Structural and Functional Integration of TRIM5alpha Domains for HIV Capsid Binding

用于 HIV 衣壳结合的 TRIM5alpha 结构域的结构和功能整合

• 批准号: 9042851
• 负责人: Jonathan Mark Wagner
• 金额: $ 5.8万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9042851
• 关键词: Attention; Behavior; Binding; Binding Sites; Boxing; Capsid; Capsid Proteins; Cells; Chromosomes, Human, Pair 11; Coiled-Coil Domain; Complement; Complex; Crystallization; Data; Data Set; Defense Mechanisms; Dimerization; Disulfides; Electron Spin Resonance Spectroscopy; Electrons; Epitopes; Equilibrium; Family member; Fluorescence Resonance Energy Transfer; Goals; HIV; Homodimerization; Homologous Gene; Imagery; Immune system; In Vitro; Individual; Intercept; Invaded; Investigation; Label; Link; Location; Measures; Mediating; Modeling; Molecular; Molecular Conformation; Molecular Structure; Movement; Nucleosome Core Particle; Pattern recognition receptor; Positioning Attribute; Protein Family; Proteins; Recombinants; Research; Resolution; Rest; Reverse Transcription; Role; Shapes; Signal Pathway; Site; Spin Labels; Structure; TRIM Motif; Testing; Therapeutic; Time; Tube; Viral; Virus; Virus Diseases; Virus Replication; design; dimer; flexibility; improved; information model; monomer; particle; premature; prevent; public health relevance; research study; two-dimensional; virus core

 DESCRIPTION (provided by applicant): The Tripartite Motif (TRIM) proteins are important components of first line cellular defense mechanisms against invading viruses. One TRIM family member, TRIM5α, directly binds and disassembles incoming human immunodeficiency virus (HIV) cores, preventing reverse transcription and inhibiting viral replication. At the same time, TRIM5α acts as a pattern recognition receptor that stimulates downstream proinflammatory signaling pathways. In order to accomplish these, TRIM5α first dimerizes through its coiled-coil domain and the dimers further assemble via their B-box 2 domains into a two-dimensional hexagonal lattice that surrounds HIV core particles. The hexagonal lattice contains regularly spaced capsid binding SPRY domains that mediate direct interactions with the proteinaceous HIV capsid shell. Each individual SPRY domain interacts very weakly, but the assembled TRIM network binds avidly by aligning SPRY domains with regularly spaced capsid epitopes. Recent structures of individual TRIM5α domains have suggested that the spacing and orientation of SPRY domains in TRIM5α might be controlled by a four-way packing interaction between two SPRY domains resting on two coiled-coil domains. However, a structure of the TRIM5α dimer including both coiled-coil and SPRY domains is necessary to confirm this. Furthermore, it appears that SPRY domains may be able to release from the coiled-coil domains with the intervening linker 2 regions acting as a flexible tether. This study will investigate the structureof the TRIM5α coiled-coil and SPRY dimer and the dynamic movements that may be associated with HIV capsid binding. We expect to discover the locations and orientations of capsid binding SPRY domains within the network surrounding HIV capsid particles. This will inform our understanding of the molecular defenses used by the cell to destroy viruses and may ultimately improve our ability to design therapeutics that mimic or complement these complex cellular machines.

 描述（由申请人提供）：三分基序（TRIM）蛋白是抵抗入侵病毒的一线细胞防御机制的重要组成部分。TRIM家族的一个成员TRIM 5 α直接结合并分解进入的人类免疫缺陷病毒（HIV）核心，阻止逆转录并抑制病毒复制。同时，TRIM 5 α作为模式识别受体，刺激下游促炎信号通路。为了实现这些，TRIM 5 α首先通过其卷曲螺旋结构域进行二聚化，二聚体通过其B-box 2结构域进一步组装成围绕HIV核心颗粒的二维六边形晶格。六边形晶格含有规则间隔的衣壳结合SPRY结构域，其介导与蛋白质HIV衣壳壳的直接相互作用。每个单独的SPRY结构域相互作用非常弱，但组装的TRIM网络通过将SPRY结构域与规则间隔的衣壳表位对齐而强烈结合。最近对TRIM 5 α结构域的结构研究表明，TRIM 5 α中SPRY结构域的空间和方向可能受到位于两个卷曲螺旋结构域上的两个SPRY结构域之间的四向堆积相互作用的控制。然而，包括卷曲螺旋和SPRY结构域的TRIM 5 α二聚体的结构是证实这一点所必需的。此外，似乎SPRY结构域可以能够从卷曲螺旋结构域释放，其中插入接头2区域充当柔性系链。本研究将研究TRIM 5 α卷曲螺旋和SPRY二聚体的结构以及可能与HIV衣壳结合相关的动态运动。我们希望发现的位置和方向的衣壳结合SPRY结构域内的网络周围的HIV衣壳颗粒。这将使我们了解细胞用于破坏病毒的分子防御，并可能最终提高我们设计模拟或补充这些复杂细胞机器的治疗方法的能力。