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

The role of IgE in allergic disease mechanisms is performed principally through its interactions with two receptors, FC∊RI on mast cells and basophils, and CD23 (Fc∊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 Cr3 and G 4 domains (Fa-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 crosslinking membrane-bound trim∊RIc CD23 by IgE, or membrane IgE by soluble trim∊RIc 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∊RI binding site, which lies at the opposite ends of the CE3 domains. Structural comparisons with both free IgE-Fc and its Fc∊RI complex reveal not only that the conformational changes in IgE-Fc required for CD23 binding are incompatible with Fc∊RI binding, but also that the converse is true. The two binding sites are allost∊RIcally linked. We demonstrate exp∊RImentally the reciprocal inhibition of CD23 and Fc∊RI binding in solution and suggest that the mutual exclusion of receptor binding allows IgE to function independently through its two receptors. [ABSTRACT FROM AUTHOR]