登革热病毒 SLA RNA 启动子的特征及其与病毒非结构 NS5 蛋白的相互作用

IF 4.3 3区 材料科学 Q1 ENGINEERING, ELECTRICAL & ELECTRONIC
Karl Brillet , Marta Janczuk-Richter , Amanda Poon , Joanne Laukart-Bradley , Eric Ennifar , Isabelle Lebars
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引用次数: 0

摘要

登革热病毒(DENV)是人类最主要的节肢动物传播病毒病原体,每年感染人数达 4 亿。登革热病毒由四种不同的血清型(DENV-1 至 DENV-4)组成,这使得疫苗开发变得复杂。这四种血清型中的任何一种都可引起临床疾病,但感染动态各不相同。四种基因组中发现的序列变异会导致关键 RNA 主题的结构差异,这些差异被认为与 DENV-1 至 -4 的致病性程度相关。 特别是基因组 5′ 端的 RNA 干环 A (SLA),通过与病毒 NS5 聚合酶相互作用来启动负链病毒 RNA 的合成,随后对合成的 RNA 进行甲基化和封顶,从而充当病毒复制周期的关键调节器。这种相互作用的分子细节仍未得到充分描述。在此,我们报告了 DENV-1 至 -4 中 SLA 的溶液二级结构。我们的研究结果表明,四种 SLA 在结构上和动态上存在差异。其次,为了确定SLA RNA是否包含病毒NS5蛋白识别的血清型特异性决定因素,我们使用综合生物物理方法研究了DENV-1至-4的SLA与DENV2 NS5之间的相互作用。我们的研究结果表明,DENV2 的 NS5 能够与其他血清型的 SLA 结合,但可能需要其他病毒或宿主因子来稳定复合物并促进 NS5 的催化活性状态。相比之下,我们发现血清型特异性结合是由涉及 SLA RNA 内构象变化的特异性相互作用驱动的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Characterization of SLA RNA promoter from dengue virus and its interaction with the viral non-structural NS5 protein

The Dengue virus (DENV) is the most significant arthropod-borne viral pathogen in humans with 400 million infections annually. DENV comprises four distinct serotypes (DENV-1 to -4) which complicates vaccine development. Any of the four serotypes can cause clinical illness but with distinctive infection dynamics. Variations in sequences identified within the four genomes induce structural differences in crucial RNA motifs that were suggested to be correlated to the degree of pathogenicity among DENV-1 to -4. In particular, the RNA Stem-loop A (SLA) at the 5′-end of the genome, acts as a key regulator of the viral replication cycle by interacting with the viral NS5 polymerase to initiate the minus-strand viral RNA synthesis and later to methylate and cap the synthesized RNA. The molecular details of this interaction remain not fully described. Here, we report the solution secondary structures of SLA from DENV-1 to -4. Our results highlight that the four SLA exhibit structural and dynamic differences. Secondly, to determine whether SLA RNA contains serotype-specific determinants for the recognition by the viral NS5 protein, we investigated interactions between SLA from DENV -1 to -4 and DENV2 NS5 using combined biophysical approaches. Our results show that NS5 from DENV2 is able to bind SLA from other serotypes, but that other viral or host factors may be necessary to stabilize the complex and promote the catalytically active state of the NS5. By contrast, we show that a serotype-specific binding is driven by specific interactions involving conformational changes within the SLA RNA.

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来源期刊
CiteScore
7.20
自引率
4.30%
发文量
567
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