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2024

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08

Xiao Junyu/Du Shuo Reveals Assembly Mechanism of IgE High Affinity Receptor FcεRI Complex!

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Immunoglobulin E (IgE) plays a key role in allergic reactions. The high-affinity IgE receptor Fc ε RI is present inmast celland basophils, which are at the core of IgE effector function.Fceis a tetrameric complex consistingFce alpha,Fce β andFcRThe homodimer of gamma (originally calledFce γ) composition, whereFceα recognizes the Fc region of IgE (Fcε) andFce β-FcRγ promotes signal transduction.In addition, FcRγ is an important component of other immunoglobulin receptors, including IgG (FcγRI and FcγRIIIA) and IgA (FcαRI). however,FceThe molecular basis of assembly andFcRcThe structure is still unknown.

On August 21, 2024, Xiao Junyu of Peking University and Du Shuo of Changping Laboratory jointly communicatedNaturePublished online entitled"Structural insights into the high-affinity IgE receptor FcεRI complex"'s research paper,The study reportedCryo-electron microscopic structures of Fcε-FcεRI complexes.

FcεRIα plays an important role in the assembly of the receptor, interacting with FcεRIβ and the two FcRγ subunits. FcεRIβ is structured as a tight four-helix bundle, similar to the B cell antigen CD20. The FcRγ dimer has an asymmetric structure and forms a three-helix bundle with the transmembrane region of FcεRIα. A cholesterol-like molecule enhances the interaction between FcεRIβ and FcεRIα-FcRγ complexes.Mutagenesis analysis further indicated that FcRγ had similar interactions with FcεRIα and FcγRIIIA, but there were differences in interactions with FcαRI.These findings deepen the understanding of FcRγ signaling mechanisms and provide insights into the function of other FcRγ-dependent immune receptors.

In mast cells and basophils, FcεRI is a tetramer composed of one FcεRI α chain, one FcεRI β chain and two FcRγ (also known as FcεRI γ) chains, which is the key to cell degranulation and allergic reactions.FceThe alpha chain includes an extracellular domain that binds to Fcε (sFcεRIα), a single transmembrane (TM) helix, and a short cytoplasmic tail.Removal of the cytoplasmic tail of FcεRIα did not impair receptor function, suggesting that its primary role is to recognize IgE, while FcεRIβ and FcRγ chains are responsible for signal transduction.

FcεRIβ is a member of the transmembrane 4A (MS4A) family and contains intracellular immunoreceptor tyrosine activation motifs (Itam), this motif can be phosphorylated by Src family kinases, especially Lyn, thereby initiating or enhancing the IgE signaling pathway. Similarly, FcRγ also has an ITAM motif and acts as a signal adapter in the FcεRI complex.In humans, FcεRI is also present in other cell types, including antigen-presenting cells, as an αγ2 trimer lacking the FcεRI β chain. Despite its importance, the molecular mechanisms underlying FcεRI assembly are still not fully understood.

The FcR gamma chain was originally thought to beFcecomplex (hence knownFceγ), which was later considered to be a component of several other Fc receptors. These include FcγRI (also known as CD64) and FcγRIIIA (also known as CD16A), which bind IgG, and FcαRI (also known as CD89), a receptor for IgA. Therefore, it is now more widely known as the Fc receptor gamma chain (FcRγ). Binding of a specific antibody-antigen complex to its corresponding receptor triggers phosphorylation of ITAM motifs on FcRγ, which then recruits and activates spleen tyrosine kinase, initiating a range of effector functions.In addition to these effects, FcRγ is associated with a variety of other immune receptors, particularly members of the leukocyte receptor cluster (LRC) family, such as the natural cytotoxicity triggering receptor 1 (NCR1; also known as NKp46), the platelet collagen receptor glycoprotein VI (GPVI), and the osteoclast-associated receptor (OSCAR), among others.In addition, the TM region of FcRγ has significant homology with CD3ζ (CD247), which is a T cell receptor (TCR) are important components of the complex. However, the precise molecular mechanism of FcRγ function remains to be fully elucidated.
In this study, the authors revealed the cryo-electron microscopy structure of the FcεRI signaling complex, revealing the molecular complexity of its assembly. TheThe results of the study show that the FcεRI complex is organized in a 1:1:2 stoichiometric structure, and FcεRI alpha is located in the core. Notably, FcεRIβ adopts a compact four-helix bundle structure, and the tight packing of its four TMs suggests that FcεRIβ resembles CD20 and may not act as a calcium channel.In conclusion, this study improves the understanding of FcεRI assembly and function, and also provides a reference for other immune receptors that use FcεRIγ/FcRγ subunits to signal.
Professor Xiao Junyu and Associate Researcher Du Shuo of Changping Laboratory are the co-corresponding authors of this paper, and Deng Meijie and Associate Researcher Du Shuo, a 2020-level doctoral student in the School of Life Sciences of Peking University, are the co-first authors. In addition, Hou Handi, a 2023-level doctoral student in the Institute of Frontier Interdisciplinary Research of Peking University and Changping Laboratory, provided assistance for the paper.

This study was supported by the National Natural Science Foundation of China, Changping Laboratory, and the Qidong Industrial Innovation Fund of the School of Life Sciences, Peking University. The cryo-electron microscope platform of Peking University, the cryo-electron microscope platform of Changping Laboratory, and the Instrument Center of School of Life Sciences of Peking University provided important support for this project.

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