The structure of the IgE Cε2 domain and its role in stabilizing the complex with its high-affinity receptor FcεRlα

The stability of the complex between IgE and its high-affinity receptor; Fc epsilon RI, on mast cells is a critical factor in the allergic response. The long half-life of the complex of IgE bound to this receptor in situ (similar to2 weeks, compared with only hours for the comparable IgG complex) contributes to the permanent sensitization of these cells and, hence, to the immediate response to allergens. Here we show that the second constant domain of IgE, C epsilon2, which takes the place of the flexible hinge in IgG, contributes to this long half-life. When the C epsilon2 domain is deleted from the IgE Fc fragment, leaving only the C epsilon3 and C epsilon4 domains (C epsilon3-4 fragment), the rate of dissociation from the receptor is increased by greater than 1 order of magnitude. We report the structure of the C epsilon2 domain by heteronuclear NMR spectroscopy and show by chemical shift perturbation that it interacts with Fc epsilon RI alpha. By sedimentation equilibrium we show that the C epsilon2 domain binds to the C epsilon3-4 fragment of IgE. These interactions of C epsilon2 with both Fc epsilon RI alpha and C epsilon3-4 provide a structural explanation for the exceptionally slow dissociation of the IgE-Fc epsilon RI alpha complex.