiometry and suggesting mechanisms for cross-linking membrane-bound trimeric CD23 by IgE, or membrane IgE by soluble trimeric forms of CD23, both of which may contribute to the regulation of IgE synthesis by B cells. The two symmetrically located binding sites are distant from the single Fc epsilon RI binding site, which lies at the opposite ends of the C epsilon 3 domains. Structural comparisons with both free IgE-Fc and its Fc epsilon RI complex reveal not only that the conformational changes in IgE-Fc required for CD23 binding are incompatible with Fc epsilon RI binding, but also that the converse is true. The two binding sites are allosterically linked. We demonstrate experimentally the reciprocal inhibition of CD23 and Fc epsilon RI binding in solution and suggest that the mutual exclusion of receptor binding allows IgE to function independently through its two receptors.