同源受体GPR15对非典型趋化因子样肽GPR15L的分子识别-动脉网

Molecular recognition of the atypical chemokine-like peptide GPR15L by its cognate receptor GPR15

Nature 等信源发布 2024-06-25 13:19

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Dear Editor,The atypical chemoattractant receptor GPR15, a class-A GPCR, is significantly involved in colorectal cancer pathogenesis and the maintenance of intestinal immune homeostasis. Originally identified as a co-receptor for human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV), GPR15 regulates the targeted homing of T cells, notably FOXP3+ regulatory T cells (Tregs), to the lamina propria of the large intestine1.

亲爱的编辑，非典型化学引诱物受体GPR15是一种a类GPCR，与结直肠癌的发病机制和肠道免疫稳态的维持密切相关。最初被鉴定为人类免疫缺陷病毒（HIV）或猿猴免疫缺陷病毒（SIV）的共同受体，GPR15调节T细胞（特别是FOXP3+调节性T细胞（Tregs））靶向归巢至大肠固有层1。

Moreover, GPR15 mediates Tregs homing and immunosuppression in the mouse colon2. Recently, a natural ligand for GPR15, C10orf99 (GPR15L), has been identified. It is a chemokine-like peptide strongly expressed in gastrointestinal tissues, confirming that the GPR15-GPR15L axis constitutes a novel signaling pathway capable of regulating intestinal homeostasis and inflammation through the migration of immune cells3,4.GPR15L shares certain characteristics with the CC chemokine family.

此外，GPR15介导小鼠结肠中的Tregs归巢和免疫抑制。最近，已经鉴定出GPR15的天然配体C10orf99（GPR15L）。它是一种在胃肠道组织中强烈表达的趋化因子样肽，证实GPR15-GPR15L轴构成了一种新的信号通路，能够通过免疫细胞的迁移调节肠道稳态和炎症3,4.GPR15L与CC趋化因子家族具有某些特征。

Its uniqueness lies in the C-terminal region, serving as the activation domain, distinguishing it from traditional chemokines4. Specifically, the 11 amino acids at the C-terminus of GPR15L (GPR15LC11) have been shown to exhibit potent efficacy in activating GPR155.Understanding the molecular recognition between the GPR15L–GPR15 pair and the signaling mechanism of GPR15 via its downstream Gi proteins is crucial to providing insight into the development of peptide-derived ligands and pharmaceuticals to treat intestinal disorders.

它的独特性在于C末端区域，作为激活域，将其与传统趋化因子区分开来4。具体而言，GPR15L（GPR15LC11）C末端的11个氨基酸已显示出激活GPR155的有效功效。了解GPR15L-GPR15对之间的分子识别以及GPR15通过其下游Gi蛋白的信号传导机制对于深入了解肽衍生配体和药物治疗肠道疾病的发展至关重要。

To this end, we present the Cryo-EM structure of the GPR15–Gi complex bound to GPR15LC11 at 2.9 Å resolution (Fig. 1a, b; Supplementary Figs. S1, S2, S3, Table S1 and Materials and Methods). This structural elucidation marks a significant stride towards unraveling the intricacies of GPR15-mediated signaling and provides a solid foundati.

为此，我们介绍了以2.9Å分辨率与GPR15LC11结合的GPR15-Gi复合物的低温EM结构（图1a，b；补充图S1，S2，S3，表S1以及材料和方法）。这种结构阐明标志着朝着解开GPR15介导的信号传导的复杂性迈出了重要的一步，并提供了坚实的基础。

Data availability

数据可用性

The atomic coordinates and the electron microscopy maps of the GPR15LC11–GPR15–Gi have been deposited in the Protein Data Bank (PDB) under accession code 8ZQE, and Electron Microscopy Data Bank (EMDB) under accession code EMD-60384.

GPR15LC11–GPR15–Gi的原子坐标和电子显微镜图已以登录号8ZQE保存在蛋白质数据库（PDB）中，并以登录号EMD-60384保存在电子显微镜数据库（EMDB）中。

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Download referencesAcknowledgementsThis work was supported by the National Natural Science Foundation of China (32071194 to F.X.), and Shanghai JiaoTong University School of Medicine–ShanghaiTech University Cross-funded Collaborative Program (JYJC202233 to F.X.). The cryo-EM data were collected at the Bio-EM Facility, ShanghaiTech University, with the assistance of Qianqian Sun, Li Wang, and other staff members.

