The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health and Medical Sciences, Blegdamsvej 3B, 2200, Copenhagen, Denmark.
Department of Chemistry - BMC, Uppsala University, Box 576, Husargatan 3, 751 23, Uppsala, Sweden.
Nat Commun. 2021 Nov 19;12(1):6761. doi: 10.1038/s41467-021-26498-z.
Viral proteins make extensive use of short peptide interaction motifs to hijack cellular host factors. However, most current large-scale methods do not identify this important class of protein-protein interactions. Uncovering peptide mediated interactions provides both a molecular understanding of viral interactions with their host and the foundation for developing novel antiviral reagents. Here we describe a viral peptide discovery approach covering 23 coronavirus strains that provides high resolution information on direct virus-host interactions. We identify 269 peptide-based interactions for 18 coronaviruses including a specific interaction between the human G3BP1/2 proteins and an ΦxFG peptide motif in the SARS-CoV-2 nucleocapsid (N) protein. This interaction supports viral replication and through its ΦxFG motif N rewires the G3BP1/2 interactome to disrupt stress granules. A peptide-based inhibitor disrupting the G3BP1/2-N interaction dampened SARS-CoV-2 infection showing that our results can be directly translated into novel specific antiviral reagents.
病毒蛋白广泛利用短肽相互作用基序来劫持细胞宿主因子。然而，大多数当前的大规模方法无法识别这种重要的蛋白质-蛋白质相互作用。揭示肽介导的相互作用不仅为病毒与其宿主的相互作用提供了分子理解，也为开发新型抗病毒试剂奠定了基础。在这里，我们描述了一种覆盖 23 种冠状病毒株的病毒肽发现方法，该方法提供了关于直接病毒-宿主相互作用的高分辨率信息。我们确定了 18 种冠状病毒中的 269 个基于肽的相互作用，包括人类 G3BP1/2 蛋白与 SARS-CoV-2 核衣壳（N）蛋白中 ΦxFG 肽基序之间的特定相互作用。这种相互作用支持病毒复制，并且通过其 ΦxFG 基序，N 重新连接 G3BP1/2 相互作用组以破坏应激颗粒。一种基于肽的抑制剂破坏 G3BP1/2-N 相互作用，抑制了 SARS-CoV-2 感染，表明我们的结果可以直接转化为新型特异性抗病毒试剂。
