Mapping of the CD23 Binding Site on Immunoglobulin E (IgE) and Allosteric Control of the IgE-FcεRI Interaction

IgE, the antibody that mediates allergic responses, acts as part of a self-regulating protein network. Its unique effector functions are controlled through interactions of its Fc region with two cellular receptors, Fc epsilon RI on mast cells and basophils and CD23 on B cells. IgE cross-linked by allergen triggers mast cell activation via Fc epsilon RI, whereas IgE-CD23 interactions control IgE expression levels. We have determined the CD23 binding site on IgE, using a combination of NMR chemical shift mapping and site-directed mutagenesis. We show that the CD23 and Fc epsilon RI interaction sites are at opposite ends of the C epsilon 3 domain of IgE, but that receptor binding is mutually inhibitory, mediated by an allosteric mechanism. This prevents CD23-mediated cross-linking of IgE bound to Fc epsilon RI on mast cells and resulting antigen-independent anaphylaxis. The mutually inhibitory nature of receptor binding provides a degree of autonomy for the individual activities mediated by IgE-Fc epsilon RI and IgE-CD23 interactions.