Structural insights into the high-affinity IgE receptor FcεRI complex

• 成果类型: Article
• 署名作者: Deng, Meijie; Du, Shuo; Hou, Handi; Xiao, Junyu
• 署名单位: Peking University; Changping Laboratory; Peking University; Peking University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4481
• DOI: 10.1038/s41586-024-07864-5
• 发表日期: 2024-09-26
• 关键词: t-cell-receptor; human-immunoglobulin-e; gamma-chain; tyrosine phosphorylation; transmembrane domains; alpha-chain; zeta-chain; expression; subunit; association

摘要

Immunoglobulin E (IgE) plays a pivotal role in allergic responses(1,2). The high-affinity IgE receptor, Fc epsilon RI, found on mast cells and basophils, is central to the effector functions of IgE. Fc epsilon RI is a tetrameric complex, comprising Fc epsilon RI alpha, Fc epsilon RI beta and a homodimer of FcR gamma (originally known as Fc epsilon RI gamma), with Fc epsilon RI alpha recognizing the Fc region of IgE (Fc epsilon) and Fc epsilon RI beta-FcR gamma facilitating signal transduction(3). Additionally, FcR gamma is a crucial component of other immunoglobulin receptors, including those for IgG (Fc gamma RI and Fc gamma RIIIA) and IgA (Fc alpha RI)(4-8). However, the molecular basis of Fc epsilon RI assembly and the structure of FcR gamma have remained elusive. Here we elucidate the cryogenic electron microscopy structure of the Fc epsilon-Fc epsilon RI complex. Fc epsilon RI alpha has an essential role in the receptor's assembly, interacting with Fc epsilon RI beta and both FcR gamma subunits. Fc epsilon RI beta is structured as a compact four-helix bundle, similar to the B cell antigen CD20. The FcR gamma dimer exhibits an asymmetric architecture, and coils with the transmembrane region of Fc epsilon RI alpha to form a three-helix bundle. A cholesterol-like molecule enhances the interaction between Fc epsilon RI beta and the Fc epsilon RI alpha-FcR gamma complex. Our mutagenesis analyses further indicate similarities between the interaction of FcR gamma with Fc epsilon RI alpha and Fc gamma RIIIA, but differences in that with Fc alpha RI. These findings deepen our understanding of the signalling mechanisms of Fc epsilon RI and offer insights into the functionality of other immune receptors dependent on FcR gamma.