HARC Center: HIV Accessory and Regulatory Complexes

HARC 中心:HIV 辅助和调节复合体

基本信息

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质,它被结合到病毒粒子中,并驱动早期(运输 整合前)和晚期(细胞凋亡)的病毒生命周期步骤。尽管进行了20多年的研究,但 VPR加速病毒复制的机制尚不清楚[40-42]。范围广泛的 VPR具有多种分子功能,包括在G2细胞周期停滞和前整合中的作用 复合体[43-46],可能反映了一种多用途的接头蛋白。最近,一种脱氧核苷SAMHDI 三磷酸三磷酸水解酶被发现是一种髓系和树突状细胞限制因子,即 被HLV-2 VPX[47,48]所克服,一个被认为执行VPR的一些功能的VPR的旁跑。就像Vif和 VPU、VPR和VPX都与宿主泛素机制相互作用。VPR结合Cullin4环盒泛素 连接酶(CRL4)复合体[49,50],表明VPR可能通过 降解途径。由于它在许多关键的艾滋病毒感染过程中发挥核心作用,vpr代表着一种 结构-功能研究的令人兴奋的靶点,并将VPR定位为可行的治疗靶点。没有 然而,只有通过清楚地定义宿主蛋白和途径,才能普遍接受其功能模型(S) 在分子水平上被VPR扰乱--如本提案中所概述的--VPR真正的靶向活性 会被揭穿。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 到目前为止所描述的。令人鼓舞的是,这些新的相互作用揭示了宿主复合体和合作伙伴(例如动力蛋白 和C0P9)在功能上与许多VPR活动相关联。通过评估功能意义和能力 从结构复合体出发,我们将开发和测试关于VPR-宿主相互作用的新假说。 PR:许多病毒除了裂解外,还编码解除宿主防御或劫持宿主进程的蛋白酶 病毒底物。例如,脊髓灰质炎病毒PR通过裂解翻译起始来抑制宿主蛋白质的合成 因素,而鼻病毒PR裂解核孔复合体和先天参与的适配器蛋白 免疫反应[51-58]。HIV-1 PR在病毒粒子过程中处理病毒Gag和GagPol多蛋白 成熟,但它在影响宿主功能方面的作用尚不清楚。在体外,PR可切割几种哺乳动物蛋白质 [59-65],但尚不清楚在HIV感染过程中是否发生了卵裂,也不知道宿主中存在多少活性酶 病毒生命周期中的细胞[66,67]。HARC中心蛋白质组学/基因组学核心发现新宿主 与PR的非活性版本相互作用的蛋白质,包括参与免疫反应、剪接、 翻译、细胞生长和细胞凋亡[1,29]。细胞中的活性PR可以切割其中的一些蛋白质,包括一种 真核细胞翻译起始因子3复合体d亚基的RNA结合域中的单一位点 (ElF3d)。ElF3d的切割效率几乎与Gag一样高。一个有趣的假设是elF3d招募了 翻译起始复合体进入HIV基因组,阻碍逆转录。我们的结构 这种PR-宿主复合体的研究将是PR与大分子底物的第一次,提供了新的 关于底物识别的知识。我们对潜在宿主PR底物在HIV中的作用的分析 复制有可能为公关职能建立新的范例,将公关与维生素VPU的角色联系起来,以及 VPR,并定义了新型PR-宿主络合物的结构。

项目成果

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Charles Scott Craik其他文献

Charles Scott Craik的其他文献

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{{ 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:
    $ 28.48万
  • 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:
    $ 28.48万
  • 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:
    $ 28.48万
  • 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:
    $ 28.48万
  • 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:
    $ 28.48万
  • 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:
    $ 28.48万
  • 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:
    $ 28.48万
  • 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:
    $ 28.48万
  • 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:
    $ 28.48万
  • 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:
    $ 28.48万
  • 项目类别:

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