Vertebrate-class-specific binding modes of the alphavirus receptor MXRA8.

IF 45.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Cell Pub Date : 2023-10-26 Epub Date: 2023-10-06 DOI:10.1016/j.cell.2023.09.007

Ofer Zimmerman, Maxwell I Zimmerman, Saravanan Raju, Christopher A Nelson, John M Errico, Emily A Madden, Autumn C Holmes, Ahmed O Hassan, Laura A VanBlargan, Arthur S Kim, Lucas J Adams, Katherine Basore, Bradley M Whitener, Sathvik Palakurty, Hannah G Davis-Adams, Chengqun Sun, Theron Gilliland, James T Earnest, Hongming Ma, Gregory D Ebel, Christian Zmasek, Richard H Scheuermann, William B Klimstra, Daved H Fremont, Michael S Diamond

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Abstract

MXRA8 is a receptor for chikungunya (CHIKV) and other arthritogenic alphaviruses with mammalian hosts. However, mammalian MXRA8 does not bind to alphaviruses that infect humans and have avian reservoirs. Here, we show that avian, but not mammalian, MXRA8 can act as a receptor for Sindbis, western equine encephalitis (WEEV), and related alphaviruses with avian reservoirs. Structural analysis of duck MXRA8 complexed with WEEV reveals an inverted binding mode compared with mammalian MXRA8 bound to CHIKV. Whereas both domains of mammalian MXRA8 bind CHIKV E1 and E2, only domain 1 of avian MXRA8 engages WEEV E1, and no appreciable contacts are made with WEEV E2. Using these results, we generated a chimeric avian-mammalian MXRA8 decoy-receptor that neutralizes infection of multiple alphaviruses from distinct antigenic groups in vitro and in vivo. Thus, different alphaviruses can bind MXRA8 encoded by different vertebrate classes with distinct engagement modes, which enables development of broad-spectrum inhibitors.

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α病毒受体MXRA8的脊椎动物类特异性结合模式。

MXRA8是基孔肯雅病毒（CHIKV）和其他哺乳动物宿主的关节炎原性α病毒的受体。然而，哺乳动物MXRA8不与感染人类和具有鸟类宿主的阿尔法病毒结合。在这里，我们表明，鸟类而非哺乳动物的MXRA8可以作为Sindbis、西方马脑炎（WEEV）和与鸟类宿主相关的α病毒的受体。鸭MXRA8与WEEV复合物的结构分析揭示了与哺乳动物MXRA8结合CHIKV相比的反向结合模式。哺乳动物MXRA8的两个结构域都结合CHIKV E1和E2，而鸟类MXRA8只有结构域1与WEEV E1结合，并且与WEEV E2没有明显的接触。利用这些结果，我们产生了一种嵌合的禽-哺乳动物MXRA8诱饵受体，该受体在体外和体内中和来自不同抗原群的多种α病毒的感染。因此，不同的α病毒可以以不同的接合模式结合由不同脊椎动物类编码的MXRA8，这使得能够开发广谱抑制剂。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.