Allostery and Hijacking of Host Membrane Traffic by HIV-1 Accessory Proteins

HIV-1 辅助蛋白对宿主膜运输的变构和劫持

基本信息

  • 批准号:
    10460353
  • 负责人:
  • 金额:
    $ 64.68万
  • 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:
    2015-06-18 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Nef is an HIV-1 accessory protein whose function is to undermine host defenses. Long term infection with HIV strains bearing defective nef alleles leads to AIDS only over many years, suggesting Nef could be targeted as part of functional cure strategies. This basic research proposal seeks will elucidate the mechanisms of action of Nef. Nef targets include CD3, CD4, CD8, CD28, CXCR4, MHC-I, SERINC3/5, and for HIV-1 group O and SIV, BST2/tetherin. Nef substrates are downmodulated by via the clathrin-coated vesicle (CCV) pathway. Nef does not interact directly with clathrin, but rather with various members of a family of heterotetrameric adaptors known as the adaptor protein (AP) complexes, AP-1 and AP-2. The ability of the human immune system to detect and kill virally infected cells relies on proper presentation of viral antigens on the cell surface by MHC-I complexes. Nef subverts this process by promoting MHC-I complex downregulation by hijacking AP-1 and its associated small GTPase Arf1 at the TGN. MHC-I contains an incomplete version of the normal Tyr-based sorting motif. Nef complements this defective motif and converts MHC-I into a substrate for AP-1 mediated sorting to the lysosome for degradation. Structures of Nef assembled with AP-1 and the MHC-I cytosolic tail in solution suggested that Nef promotes the assembly of hexagonal lattices whose symmetry matches that of clathrin. Now, the previous solution studies will be followed up by reconstitution and structure determination of Nef, MHC-I tail, AP-1 and Arf1 in their functional setting on lipid membranes. Downmodulation of CD28 by Nefs is conserved across SIV and HIV and is mediated by AP-2. CD28 downmodulation phenotypes of Nef mutations follow a distinct pattern from other receptors, and the structural basis for this mode of CD28 is unknown. The structure of the CD28:HIV-1 Nef:AP-2 complex will be determined and leveraged to design mutations that uniquely perturb the CD28 binding site. Of the many host substrates of Nef, the most significant for viral infectivity are the multipass integral membrane proteins SERINC3 and 5. The SERINC binding site appears, on the basis of Nef phenotypes, to overlap with the site used by SIVsmm Nef to downmodulate simian tetherin, but is otherwise distinct from the known locations of CD3, CD4, and MHC-I sites. SERINCs do not share any obvious motifs with other substrates. SERINCs have been purified in monodisperse form suitable for structure determination. The cryo-EM structure of lipid- or detergent embedded SERINC3 or 5 in complex with AP-2 and HIV-1 Nef will be determined, completing a major goal in the field.
项目总结

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)

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James H Hurley其他文献

James H Hurley的其他文献

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{{ truncateString('James H Hurley', 18)}}的其他基金

Biophysics Training Program
生物物理学培训计划
  • 批准号:
    10494714
  • 财政年份:
    2023
  • 资助金额:
    $ 64.68万
  • 项目类别:
Allostery and Hijacking of Host Membrane Traffic by HIV-1 Accessory Proteins
HIV-1 辅助蛋白对宿主膜运输的变构和劫持
  • 批准号:
    10669213
  • 财政年份:
    2015
  • 资助金额:
    $ 64.68万
  • 项目类别:
Allostery and Hijacking of Host Membrane Traffic by HIV-1 Accessory Proteins
HIV-1 辅助蛋白对宿主膜运输的变构和劫持
  • 批准号:
    10092840
  • 财政年份:
    2015
  • 资助金额:
    $ 64.68万
  • 项目类别:
Allostery and Hijacking of Host Membrane Traffic by HIV-1 Accessory Proteins
HIV-1 辅助蛋白对宿主膜运输的变构和劫持
  • 批准号:
    10227220
  • 财政年份:
    2015
  • 资助金额:
    $ 64.68万
  • 项目类别:
Autophagy initiation by the Atg1 complex
Atg1 复合物启动自噬
  • 批准号:
    8755870
  • 财政年份:
    2014
  • 资助金额:
    $ 64.68万
  • 项目类别:
Autophagy initiation by the Atg1 complex
Atg1 复合物启动自噬
  • 批准号:
    9120391
  • 财政年份:
    2014
  • 资助金额:
    $ 64.68万
  • 项目类别:
Biochemical, Biophysical, and Structural Mechanisms of HIV-1 Budding and Release
HIV-1 萌芽和释放的生化、生物物理和结构机制
  • 批准号:
    8731680
  • 财政年份:
    2014
  • 资助金额:
    $ 64.68万
  • 项目类别:
Biochemical, Biophysical, and Structural Mechanisms of HIV-1 Budding and Release
HIV-1 萌芽和释放的生化、生物物理和结构机制
  • 批准号:
    10555194
  • 财政年份:
    2014
  • 资助金额:
    $ 64.68万
  • 项目类别:
The Autophagy Initiation Complexes
自噬起始复合物
  • 批准号:
    9982076
  • 财政年份:
    2014
  • 资助金额:
    $ 64.68万
  • 项目类别:
The Autophagy Initiation Complexes
自噬起始复合物
  • 批准号:
    10242820
  • 财政年份:
    2014
  • 资助金额:
    $ 64.68万
  • 项目类别:
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