ROLE OF VIRAL IRES-RIBOSOME INTERACTIONS IN TRANLATION

真核细胞的生存能力依赖于蛋白质合成起始的严格调控。 有越来越多的证据表明，这种调节涉及重要的构象变化内的 核糖体的小（40S）亚基。为了探讨其分子基础和功能作用， 这些构象的变化，在40S亚基，我们将审查方面的翻译起始 由病毒基因表达控制的调节。许多病毒，如丙型肝炎， 核糖体进入位点（IRES）在他们的信使RNA，规避传统的启动。这些 IRES不需要完整的翻译起始因子来发挥功能。这使得 病毒绕过在病毒感染时抑制翻译的细胞途径。了解 病毒IRES使用的分子机制将大大有助于抗病毒策略的发展， 对抗毁灭性的人类病毒性疾病。蟋蟀麻痹病毒含有和IRES（CrPV IRES） 它不需要任何起始因子，甚至不需要起始tRNA。 有趣的是，CrPV IRES在所有类型的真核生物核糖体上起作用，包括人类核糖体。 核糖体因此，阐明其潜在的作用机制将揭示 真核生物核糖体对翻译起始起重要作用。 该提案的具体目标如下。1)40S亚基的构象变化图 在翻译起始期间由丙型肝炎病毒IRES诱导，和2）映射构象变化 在翻译起始期间由蟋蟀麻痹病毒IRES诱导的40S亚基中。

The viability of eukaryotic cells relies upon the tight regulation of the initiation of protein synthesis. There is mounting evidence that this regulation involves important conformational changes within the small (40S) subunit of the ribosome. In order to probe the molecular basis and functional roles of these conformational changes in the 40S subunit, we will examine aspects of translation initiation regulation controlled by viral gene expression. Many viruses such as hepatitis C contain internal ribosome entry sites (IRESs) in their messenger RNAs that circumvent conventional initiation. These IRESs do not require the full complement of translation initiation factors to function. This enables viruses to bypass cellular pathways that inhibit translation upon viral infection. Understanding the molecular mechanisms used by viral IRESs will greatly aid in the development of antiviral strategies to combat devastating human viral diseases. The Cricket Paralysis Virus contains and IRES (CrPV IRES) that requires none of the initiation factors, and even circumvents the need for initiator tRNA. Interestingly, the CrPV IRES functions on all classes of eukaryotic ribosome, including human ribosomes. Elucidating its underlying mechanism of action will therefore reveal general features of eukaryotic ribosomes important for translation initiation. The specific aims of the proposal are the following. 1) Map conformational changes in the 40S subunit induced by the hepatitis C Virus IRES during translation initiation, and 2) map conformational changes in the 40S subunit induced by the Cricket Paralysis Virus IRES during translation initiation.