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, FcϵRI on mast cells and basophils and CD23 on B cells. IgE cross-linked by allergen triggers mast cell activation via FcϵRI, 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 FcϵRI interaction sites are at opposite ends of the Cϵ3 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 FcϵRI 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-FcϵRI and IgE-CD23 interactions. Background: Immunoglobulin E (IgE) has two cellular receptors, FcϵRI and CD23, that mediate distinct functional effects. Results: We have identified the CD23 binding site on IgE and show that FcϵRI and CD23 allosterically compete for binding. Conclusion: A mechanism of communication exists within the IgE molecule to prevent simultaneous engagement with the two receptors. Significance: Competition between IgE receptors explains ligand cross-regulation.