Multifaceted interactions between lentiviral Vif and host molecules for viral infectivity enhancement
慢病毒 Vif 与宿主分子之间的多方面相互作用增强病毒感染力
基本信息
- 批准号:10774368
- 负责人:
- 金额:$ 7.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-06-15 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalBindingBiochemicalBiophysicsCD4 Positive T LymphocytesCapsid ProteinsCell Cycle ArrestClassificationCommunitiesComparative StudyComplexCryoelectron MicroscopyCyclophilin ACytidine DeaminaseDeaminationDegradation PathwayEvolutionFluorescenceGoalsHIVHIV-1Host Defense MechanismImmuneImmune systemIn VitroInfectionIntegration Host FactorsInvadedKnowledgeMammalsMediatingMethodsMolecularMutagenesisPPP2R5A genePathway interactionsPeptidylprolyl IsomerasePrimate LentivirusesProtein FamilyProtein IsoformsProtein phosphataseProteinsResearchResearch DesignResearch Project GrantsResolutionReverse TranscriptionSheepSpectrum AnalysisStructureSystemTechniquesTherapeuticTranscriptUbiquitinValidationViralViral PhysiologyViral ProteinsVirionVirus DiseasesVirus InhibitorsVirus ReplicationVisna-maedi virusWorkX-Ray Crystallographycellular targetingcofactorcombatdesignexperimental studyfactor Ain vivoinhibitorinsightmulticatalytic endopeptidase complexnovel therapeuticspathogenreconstructionrecruitstructural biologytooltranscription factorubiquitin-protein ligase
项目摘要
PROJECT DESCRIPTION
The APOBEC3 (A3) family of proteins are cellular cytidine deaminases that suppress human
immunodeficiency virus type 1 (HIV-1) infection by hypermutation of viral reverse transcripts and physically
blocking reverse transcription. To evade this host defense mechanism, HIV-1 expresses the virion infectivity
factor (Vif), which hijacks a cellular E3 ubiquitin ligase complex and targets A3 proteins (A3F/G/H/D) for
proteasome-mediated degradation. Besides degrading A3s, HIV-1 Vif also causes G2 cell cycle arrest by
targeting multiple protein phosphatase 2A (PP2A) regulators (PPP2R5 proteins) for degradation. Adding to the
complexity of Vif-host protein interactions, HIV-1 Vif utilizes the transcription factor CBFβ as a non-canonical
cofactor, while maedi-visna virus (MVV) Vif co-opts the prolyl isomerase cyclophilin A (CypA) instead. Our goal
is to establish the biochemical and structural principles for the multifaceted activities of lentiviral Vif molecules
that recruit cellular factors to degrade host proteins via ubiquitin-proteasome pathways. To achieve our goal,
we will use a combination of biochemical, biophysical, structural biology, and cellular functional techniques. To
establish the mechanisms by which A3 proteins are targeted by the HIV-1 Vif (Aim1), we will determine high-
resolution structures of the A3-Vif-E3 interaction complexes, validate these structures by structure-guided
mutagenesis experiments in vitro and in vivo, and interrogate the molecular determinants of Vif/A3/E3 ligase
assembly and activation. In addition, we will also study the degradation-independent mode of Vif inhibition of
A3 deamination and antiviral activities. To better understand CypA-mediated formation of MVV Vif-E3 ubiquitin
ligase (Aim2), we will assemble MVV Vif/CypA/E3 ligase complexes with or without A3 substrates, determine
their high-resolution structures, and perform biochemical and functional validations of our structural
observations. The influences of capsid proteins on the assembly and activation of MVV Vif-E3 ligase will also
be investigated. To delineate the mechanisms of PPP2R5/PP2A recruitment by lentiviral Vif-E3 ubiquitin
ligases (Aim3), we will investigate the effects of PPP2R5 proteins on the assemblies of the CBFβ-mediated
HIV-1 Vif and CypA-mediated MVV Vif-E3 ligases, obtain high-resolution structures, and perform structure-
guided validations. Our comprehensive research design provides a robust approach that will generate
unprecedented insights into the diverse functions of lentiviral Vif molecules.
