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.

项目概要/摘要 HIV-1衣壳和病毒编码RNA等病毒成分可以触发强大的先天防御被宿主细胞感知时的机制。三联基序 (TRIM) 蛋白是泛素 E3 连接酶，在感知这些病毒成分方面发挥着重要作用：TRIM5a 蛋白的建立是为了识别 HIV-1 和逆转录病毒衣壳的传入，TRIM25 在传感中具有重要但仍然神秘的作用病毒RNA。该 R01 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，我们建议：(1) 阐明 TRIM5a 如何识别 HIV-1 和逆转录病毒的分子细节通过前所未有的晶格到晶格模式识别机制来识别衣壳，（2）了解如何 TRIM5a/衣壳复合物中多种不同的蛋白质-蛋白质相互作用共同确定限制性 (3) 开发新的生化重建方法来概括和分析 TRIM5a- 体外介导的限制。在目标 2 中，我们建议：（1）阐明 TRIM25 的分子细节识别病毒 RNA，并且 (2) 了解这种活性如何与泛素化相协调，以便能够识别病毒基因组和病毒编码的信使RNA。这些研究的见解可能会提出对抗 HIV-1 和其他病毒感染的新方法。