IRES-mediated translation initiation on viral mRNAs
IRES 介导的病毒 mRNA 翻译起始
基本信息
- 批准号:7616051
- 负责人:
- 金额:$ 22.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2002
- 资助国家:美国
- 起止时间:2002-05-01 至 2013-11-30
- 项目状态:已结题
- 来源:
- 关键词:AccountingAddressAffinityAntiviral AgentsAttenuatedBindingBinding ProteinsBinding SitesBiochemicalCell ExtractsCellsChemicalsClassical swine fever virusCodon NucleotidesComplexDefectDevelopmentElementsEncephalomyocarditis virusFamily PicornaviridaeFoot-and-Mouth Disease VirusFoundationsGenomeHela CellsHepatitis C virusHuman poliovirusHydroxyl RadicalIn VitroIndiumInitiator CodonInitiator tRNAInternal Ribosome Entry SiteInvestigationLightMapsMarinesMediatingMessenger RNAMolecularNeuronsPeptide Initiation FactorsPestivirusPhosphorylationPhosphorylation InhibitionPlayPoliovirusesPositioning AttributeProcessProtein BiosynthesisProteinsPyrimidinePyrimidinesRNARNA VirusesRecruitment ActivityRelaxationResearchResistanceRibosomesRoleScanningSiteSpecificityStagingStructureTrans-ActivatorsTransfer RNATranslatingTranslation InitiationTranslationsViralViral PathogenesisViral ProteinsVirusWorkbasecell typecis acting elementdesigneukaryotic initiation factor-5Bhuman diseaseinhibitor/antagonistinsightneurovirulencepublic health relevancereconstitution
项目摘要
DESCRIPTION (provided by applicant): The genomes of many positive sense RNA viruses contain an internal ribosomal entry site (IRES) that mediates end-independent initiation of translation. IRESs belong to different structural classes and use distinct mechanisms for initiation. Our proposed studies of the process of initiation on representatives of four classes of IRES that use distinct mechanisms will identify important cis-acting elements and provide detailed mechanistic insights into the actions of canonical initiation factors and cellular IRES trans-acting factors (ITAFs) in promoting internal ribosomal entry. Our studies will address mechanisms of increasing complexity. The ~180 nt-long intergenomic region (IGR) IRESs of dicistroviruses mediate initiation without initiator tRNA or initiation factors and the first elongation cycle consequently occurs without deacylated tRNA in the ribosomal P site. We will characterize whether elements in the IRES play an analogous role during elongation to deacylated tRNA when it has been translocated to the E site. The IRES of classical swine fever virus, a pestivirus, is substantially resistant to inhibition by eIF2 phosphorylation, which can be accounted for by the use of two exceptional eIF2-independent mechanisms of initiation. We will determine whether these mechanisms account for the relaxation on this IRES of the ribosome's normally strict avoidance of initiation at non-AUG codons. Type 2 picornavirus IRESs such as the encephalomyocarditis virus IRES bind specifically to eIF4G/eIF4A: we will investigate how these factors promote recruitment of 43S complexes to the initiation codon, how ITAFs induce conformational changes in these IRESs and why only a subset of type 2 IRESs require their activity. The mechanism of initiation on type 1 picornaviruses (e.g. poliovirus) is not known, but also involves specific interaction with eIF4G. We shall characterize this interaction in detail, validate previously identified candidate ITAFs and if necessary isolate additional ITAFs to reconstitute the entire initiation process on this IRES in vitro. We will then characterize interactions between factors and the IRES using chemical/enzymatic footprinting and directed hydroxyl radical cleavage. The studies will provide a framework for understanding of mechanistic details of IRES-mediated initiation, for understanding the cell-type specificity of IRES function and for the design of inhibitors. PUBLIC HEALTH RELEVANCE: The genomes of a number of viruses, including poliovirus, hepatitis C virus and foot-and-mouth disease virus contain structured RNA elements known as `internal ribosomal entry sites' that promote viral protein synthesis by mechanisms that are distinct from those used by the cell. The size and complexity of IRESs varies, but they all coordinate the activities of protein factors in order to recruit ribosomes to translate viral proteins and are consequently essential for virus viability. We are investigating how IRESs work, which may give insights that, will eventually be used in the development of antiviral drugs.
