HARC Center: HIV Accessory and Regulatory Complexes
HARC 中心:HIV 辅助和调节复合体
基本信息
- 批准号:9135467
- 负责人:
- 金额:$ 27.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:Adaptor Signaling ProteinAffectApoptosisBindingBoxingCell CycleCell Cycle ArrestCellsCleaved cellComplexData SetDegradation PathwayDendritic CellsDynein ATPaseEnzymesEukaryotic Initiation FactorsGenomicsHIVHIV GenomeHIV InfectionsHIV-1Host DefenseHuman poliovirusImmune responseIn VitroIntegration Host FactorsKnowledgeLife Cycle StagesLigaseLinkModelingMolecularMyeloid CellsN-terminalNuclear Pore ComplexPathway interactionsPeptide HydrolasesPeptide Initiation FactorsPolyproteinsPositioning AttributeProcessProkaryotic Initiation Factor-3Protein BiosynthesisProteinase 3ProteinsProteomicsRNA Recognition MotifRNA SplicingRecruitment ActivityResearchReverse TranscriptionRhinovirusRoleSiteStructureTestingTranslation InitiationTranslationsUbiquitinUbiquitinationViralVirionVirusVirus DiseasesVirus Replicationcell growthnovelprotein complextherapeutic targettripolyphosphate
项目摘要
VPR: Vpr is a conserved multi-functional protein that is incorporated into virions and drives early (transport of
pre-integration complex) and late (apoptosis) viral life cycle steps. Despite more than 20 years of research, the
mechanism by which Vpr accelerates virus replication is not well understood [40-42]. A wide range of
molecular functions has been ascribed to Vpr, including roles in G2 cell cycle arrest and pre-integration
complexes [43-46], perhaps reflecting a multi-purpose adaptor protein. Recently, SAMHDI, a deoxynucleoside
triphosphate triphosphohydrolase, was found to be a myeloid and dendritic cell restriction factor that is
overcome by HlV-2 Vpx [47, 48], a parajog of Vpr believed to carry out some functions of Vpr. Like Vif and
Vpu, both Vpr and Vpx interact with the host ubiquitin machinery. Vpr binds the Cullin4 RING Box Ubiqultin
Ligase (CRL4) complex [49, 50], suggesting that Vpr may overcome additional host restrictions via the
degradation pathway. Due to its central roles in a number of key HIV infection processes, Vpr represents an
exciting target for structure-function studies and positions Vpr as a viable therapeutic target. With no
universally accepted model for its functions, however, only by clearly defining the host proteins and pathway(s)
perturbed by Vpr at the molecular level-as outlined in this proposal-will the bona fide targetable activity of Vpr
be revealed. The HARC Proteomics/Genomics Core compiled the most extensive Vpr-host interaction data set
described to date. Encouragingly, these novel interactions reveal host complexes and partners (e.g. dynein
and C0P9) functionally linked with many Vpr activities. By evaluating the functional significance and ability to
form structured complexes, we will develop and test new hypotheses about Vpr-host interactions.
PR: Many viruses encode proteases that disarm host defenses or hijack host processes in addition to cleaving
viral substrates. For example, poliovirus PR inhibits host protein synthesis by cleaving translation initiation
factors, while rhinovirus PR cleaves the nuclear pore complex and adaptor proteins involved in the innate
immune response [51-58]. HIV-1 PR processes the viral Gag and GagPol polyproteins during virion
maturation, but its role in affecting host functions is unclear. In vitro, PR cleaves several mammalian proteins
[59-65], but it is not known if cleavage occurs during HIV infection or how much active enzyme exists in host
cells during the viral life cycle [66, 67]. The HARC Center Proteomics/Genomics Core uncovered novel host
proteins that interact with, an inactive version of PR, including proteins involved in immune responses, splicing,
translation, cell growth, and apoptosis [1, 29]. Active PR in cells cleaved some of these proteins, including a
single site in the RNA binding domain of the d subunit of the eukaryotic translation initiation factor 3 complex
(elF3d). elF3d was cleaved nearly as efficiently as Gag. An intriguing hypothesis is that elF3d recruits the
translation initiation complex to the entering HIV genome, obstructing reverse transcription. Our structural
studies of such PR-host complexes will be the first of PR with a macromolecular substrate, providing new
knowledge on substrate recognition. Our analyses of the roles of potential host PR substrates in HIV
replication have the potential to establish new paradigms for PR function, link PR to the roles of Vit Vpu, and
Vpr, and define the structures of novel PR-host complexes.
