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Structural Virology of Tripartite Motif Proteins

三联基序蛋白的结构病毒学

基本信息

批准号：
10213609
负责人：
Owen Pornillos
金额：
$ 32.75万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10213609
关键词：
AIDS/HIV problem Amino Acid Motifs Antiviral Agents Binding Biochemical Capsid Cells Characteristics Coiled-Coil Domain Complex Defense Mechanisms Dengue Virus Enzymes Epitopes Funding Genome Goals HIV-1 In Vitro Intercept Lead Mediating Messenger RNA Methods Modeling Molecular Molecular Structure Molecular Target Murine leukemia virus Nucleic Acids Pathway interactions Pattern Recognition Positioning Attribute Predisposition Process Protein Family Proteins Public Health RNA RNA Binding RNA Viruses RNA-Binding Proteins Reagent Research Retroviridae Reverse Transcription Role Signal Transduction Specificity Structure Surface TRIM Motif TRIM25 gene Techniques Testing Ubiquitin family Ubiquitination Viral Viral Genome Virus Virus Diseases fighting influenzavirus insight member novel novel therapeutic intervention novel therapeutics programs protein protein interaction reconstitution recruit sensor structural biology ubiquitin-protein ligase viral RNA viral genomics virology

项目摘要

Project Summary/Abstract Virus components such as the HIV-1 capsid and virus-encoded RNA can trigger powerful innate defense mechanisms when sensed by the host cell. Tripartite motif (TRIM) proteins are ubiquitin E3 ligases that perform important roles in sensing these virus components: TRIM5a proteins are established to recognize the incoming capsids of HIV-1 and retroviruses, and TRIM25 has an important but still enigmatic role in sensing viral RNA. The principal goals of this R01 project are to elucidate the molecular mechanisms of these sensors. In Aim 1, we propose to: (1) elucidate the molecular details of how TRIM5a recognizes HIV-1 and retroviral capsids through an unprecedented mechanism of lattice-to-lattice pattern recognition, (2) understand how multiple different protein-protein interactions in the TRIM5a/capsid complex cooperate to determine restriction susceptibility, and (3) develop novel biochemical reconstitution methods to recapitulate and analyze TRIM5a- mediated restriction in vitro. In Aim 2, we propose to: (1) elucidate the molecular details of how TRIM25 recognizes viral RNA, and (2) understand how this activity is coordinated with ubiquitination in order to enable recognition of both viral genomes and virally-encoded messenger RNA. Insights from these studies are likely to suggest novel ways to fight HIV-1 and other viral infections.

项目总结/摘要 HIV-1衣壳和病毒编码的RNA等病毒成分可以触发强大的先天防御当被宿主细胞感知时，三分基序（TRIM）蛋白是泛素E3连接酶，在检测这些病毒成分中发挥重要作用：TRIM 5a蛋白被建立来识别 HIV-1和逆转录病毒的传入衣壳，TRIM 25在感知HIV-1和逆转录病毒的传入衣壳中具有重要但仍然神秘的作用。病毒RNA这个R 01项目的主要目标是阐明这些传感器的分子机制。在目标1中，我们提出：（1）阐明TRIM 5a如何识别HIV-1和逆转录病毒的分子细节衣壳通过前所未有的机制晶格模式识别，（2）了解如何 TRIM 5a/衣壳复合物中多种不同的蛋白质-蛋白质相互作用共同决定限制性内切酶的活性易感性，以及（3）开发新型生化重建方法来概括和分析TRIM 5a- 介导的体外限制性酶切。在目标2中，我们提出：（1）阐明TRIM 25如何在分子水平上与其他细胞结合的细节。识别病毒RNA，以及（2）了解这种活动如何与泛素化协调，以使病毒基因组和病毒编码的信使RNA的识别。从这些研究中获得的见解可能会提出了对抗HIV-1和其他病毒感染的新方法。