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Publication Abstract from PubMed

Allergic diseases, affecting over a quarter of individuals in industrialized countries, have become significant public health concerns(1,2). The high-affinity Fc receptor for IgE (FcepsilonRI), mainly present on mast cells and basophils, plays a crucial role in allergic diseases(3-5). Monomeric IgE binding to FcepsilonRI regulates mast cell survival, differentiation, and maturation(6-8). However, the underlying molecular mechanism remains unclear. Here we demonstrate that, prior to IgE binding, FcepsilonRI mostly exists as a homo-dimer on human mast cell membrane. The structure of human FcepsilonRI confirms the dimeric organization, with each promoter comprising one alpha subunit, one beta subunit, and two gamma subunits. The transmembrane helices of the alpha subunits form a layered arrangement with those of the gamma and beta subunits. The dimeric interface is mediated by a four-helix bundle of the alpha and gamma subunits at the intracellular juxtamembrane region. Cholesterol-like molecules embedded within the transmembrane domain may stabilize the dimeric assembly. Upon IgE binding, the dimeric FcepsilonRI dissociates into two protomers, each binding to an IgE molecule. Importantly, this process elicits transcriptional activation of Egr1/3 and Ccl2 in rat basophils, which can be attenuated by inhibiting the FcepsilonRI dimer-to-monomer transition. Collectively, our study unveils the mechanism of antigen-independent, IgE-mediated FcepsilonRI activation.

Molecular mechanism of IgE-mediated FcepsilonRI activation.,Chen M, Su Q, Shi Y Nature. 2024 Oct 23. doi: 10.1038/s41586-024-08229-8. PMID:39442557^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.