Asymmetric genome organization in an RNA virus revealed via graph-theoretical analysis of tomographic data.
Asymmetric genome organization in an RNA virus revealed via graph-theoretical analysis of tomographic data.
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DOI：
10.1371/journal.pcbi.1004146
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发表时间：
2015-03
影响因子：
4.3
通讯作者：
Twarock R
中科院分区：
文献类型：
--
作者：
Geraets JA;Dykeman EC;Stockley PG;Ranson NA;Twarock R
低温电子显微镜允许三维结构的病毒病原体被确定在显着的细节。特别是，利用在许多病毒中看到的二十面体结构的对称平均技术，已经确定了封装病毒基因组的蛋白质容器的高分辨率。相比之下，不对称成分的结构确定仍然是一个挑战，需要新的分析方法来揭示这些特征并表征它们在感染过程中的功能作用。由于病毒基因组在单链RNA病毒组装中的重要合作作用，我们开发了一种新的分析方法，揭示了病毒基因组在这类病毒衣壳附近的不对称结构组织。该方法利用基于二十面体平均重构知识和rna -衣壳蛋白接触作用的基因组组织几何约束来分析低温电子层析数据。我们将这种方法应用于模型病毒的低分辨率断层扫描数据，并推断其基因组与衣壳蛋白壳接触的独特不对称组织。这为分析病毒基因组提供了前所未有的机会，揭示了抗病毒药物设计中可以针对的保守结构特征和机制。病毒对人类的毁灭性疾病负有责任，并对牲畜和作物造成重大的商业损失。它们的遗传物质通过一种叫做病毒衣壳的蛋白质容器被运送到宿主体内，这种蛋白质容器就像特洛伊木马一样：它们将货物释放到宿主细胞中，劫持宿主细胞的分子机制，以生产后代病毒。利用病毒衣壳对称结构的成像技术已被用于确定其原子分辨率的组织细节，从而开辟了针对特定表面结构设计抗病毒药物的可能性。在许多病毒中，由于基因组在衣壳形成中的作用，它们呈现出特定的组织。为了设计另一类干扰这一过程的抗病毒药物，了解病毒衣壳内基因组的不对称组织是很重要的。这是目前的一个挑战，因为无法使用用于实现蛋白质容器高分辨率结构的平均技术。我们提出了一种新的方法，并证明了它对测试病毒的预测能力。这为更好地理解病毒rna在病毒组装中的功能作用及其在抗病毒药物设计中的利用铺平了道路。
Cryo-electron microscopy permits 3-D structures of viral pathogens to be determined in remarkable detail. In particular, the protein containers encapsulating viral genomes have been determined to high resolution using symmetry averaging techniques that exploit the icosahedral architecture seen in many viruses. By contrast, structure determination of asymmetric components remains a challenge, and novel analysis methods are required to reveal such features and characterize their functional roles during infection. Motivated by the important, cooperative roles of viral genomes in the assembly of single-stranded RNA viruses, we have developed a new analysis method that reveals the asymmetric structural organization of viral genomes in proximity to the capsid in such viruses. The method uses geometric constraints on genome organization, formulated based on knowledge of icosahedrally-averaged reconstructions and the roles of the RNA-capsid protein contacts, to analyse cryo-electron tomographic data. We apply this method to the low-resolution tomographic data of a model virus and infer the unique asymmetric organization of its genome in contact with the protein shell of the capsid. This opens unprecedented opportunities to analyse viral genomes, revealing conserved structural features and mechanisms that can be targeted in antiviral drug design. Viruses are responsible for devastating illnesses in humans and cause significant commercial losses in livestock and crops. Their genetic material is transported into their host organisms via protein containers, called viral capsids, that act as Trojan horses: they release their cargo into the cells of their hosts, hijacking their molecular machinery for the production of progeny viruses. Imaging techniques exploiting the symmetric structures of viral capsids have been used to determine details of their organization to atomic resolution, opening up the possibility to design anti-viral agents against specific surface structures. In many viruses the genomes take on specific organizations as a consequence of their roles in capsid formation. In order to design an additional class of anti-viral drugs that interfere with this process, it is important to understand the asymmetric organization of the genome inside viral capsids. This is currently a challenge, as the averaging techniques used to achieve high resolution structures of the protein containers cannot be used. We present a new approach and demonstrate its predictive power here for a test virus. This paves the way for a better understanding of the functional roles of viral RNAs in virus assembly and their exploitation in anti-viral drug design.
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