Revealed at last: Structure of the antibody-receptor complex common to all IgE-mediated allergic hypersensitivity reactions

Good news!

From the abstract:

"Immunoglobulin E (IgE) binds with high affinity to its receptor, FcεRI, on mast cells and basophils, and cross-linking of allergen-specific IgE by minute amounts of multivalent allergen stimulates a powerful and immediate allergic reaction. In this issue of Science Signaling, Zhang et al. report the three-dimensional structures of the human and murine receptors, with and without bound IgE-Fc, to reveal some intriguing differences between mouse and human in this critical antibody-receptor interaction."

From the editor's summary and abstract:

"Editor’s summary

Binding of immunoglobulin E (IgE) to its high-affinity receptor FcεRI on mast cells and basophils stimulates allergic reactions. The limited number of antibody-based therapies to treat allergies could be expanded by a better understanding of the IgE-bound receptor complex (see the Focus by Sutton). By solving the cryo-EM structures of human and mouse FcεRI bound to IgE-Fc, Zhang et al. found species-specific differences in interactions between IgE and the extracellular domains of the receptors. Unexpectedly, the binding of IgE-Fc to mouse FcεRI caused no conformational changes in the receptor. Together, these findings may inform the development of improved inhibitors of IgE-mediated allergic responses. ...

Abstract

The high-affinity immunoglobulin E (IgE) receptor (FcεRI) drives type I hypersensitivity in response to allergen-specific IgE. FcεRI is a multimeric complex typically composed of one α, one β, and two disulfide-linked γ subunits. The α subunit binds to the fragment crystallizable (Fc) region of IgE (Fcε), whereas the β and γ subunits mediate signaling through their intracellular immunoreceptor tyrosine–based activation motifs (ITAMs). Here, we report cryo–electron microscopy (cryo-EM) structures of the apo state of FcεRI and of FcεRI bound to Fcε. At the transmembrane domain (TMD), the α and γ subunits associate to form a tightly packed, three-helix bundle (αγ2 bundle) with pseudo-threefold symmetry through extensive hydrophobic and polar interactions. The αγ2 bundle further assembles with the β subunit to complete the TMD, from which multiple ITAMs might extend into the cytoplasm for downstream signaling. The apo mouse FcεRI essentially forms an identical structure to that of the Fcε-bound sensitized form, suggesting that the binding of Fcε to FcεRI does not alter the overall conformation of the receptor. Furthermore, the juxtamembrane interaction between the extracellular domains (ECDs) of mouse FcεRIα and FcεRIβ is not observed between their human counterparts, which implies potential species-specific differences in receptor stability and activation. Our findings provide a framework for understanding the general structural principles underlying Fc receptor assembly, the signaling mechanism underlying type I hypersensitivity, and the design of efficient antiallergic therapeutics."

Revealed at last: Structure of the antibody-receptor complex common to all IgE-mediated allergic hypersensitivity reactions | Science Signaling (no public access)

Architecture of the high-affinity immunoglobulin E receptor (no public access)