The stability of the complex between IgE and its high-affinity receptor, FcεRI, 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 (∼ 2 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, Cε2, which takes the place of the flexible hinge in IgG, contributes to this long half-life. When the Cε2 domain is deleted from the IgE Fc fragment, leaving only the Cε3 and Cε4 domains (Cε3-4 fragment), the rate of dissociation from the receptor is increased by greater than I order of magnitude. We report the structure of the Cε2 domain by heteronuclear NMR spectroscopy and show by chemical shift perturbation that it interacts with FcεRIα. By sedimentation equilibrium we show that the Cε2 domain binds to the Cε3-4 fragment of IgE. These interactions of Cε2 with both FcεRIα and Cε3-4 provide a structural explanation for the exceptionally slow dissociation of the IgE-FcεRIα complex.
ASJC Scopus subject areas
- Structural Biology