Vpr:Vpr是一种保守的多功能蛋白,其被并入病毒体中并驱动早期(运输病毒)。
整合前复合物)和晚期(凋亡)病毒生命周期步骤。尽管经过20多年的研究,
Vpr加速病毒复制的机制尚不清楚[40-42]。广泛的
Vpr的分子功能包括在G2期细胞周期阻滞和整合前的作用
复合物[43-46],可能反映了多用途衔接蛋白。最近,SAMHDI,一种脱氧核苷
三磷酸三磷酸水解酶被发现是一种骨髓和树突细胞限制因子,
克服了HIV-2 Vpx [47,48],一个parajog的Vpr相信执行一些功能的Vpr。就像维芙和
Vpu、Vpr和Vpx都与宿主泛素机制相互作用。Vpr结合Cullin 4 RING盒Ubiqultin
连接酶(CRL 4)复合物[49,50],表明Vpr可以通过连接酶(CRL 4)复合物克服额外的宿主限制。
降解途径由于Vpr在许多关键的艾滋病毒感染过程中发挥着核心作用,因此Vpr代表了一种
令人兴奋的结构-功能研究的目标和立场Vpr作为一个可行的治疗目标。没有
然而,只有通过明确定义宿主蛋白和途径,
在分子水平上受到Vpr的干扰--如本提案所述--将使Vpr真正的靶向活性
被揭露。HARC蛋白质组学/基因组学核心汇编了最广泛的Vpr-宿主相互作用数据集
描述到目前为止。令人鼓舞的是,这些新的相互作用揭示了宿主复合物和伴侣(例如动力蛋白
和C 0 P9)在功能上与许多Vpr活性相关。通过评估其功能意义和能力,
形成结构化的复合物,我们将开发和测试有关Vpr主机相互作用的新假设。
PR:许多病毒编码的蛋白酶除了裂解外,还能解除宿主的防御或劫持宿主的过程
病毒底物。例如,脊髓灰质炎病毒PR通过切割翻译起始来抑制宿主蛋白质合成
因子,而鼻病毒PR切割核孔复合物和衔接蛋白参与先天性
免疫反应[51-58]。HIV-1 PR在病毒体期间加工病毒Gag和GagPol多聚蛋白
成熟,但其在影响宿主功能中的作用尚不清楚。在体外,PR切割几种哺乳动物蛋白质
[59-65],但尚不清楚在HIV感染期间是否发生裂解或宿主中存在多少活性酶
细胞在病毒的生命周期[66,67]。HARC中心蛋白质组学/基因组学核心发现了新的宿主
与PR的非活性形式相互作用的蛋白质,包括参与免疫应答,剪接,
翻译、细胞生长和凋亡[1,29]。细胞中活跃的PR裂解了这些蛋白质中的一些,包括
真核生物翻译起始因子3复合体d亚基RNA结合域中的单个位点
(elF3d)。eIF 3d几乎与Gag一样有效地被切割。一个有趣的假设是,elF 3d招募了
翻译起始复合物进入HIV基因组,阻碍逆转录。我们的结构
这种PR-主体复合物的研究将是第一个PR与大分子底物,提供新的
底物识别知识。我们分析了潜在的宿主PR底物在HIV中的作用,
复制有可能为PR功能建立新的范例,将PR与Vit Vpu的作用联系起来,
Vpr,并定义新的PR-主体复合物的结构。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Charles Scott Craik其他文献
Charles Scott Craik的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Charles Scott Craik', 18)}}的其他基金
Developing Antivirals Targeting Proteases and Polymerases of Coronaviruses, Picornaviruses and Bunyavirales
开发针对冠状病毒、小核糖核酸病毒和布尼亚病毒的蛋白酶和聚合酶的抗病毒药物
- 批准号:
10512628 - 财政年份:2022
- 资助金额:
$ 27.37万 - 项目类别:
New radiotracer development to study immune cell mobilization of granzyme proteolytic activity
开发新的放射性示踪剂来研究免疫细胞动员颗粒酶蛋白水解活性
- 批准号:
10231735 - 财政年份:2021
- 资助金额:
$ 27.37万 - 项目类别:
New radiotracer development to study immune cell mobilization of granzyme proteolytic activity
开发新的放射性示踪剂来研究免疫细胞动员颗粒酶蛋白水解活性
- 批准号:
10395587 - 财政年份:2021
- 资助金额:
$ 27.37万 - 项目类别:
New radiotracer development to study immune cell mobilization of granzyme proteolytic activity
开发新的放射性示踪剂来研究免疫细胞动员颗粒酶蛋白水解活性
- 批准号:
10591415 - 财政年份:2021
- 资助金额:
$ 27.37万 - 项目类别:
Probing the Role of Chaperone-TPR Complexes in Tau Proteostasis
探讨分子伴侣-TPR 复合物在 Tau 蛋白质稳态中的作用
- 批准号:
10029781 - 财政年份:2020
- 资助金额:
$ 27.37万 - 项目类别:
Non-invasive Differentiation of Benign Lesions from Aggressive Pancreatic Cancer
良性病变与侵袭性胰腺癌的无创鉴别
- 批准号:
8823694 - 财政年份:2015
- 资助金额:
$ 27.37万 - 项目类别:
Extracellular Proteolysis as a Molecular Stratification Tool for Cancer
细胞外蛋白水解作为癌症的分子分层工具
- 批准号:
8829207 - 财政年份:2014
- 资助金额:
$ 27.37万 - 项目类别:
Antibodies for Characterizing the Structure and Function of Proteases
用于表征蛋白酶结构和功能的抗体
- 批准号:
8702411 - 财政年份:2014
- 资助金额:
$ 27.37万 - 项目类别:
Allosteric Inhibition of a Family of Proteolytic Enzymes
蛋白水解酶家族的变构抑制
- 批准号:
8577916 - 财政年份:2013
- 资助金额:
$ 27.37万 - 项目类别:
Allosteric Inhibition of a Family of Proteolytic Enzymes
蛋白水解酶家族的变构抑制
- 批准号:
8698774 - 财政年份:2013
- 资助金额:
$ 27.37万 - 项目类别:
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 27.37万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 27.37万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 27.37万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 27.37万 - 项目类别:
Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 27.37万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 27.37万 - 项目类别:
Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 27.37万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 27.37万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 27.37万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 27.37万 - 项目类别:
Studentship