Evolution of the Vif E3 Ubiquitin Ligase

Vif E3 泛素连接酶的演变

基本信息

项目摘要

 DESCRIPTION (provided by applicant): Evolutionary pressures placed upon lentiviruses, such as HIV, and their affected hosts have resulted in a molecular "arms race" which has shaped both host immunity and pathogen immune evasion strategies. Central to this race is the HIV protein Virion Infectivity Factor (Vif), an immunomodulatory protein critical to the replicatio cycle of nearly all lentiviruses. The primary function of Vif is to counteract the antiviral effect of the host APOBEC3 (A3) innate immune proteins. A3 proteins are restriction factors that inhibit lentiviral replication by inducing hypermutation of the viral genome. Vif antagonizes A3 by hijacking a cellular Cullin-RING ubiquitin ligase, resulting in the ubiquitination and subsequent targeting of APOBEC3 for proteasomal degradation. Despite the central role of Vif in the HIV replication cycle and an extensive body of literature describing HIV pathogenesis, we still do not have a clear molecular understanding of how Vifs bind and ubiquitinate A3. This research plan seeks to combine biochemistry, enzymology, and structural biology to understand how Vif inhibits A3 at a molecular level, and determine how A3 inhibition relates to the evolutionary events that allowed HIV to "jump" from monkeys to humans. Lentiviral Vifs have evolved to specifically counteract the effects of the A3 from their animal hosts. To determine the biochemical basis for species-specific A3 recognition I will use a panel of HIV and SIV Vif E3 ligases and their respective A3G proteins to carry out binding and in vitro ubiquitination assays and address the question: is A3G species-specificity conferred during the ground state, binding to Vif, or the transition state, the catalytic step, of the enzyme catalyzed ubiquitination reactio? To provide the molecular determinants that govern Vifs' ability to confer species-specific recognition of A3G, I will utilize low- and high-resolution structural techniques that allow me to visualize the A3G-Vif interface at atomic resolution. Mutational analyses, using in vitro ubiquitination assays and cell-base infectivity assays, will be used to link structure to phenotype and validate the biological relevance of the structural model. The successful completion of these studies will provide "snapshots" of Vif from different stages of lentivirial evolution, and our combined structural and functional approach will provide detailed insight into the Vif- A3 interaction. Together these studies will allow us to "see" the Vif-A3 interaction, characterize the evolutionary steps required for species-species transmission into human populations, and ultimately aid in the development of innovative therapeutics to counter viral infection.
 描述(由申请方提供):对慢病毒(如HIV)及其受影响宿主施加的进化压力导致了分子“军备竞赛”,这形成了宿主免疫和病原体免疫逃避策略。这一竞争的核心是HIV蛋白病毒粒子亲和因子(Vif),一种对几乎所有慢病毒的复制周期至关重要的免疫调节蛋白。Vif的主要功能是抵消宿主APOBEC 3(A3)先天免疫蛋白的抗病毒作用。A3蛋白是通过诱导病毒基因组的超突变来抑制慢病毒复制的限制性因子。Vif通过劫持细胞Cullin-RING泛素连接酶拮抗A3,导致泛素化和随后靶向APOBEC 3进行蛋白酶体降解。尽管Vif在HIV复制周期中起着核心作用,并且有大量文献描述了HIV发病机制,但我们仍然没有对Vif如何结合和泛素化A3有明确的分子理解。这项研究计划旨在将联合收割机生物化学、酶学和结构生物学结合起来,以了解Vif如何在分子水平上抑制A3,并确定A3抑制与允许HIV从猴子“跳跃”到人类的进化事件之间的关系。慢病毒VIF已经进化到专门抵消来自其动物宿主的A3的影响。为了确定物种特异性A3识别的生物化学基础,我将使用一组HIV和SIV Vif E3连接酶及其各自的A3 G蛋白进行结合和体外泛素化测定,并解决以下问题:A3 G物种特异性是在基态与Vif结合时赋予的,还是在酶催化的泛素化反应的过渡态(催化步骤)赋予的?为了提供控制VIF赋予A3 G物种特异性识别能力的分子决定因素,我将利用低分辨率和高分辨率结构技术,使我能够以原子分辨率可视化A3 G-Vif界面。突变分析,使用体外泛素化测定和细胞基础感染性测定,将用于连接结构和表型 并验证结构模型的生物相关性。这些研究的成功完成将提供来自慢病毒进化不同阶段的Vif的“快照”,并且我们结合的结构和功能方法将提供对Vif- A3相互作用的详细了解。总之,这些研究将使我们能够“看到”Vif-A3相互作用, 研究人员发现,这是种-种传播到人类群体所需的进化步骤,并最终有助于开发对抗病毒感染的创新疗法。

项目成果

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Jennifer Binning其他文献

Jennifer Binning的其他文献

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{{ truncateString('Jennifer Binning', 18)}}的其他基金

The role of HPV E1 in regulating the NRF2-KEAP1 pathway
HPV E1在调节NRF2-KEAP1通路中的作用
  • 批准号:
    10646778
  • 财政年份:
    2023
  • 资助金额:
    $ 2.53万
  • 项目类别:
Biophysical basis for enzyme mediated deglycation in protein repair
蛋白质修复中酶介导的去糖化的生物物理学基础
  • 批准号:
    10276570
  • 财政年份:
    2021
  • 资助金额:
    $ 2.53万
  • 项目类别:
Biophysical basis for enzyme mediated deglycation in protein repair
蛋白质修复中酶介导的去糖化的生物物理学基础
  • 批准号:
    10601090
  • 财政年份:
    2021
  • 资助金额:
    $ 2.53万
  • 项目类别:
Biophysical basis for enzyme mediated deglycation in protein repair
蛋白质修复中酶介导的去糖化的生物物理学基础
  • 批准号:
    10415210
  • 财政年份:
    2021
  • 资助金额:
    $ 2.53万
  • 项目类别:
Biophysical basis for enzyme mediated deglycation in protein repair
蛋白质修复中酶介导的去糖化的生物物理学基础
  • 批准号:
    10798655
  • 财政年份:
    2021
  • 资助金额:
    $ 2.53万
  • 项目类别:
Evolution of the Vif E3 Ubiquitin Ligase
Vif E3 泛素连接酶的演变
  • 批准号:
    9233738
  • 财政年份:
    2016
  • 资助金额:
    $ 2.53万
  • 项目类别:
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