下载参考文献致谢这项工作得到了国家自然科学基金（32071194至F.X.）和上海交通大学医学院-上海理工大学交叉资助合作项目（JYJC202233至F.X.）的支持。在孙倩倩，王丽和其他工作人员的帮助下，在上海理工大学生物电磁设施收集了低温电磁数据。

We also thank the staff of the Cell Expression, Assay, Cloning, and Purification Core Facilities of the iHuman Institute for their support. We thank Niandong Wang, Xi Lin, Yuxiang Chen, Lier Liu, Wentong Wang and Yue Shi for their help in this study.Author informationAuthor notesThese authors contributed equally: Zhongyuan Zhang, You Zheng.Authors and AffiliationsiHuman Institute, ShanghaiTech University, Shanghai, ChinaZhongyuan Zhang, You Zheng, Lu Xu, Yang Yue, Kexin Xu, Fei Li & Fei XuSchool of Life Science and Technology, ShanghaiTech University, Shanghai, ChinaZhongyuan Zhang, Kexin Xu & Fei XuShanghai Clinical Research and Trial Center, Shanghai, ChinaFei XuAuthorsZhongyuan ZhangView author publicationsYou can also search for this author in.

我们还感谢iHuman研究所细胞表达，测定，克隆和纯化核心设施的工作人员的支持。我们感谢王念东，西林，陈玉祥，刘立尔，王文通和岳石在这项研究中的帮助。作者信息作者注意到这些作者做出了同样的贡献：张中原，尤政。作者和附属机构上海理工大学人类研究所，上海，中国张中原，尤政，陆旭，杨跃，徐可欣，费莉和徐飞飞上海理工大学生命科学与技术学院，上海，中国张中原，徐可欣和徐飞飞上海临床研究与试验中心，中国徐飞飞作者张中原观点作者出版物您也可以在中搜索这位作者。

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PubMed Google ScholarContributionsZ.Z. designed the expression constructs, purified the receptor complexes, prepared the final samples for cryo-EM sample and cryo-EM data collection, and participated in the figure and manuscript preparation. Y.Z. did the EM data processing and structure determination.

PubMed谷歌学术贡献。Z、设计表达构建体，纯化受体复合物，制备用于冷冻EM样品和冷冻EM数据收集的最终样品，并参与图形和手稿的制备。Y、 Z.进行了EM数据处理和结构确定。

L.X. and Y.Y. participated in the project discussion and the figure preparation. K.X. assisted in the purification of the receptor. F.L. performed the cAMP functional assay. F.X. initiated the project, conceived and supervised the research, and wrote the manuscript with input from all authors.Corresponding authorCorrespondence to.

五十、 X.和Y.Y.参与了项目讨论和图形准备。K、 X.协助纯化受体。F、 L.进行cAMP功能测定。F、 X.启动了该项目，构思并监督了研究，并在所有作者的投入下撰写了手稿。对应作者对应。

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Reprints and permissionsAbout this articleCite this articleZhang, Z., Zheng, Y., Xu, L. et al. Molecular recognition of the atypical chemokine-like peptide GPR15L by its cognate receptor GPR15.

转载和许可本文引用本文Zhang，Z.，Zheng，Y.，Xu，L。等人。通过其同源受体GPR15对非典型趋化因子样肽GPR15L的分子识别。

Cell Discov 10, 69 (2024). https://doi.org/10.1038/s41421-024-00698-5Download citationReceived: 22 March 2024Accepted: 05 June 2024Published: 25 June 2024DOI: https://doi.org/10.1038/s41421-024-00698-5Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

Cell Discov 10,69（2024）。https://doi.org/10.1038/s41421-024-00698-5Download引文接收日期：2024年3月22日接受日期：2024年6月5日发布日期：2024年6月25日OI：https://doi.org/10.1038/s41421-024-00698-5Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。。

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