Immunoglobulin E (IgE) plays a pivotal role in allergic responses^1,2. The high-affinity IgE receptor, FcεRI, found on mast cells and basophils, is central to the effector functions of IgE. FcεRI is a tetrameric complex, comprising FcεRIα, FcεRIβ and a homodimer of FcRγ (originally known as FcεRIγ), with FcεRIα recognizing the Fc region of IgE (Fcε) and FcεRIβ–FcRγ facilitating signal transduction³. Additionally, FcRγ is a crucial component of other immunoglobulin receptors, including those for IgG (FcγRI and FcγRIIIA) and IgA (FcαRI)^4,5,6,7,8. However, the molecular basis of FcεRI assembly and the structure of FcRγ have remained elusive. Here we elucidate the cryogenic electron microscopy structure of the Fcε–FcεRI complex. FcεRIα has an essential role in the receptor’s assembly, interacting with FcεRIβ and both FcRγ subunits. FcεRIβ is structured as a compact four-helix bundle, similar to the B cell antigen CD20. The FcRγ dimer exhibits an asymmetric architecture, and coils with the transmembrane region of FcεRIα to form a three-helix bundle. A cholesterol-like molecule enhances the interaction between FcεRIβ and the FcεRIα–FcRγ complex. Our mutagenesis analyses further indicate similarities between the interaction of FcRγ with FcεRIα and FcγRIIIA, but differences in that with FcαRI. These findings deepen our understanding of the signalling mechanisms of FcεRI and offer insights into the functionality of other immune receptors dependent on FcRγ.

免疫球蛋白 E (IgE) 在过敏反应中发挥着关键作用^1,2 。高亲和力 IgE 受体 FcεRI 存在于肥大细胞和嗜碱性粒细胞上，是 IgE 效应子功能的核心。 FcεRI 是一种四聚体复合物，包含 FcεRIα、FcεRIβ 和 FcRγ 同二聚体（最初称为 FcεRIγ），其中 FcεRIα 识别 IgE (Fcε) 的 Fc 区，FcεRIβ-FcRγ 促进信号转导³ 。此外，FcRγ 是其他免疫球蛋白受体的重要组成部分，包括 IgG（FcγRI 和 FcγRIIIA）和 IgA (FcαRI) ^4,5,6,7,8的受体。然而，FcεRI 组装的分子基础和 FcRγ 的结构仍然难以捉摸。在这里，我们阐明了 Fcε-FcεRI 复合物的低温电子显微镜结构。 FcεRIα 在受体组装中起着重要作用，与 FcεRIβ 和两个 FcRγ 亚基相互作用。 FcεRIβ 的结构为紧凑的四螺旋束，类似于 B 细胞抗原 CD20。 FcRγ二聚体表现出不对称结构，并与FcεRIα的跨膜区域卷曲形成三螺旋束。类胆固醇分子增强 FcεRIβ 和 FcεRIα-FcRγ 复合物之间的相互作用。我们的诱变分析进一步表明 FcRγ 与 FcεRIα 和 FcγRIIIA 的相互作用之间存在相似性，但与 FcαRI 的相互作用存在差异。这些发现加深了我们对 FcεRI 信号传导机制的理解，并为了解依赖于 FcRγ 的其他免疫受体的功能提供了见解。