Structural Virology of Tripartite Motif Proteins

三联基序蛋白的结构病毒学

• 批准号: 8788597
• 负责人: Owen Pornillos
• 金额: $ 32.82万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8788597
• 关键词: Adopted; Antiviral Response; Architecture; Area; Avidity; Binding; Biochemical; Biological; Biological Process; Boxing; C-terminal; Capsid; Cell Signaling Process; Cell physiology; Cells; Coiled-Coil Domain; Coupled; Dimerization; Disease; Elements; Enzymes; Epitopes; Family; Family member; Goals; HIV-1; Human; Infection; Malignant Neoplasms; Mediating; Modeling; Molecular; N-terminal; Outcome; Positioning Attribute; Protein Family; Proteins; Public Health; Relative (related person); Retroviridae; Role; Series; Signal Pathway; Site; Structure; Surface; TRIM Motif; Techniques; Testing; Ubiquitination; Viral; Work; base; developmental disease; dimer; human TRIM25 protein; protein function; protein protein interaction; public health relevance; research study; response; retroviral-mediated; self assembly; structural biology; ubiquitin-protein ligase; virology

DESCRIPTION (provided by applicant): Tripartite motif or TRIM proteins comprise the largest superfamily of RING-domain E3 ubiquitin ligases. These enzymes function in a wide variety of important cellular processes, particularly in innate antiviral response mechanisms. A defining feature of TRIM proteins is that they are composed of multiple domains, with each domain conferring a specific biochemical functionality to the protein. For these studies, we have a special focus on TRIM5j, which functions in the cell as a restriction factor that inhibits HIV-1 replication. We propose to: (1) Determine the structure of a complete tripartite motif in order to understand the molecular details of how the different constituent domains integrate structurally with each other. We will also determine the molecular principles that govern dimerization and higher-order assembly, which are important elements of TRIM protein function. (2) Define how the different domains of TRIM5j coordinate their biochemical activities, in order to recognize the incoming capsids of HIV-1 and restrict viral replication. We will use a multi-component, integrative approach that combines structural, biochemical, and cell biological techniques. The expected outcome is a comprehensive, molecular level understanding of TRIM5j-mediated inhibition of HIV-1 replication.

描述（由申请人提供）：三联基序或 TRIM 蛋白包含最大的 RING 结构域 E3 泛素连接酶超家族。这些酶在多种重要的细胞过程中发挥作用，特别是在先天抗病毒反应机制中。 TRIM 蛋白的一个决定性特征是它们由多个结构域组成，每个结构域赋予蛋白质特定的生化功能。在这些研究中，我们特别关注 TRIM5j，它在细胞中作为抑制 HIV-1 复制的限制因子发挥作用。我们建议：（1）确定完整的三部分基序的结构，以了解不同组成域如何在结构上相互整合的分子细节。我们还将确定控制二聚化和高阶组装的分子原理，它们是 TRIM 蛋白功能的重要组成部分。 (2) 定义 TRIM5j 的不同结构域如何协调其生化活性，以识别进入的 HIV-1 衣壳并限制病毒复制。我们将使用结合结构、生化和细胞生物学技术的多组分综合方法。预期结果是对 TRIM5j 介导的 HIV-1 复制抑制有全面的分子水平了解。