Structural determinants of viral RNAs resistant to exoribonucleases in the alphavirus supergroup

甲病毒超群中抗核糖核酸外切酶的病毒RNA的结构决定因素

• 批准号: 10311545
• 负责人: Quentin Vicens
• 金额: $ 19.09万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311545
• 关键词: 3-Dimensional; Address; Alphavirus; Biochemical; Biological Assay; Biology; Chemicals; Computing Methodologies; Data; Digestion; Distant; Elements; Evolution; Exonuclease; Exoribonucleases; Family; Flavivirus; Foundations; Future; Genome; Hepatitis E virus; Infection; Knowledge; Learning; Light; Membrane Proteins; Methods; Modeling; Mutagenesis; Nucleotides; Pathogenicity; Pathway interactions; Plant Viruses; Process; Production; RNA; RNA Folding; RNA Viruses; Resistance; Role; Structure; Surface; Taxonomy; Techniques; Testing; Time; Tombusviridae; Variant; Viral; Virus; Virus Diseases; Work; X-Ray Crystallography; base; chikungunya; human pathogen; improved; member; molecular clock; resistance mechanism; structural biology; three dimensional structure; viral RNA; virome

Summary Structured elements within genomes of RNA viruses have critical roles during infection. Examples are exonuclease-resistant RNAs (xrRNAs) that resist degradation by host cellular exoribonucleases, leading to the production of viral subgenomic RNAs. Detailed three-dimensional structural studies of xrRNAs from flaviviruses and a subset of plant viruses led to a mechanistic model in which xrRNAs block enzymatic digestion using a ring-like structure that braces against the protein surface. Very recently, a new xrRNA class was found in the more distantly related and diverse alphavirus supergroup, which includes several important human pathogens. Initially found in the Benyviridae and several other virus families, this xrRNA has no obvious similarity to those previously studied. Thus, we do not know how it folds, how it blocks the host exonuclease, and how widespread it is distributed. These fundamental gaps in knowledge block progress in understanding what could be a pervasive and important RNA element in the alphavirus supergroup and beyond. In addition, because xrRNAs have been found in several major superfamilies of viruses, they may represent a `molecular clock' that could help us understand virus evolution and pathogenicity. To that end, understanding the fold of the xrRNA from Benyviridae is critical. Here, we propose to address these key unknowns and enable future studies by pursuing two aims. First, we will determine the structural basis of exonuclease resistance by the new class of xrRNA from Benyviridae. This aim will use advanced structural biology methods to inform not only on the mechanism for resistance to degradation, but also enable accurate searches for similar motifs throughout the alphavirus supergroup. Second, we will determine the distribution of the xrRNA fold from Benyviridae across the viral world. This aim combines computational and biochemical approaches, which has previously led to successfully characterizing xrRNAs that were also considered `exotic' at the time. Exploring how widespread this new class of xrRNAs is has the potential to illuminate the biology of viruses of diverse but related alphavirus supergroup members, expand our knowledge of RNA structure in the viral world, and motivate futures studies into the roles of xrRNAs in virus-induced disease.

概括 RNA病毒基因组中的结构化元素在感染过程中具有关键作用。例如 抗核酸酶的RNA（XRRNA），可抵抗宿主细胞驱虫核酸酶降解，导致导致 病毒亚基因组RNA的产生。 XRRNA的详细的三维结构研究 一部分植物病毒导致了一种机械模型，其中XRRNA使用A酶消化阻止 环状结构，靠在蛋白质表面。最近，在 更远的相关和多样化的α病毒超组，其中包括几种重要的人类病原体。 最初在Benyviridae和其他几个病毒家族中发现，该XRRNA与那些没有明显的相似性 先前研究过。因此，我们不知道它如何折叠，如何阻止主机外切酶以及如何阻止 广泛分发。这些知识的基本差距阻碍了理解什么可能 成为α超级组及以后的普遍且重要的RNA元素。另外，因为 Xrrnas已在几种主要的超级家族病毒中发现，它们可能代表一个“分子时钟” 可以帮助我们了解病毒的进化和致病性。为此，了解XRRNA的折叠 来自Benyviridae至关重要。在这里，我们建议解决这些关键未知数，并通过 追求两个目标。首先，我们将确定新的核酸酶抵抗的结构基础 来自Benyviridae的XRRNA类。此目标将使用先进的结构生物学方法不仅告知 关于抵抗降解的机制，但也可以准确搜索相似的基线 在整个alphavirus超组中。其次，我们将确定XrRNA折叠的分布 整个病毒世界中的贝尼维迪科。这个目的结合了计算和生化方法， 以前已导致成功地描述了当时也被认为是“异国情调”的XRRNA。 探索这一新类XRRNA的广泛性有可能阐明病毒的生物学 多样化但相关的α病毒超组成员，扩展了我们对病毒世界中RNA结构的了解， 并激励未来研究XRRNA在病毒诱导的疾病中的作用。