描述(由申请人提供):许多正义RNA病毒的基因组含有介导末端独立翻译起始的内部核糖体进入位点(IRES)。 IRES 属于不同的结构类别并使用不同的启动机制。我们对使用不同机制的四类 IRES 代表的启动过程提出的研究将识别重要的顺式作用元件,并为经典启动因子和细胞 IRES 反式作用因子 (ITAF) 在促进中的作用提供详细的机制见解。内部核糖体进入。我们的研究将解决日益复杂的机制。双顺反子病毒约 180 nt 长的基因组间区域 (IGR) IRES 在没有起始 tRNA 或起始因子的情况下介导起始,因此在核糖体 P 位点没有脱酰化 tRNA 的情况下发生第一个延伸周期。我们将表征当 tRNA 易位至 E 位点时,IRES 中的元件在脱酰化 tRNA 的延伸过程中是否发挥类似的作用。经典猪瘟病毒(一种瘟病毒)的 IRES 对 eIF2 磷酸化的抑制具有显着的抵抗力,这可以通过使用两种特殊的不依赖于 eIF2 的启动机制来解释。我们将确定这些机制是否可以解释核糖体通常严格避免非 AUG 密码子起始的 IRES 的放松。 2 型小核糖核酸病毒 IRES(例如脑心肌炎病毒 IRES)与 eIF4G/eIF4A 特异性结合:我们将研究这些因素如何促进 43S 复合物募集至起始密码子、ITAF 如何诱导这些 IRES 中的构象变化以及为什么只有 2 型 IRES 的一个子集需要他们的活动。 1 型小核糖核酸病毒(例如脊髓灰质炎病毒)的启动机制尚不清楚,但也涉及与 eIF4G 的特异性相互作用。我们将详细描述这种相互作用,验证先前确定的候选 ITAF,并在必要时分离其他 ITAF,以在体外重建 IRES 的整个启动过程。然后,我们将使用化学/酶足迹和定向羟基自由基裂解来表征因素与 IRES 之间的相互作用。这些研究将为了解 IRES 介导的启动机制细节、了解 IRES 功能的细胞类型特异性以及抑制剂的设计提供一个框架。公共卫生相关性:许多病毒的基因组,包括脊髓灰质炎病毒、丙型肝炎病毒和口蹄疫病毒,都含有被称为“内部核糖体进入位点”的结构化 RNA 元件,它们通过不同于其他病毒的机制促进病毒蛋白质合成。被细胞使用。 IRES 的大小和复杂性各不相同,但它们都协调蛋白质因子的活性,以招募核糖体翻译病毒蛋白质,因此对于病毒的生存能力至关重要。我们正在研究 IRES 的工作原理,这可能会提供最终用于抗病毒药物开发的见解。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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CHRISTOPHER Ulrich Tristram HELLEN其他文献
CHRISTOPHER Ulrich Tristram HELLEN的其他文献
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{{ truncateString('CHRISTOPHER Ulrich Tristram HELLEN', 18)}}的其他基金
Mechanisms of SARS-CoV2 translation initiation and shut-off of cellular protein synthesis
SARS-CoV2翻译启动和细胞蛋白质合成关闭的机制
- 批准号:
10354475 - 财政年份:2022
- 资助金额:
$ 22.26万 - 项目类别:
Mechanisms of SARS-CoV2 translation initiation and shut-off of cellular protein synthesis
SARS-CoV2翻译启动和细胞蛋白质合成关闭的机制
- 批准号:
10609872 - 财政年份:2022
- 资助金额:
$ 22.26万 - 项目类别:
Alternative mechanisms of different stages in eukaryotic translation
真核翻译不同阶段的替代机制
- 批准号:
10408702 - 财政年份:2012
- 资助金额:
$ 22.26万 - 项目类别:
Alternative mechanisms of different stages in eukaryotic translation
真核翻译不同阶段的替代机制
- 批准号:
10161790 - 财政年份:2012
- 资助金额:
$ 22.26万 - 项目类别:
IRES-mediated translation initiation on viral mRNAs
IRES 介导的病毒 mRNA 翻译起始
- 批准号:
6457319 - 财政年份:2002
- 资助金额:
$ 22.26万 - 项目类别:
IRES-mediated translation initiation on viral mRNAs
IRES 介导的病毒 mRNA 翻译起始
- 批准号:
6738149 - 财政年份:2002
- 资助金额:
$ 22.26万 - 项目类别:
IRES-mediated translation initiation on viral mRNAs
IRES 介导的病毒 mRNA 翻译起始
- 批准号:
7750592 - 财政年份:2002
- 资助金额:
$ 22.26万 - 项目类别:
IRES-mediated translation initiation on viral mRNAs
IRES 介导的病毒 mRNA 翻译起始
- 批准号:
8197408 - 财政年份:2002
- 资助金额:
$ 22.26万 - 项目类别:
IRES-mediated translation initiation on viral mRNAs
IRES 介导的病毒 mRNA 翻译起始
- 批准号:
6622818 - 财政年份:2002
- 资助金额:
$ 22.26万 - 项目类别:
IRES -mediated translation initiation on viral mRNAs
IRES 介导的病毒 mRNA 翻译起始
- 批准号:
7668340 - 财政年份:2002
- 资助金额:
$ 22.26万 - 项目类别:
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