Structure of the Fc fragment of human IgE bound to its high-affinity receptor FcεRIα

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Abstract
The initiation of immunoglobulin-E (IgE)-mediated allergic responses requires the binding of IgE antibody to its high-affinity receptor, FcεRI. Crosslinking of FcεRI initiates an intracellular signal transduction cascade that triggers the release of mediators of the allergic response. The interaction of the crystallizable fragment (Fc) of IgE (IgE-Fc) with FcεRI is a key recognition event of this process and involves the extracellular domains of the FcεRI α-chain. To understand the structural basis for this interaction, we have solved the crystal structure of the human IgE-Fc–FcεRIα complex to 3.5-Å resolution. The crystal structure reveals that one receptor binds one dimeric IgE-Fc molecule asymmetrically through interactions at two sites, each involving one Cε3 domain of the IgE-Fc. The interaction of one receptor with the IgE-Fc blocks the binding of a second receptor, and features of this interaction are conserved in other members of the Fc receptor family. The structure suggests new approaches to inhibiting the binding of IgE to FcεRI for the treatment of allergy and asthma.