项目描述
APOBEC 3(A3)蛋白家族是细胞胞苷脱氨酶,其抑制人类免疫应答。
免疫缺陷病毒1型(HIV-1)感染通过病毒逆转录和物理
阻断逆转录。为了逃避这种宿主防御机制,HIV-1表达了病毒粒子的感染性,
因子(Vif),其劫持细胞E3泛素连接酶复合物并靶向A3蛋白(A3 F/G/H/D),
蛋白酶体介导的降解。除了降解A3,HIV-1 Vif还通过以下方式引起G2细胞周期阻滞:
靶向多种蛋白磷酸酶2A(PP 2A)调节剂(PPP 2 R5蛋白)进行降解。增加了
由于Vif-宿主蛋白相互作用的复杂性,HIV-1 Vif利用转录因子CBFβ作为非典型的
辅因子,而梅迪-维斯纳病毒(MVV)Vif替代脯氨酰异构酶亲环素A(CypA)。我们的目标
是建立慢病毒Vif分子多方面活动的生物化学和结构原理
通过泛素-蛋白酶体途径募集细胞因子降解宿主蛋白质。为了实现我们的目标,
我们将结合使用生物化学、生物物理学、结构生物学和细胞功能技术。到
建立A3蛋白被HIV-1 Vif(Aim 1)靶向的机制,我们将确定高水平的
A3-Vif-E3相互作用复合物的解析结构,通过结构引导的
体外和体内诱变实验,并询问Vif/A3/E3连接酶的分子决定簇
组装和激活。此外,我们还将研究Vif抑制的非降解依赖模式
A3脱氨基和抗病毒活性。为了更好地理解CypA介导的MVV Vif-E3泛素形成
连接酶(Aim 2),我们将组装MVV Vif/CypA/E3连接酶复合物,有或没有A3底物,确定
他们的高分辨率结构,并执行生化和功能验证我们的结构
意见。本文还研究了衣壳蛋白对MVV Vif-E3连接酶组装和活化的影响。
追究描述慢病毒Vif-E3泛素募集PPP 2 R5/PP 2A的机制
连接酶(Aim 3),我们将研究PPP 2 R5蛋白对CBFβ介导的
HIV-1 Vif和CypA介导的MVV Vif-E3连接酶,获得高分辨率结构,并进行结构-
引导验证。我们全面的研究设计提供了一个强大的方法,将产生
这是对慢病毒Vif分子的多种功能的前所未有的了解。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
FBXO32, encoding a member of the SCF complex, is mutated in dilated cardiomyopathy.
- DOI:10.1186/s13059-015-0861-4
- 发表时间:2016-01-11
- 期刊:
- 影响因子:12.3
- 作者:Al-Yacoub N;Shaheen R;Awad SM;Kunhi M;Dzimiri N;Nguyen HC;Xiong Y;Al-Buraiki J;Al-Habeeb W;Alkuraya FS;Poizat C
- 通讯作者:Poizat C
Exploring ABOBEC3A and APOBEC3B substrate specificity and their role in HPV positive head and neck cancer.
- DOI:10.1016/j.isci.2022.105077
- 发表时间:2022-10-21
- 期刊:
- 影响因子:5.8
- 作者:Papini, Christina;Wang, Zechen;Kudalkar, Shalley N.;Schrank, Travis Parke;Tang, Su;Sasaki, Tomoaki;Wu, Cory;Tejada, Brandon;Ziegler, Samantha J.;Xiong, Yong;Issaeva, Natalia;Yarbrough, Wendell G.;Anderson, Karen S.
- 通讯作者:Anderson, Karen S.
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Yong Xiong其他文献
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{{ truncateString('Yong Xiong', 18)}}的其他基金
Multifaceted interactions between lentiviral Vif and host molecules for viral infectivity enhancement
慢病毒 Vif 与宿主分子之间的多方面相互作用增强病毒感染力
- 批准号:
10640135 - 财政年份:2015
- 资助金额:
$ 7.39万 - 项目类别:
Multifaceted interactions between lentiviral Vif and host molecules for viral infectivity enhancement
慢病毒 Vif 与宿主分子之间的多方面相互作用增强病毒感染力
- 批准号:
10326954 - 财政年份:2015
- 资助金额:
$ 7.39万 - 项目类别:
Recognition of Viral DNA by APOBEC3 Proteins and their Antagonization by HIV Vif
APOBEC3 蛋白对病毒 DNA 的识别及其 HIV Vif 的拮抗作用
- 批准号:
8992425 - 财政年份:2015
- 资助金额:
$ 7.39万 - 项目类别:
Recognition of Viral DNA by APOBEC3 Proteins and their Antagonization by HIV Vif
APOBEC3 蛋白对病毒 DNA 的识别及其 HIV Vif 的拮抗作用
- 批准号:
9079350 - 财政年份:2015
- 资助金额:
$ 7.39万 - 项目类别:
Multifaceted interactions between lentiviral Vif and host molecules for viral infectivity enhancement
慢病毒 Vif 与宿主分子之间的多方面相互作用增强病毒感染力
- 批准号:
10600207 - 财政年份:2015
- 资助金额:
$ 7.39万 - 项目类别:
Multifaceted interactions between lentiviral Vif and host molecules for viral infectivity enhancement
慢病毒 Vif 与宿主分子之间的多方面相互作用增强病毒感染力
- 批准号:
10414141 - 财政年份:2015
- 资助金额:
$ 7.39万 - 项目类别:
Mechanisms of enveloped virus tethering by tetherin and viral countermeasures
系链蛋白束缚包膜病毒的机制和病毒对策
- 批准号:
8824868 - 财政年份:2011
- 资助金额:
$ 7.39万 - 项目类别:
Mechanisms of enveloped virus tethering by tetherin and viral countermeasures
系链蛋白束缚包膜病毒的机制和病毒对策
- 批准号:
8467997 - 财政年份:2011
- 资助金额:
$ 7.39万 - 项目类别:
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