Structural Virology of Tripartite Motif Proteins

三联基序蛋白的结构病毒学

• 批准号: 9306427
• 负责人: Owen Pornillos
• 金额: $ 5.49万
• 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/9306427
• 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; Health; Human; Infection; Malignant Neoplasms; Mediating; Modeling; Molecular; N-terminal; Outcome; Positioning Attribute; Protein Family; Proteins; Public Health; Retroviridae; Role; Series; Signal Pathway; Site; Structure; Surface; TRIM Motif; TRIM25 gene; Techniques; Testing; Ubiquitination; Viral; Virus Replication; Work; base; developmental disease; dimer; protein function; protein protein interaction; 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）：三方图案或修剪蛋白包括环域E3泛素连接酶的最大超家族。这些酶在各种重要的细胞过程中起作用，特别是在先天抗病毒反应机制中。装饰蛋白的一个定义特征是它们由多个结构域组成，每个结构域都赋予蛋白质特定的生化功能。对于这些研究，我们特别关注TRIM5J，该研究在细胞中起作用是抑制HIV-1复制的限制因素。我们建议：（1）确定完整的三方基序的结构，以了解不同组成域如何相互结构整合的分子细节。我们还将确定控制二聚化和高阶组装的分子原理，这是修剪蛋白功能的重要元素。 （2）定义TRIM5J的不同领域如何协调其生化活性，以识别HIV-1的传入capsids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，集成方法。预期的结果是对TRIM5J介导的HIV-1复制抑制的全面，分子水平的理解。