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
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAdaptor Protein Complex 2Adaptor Signaling ProteinAffectAllelesAntiviral AgentsAutomobile DrivingBasic ScienceBinding SitesBiochemistryBiophysicsCD28 geneCD3 AntigensCD8B1 geneCXCR4 geneCell Surface ProteinsCell membraneCell surfaceCellsClathrinClathrin-Coated VesiclesComplementComplexCryoelectron MicroscopyCytosolDetergentsDown-RegulationFamilyFundingGoalsHIVHIV-1Host DefenseHumanImageImmune systemImmunityInfectionIntegral Membrane ProteinLipidsLocationLysosomesMediatingMembraneMembrane LipidsMembrane Protein TrafficMonomeric GTP-Binding ProteinsMutationPathway interactionsPatternPhenotypeProcessProductionProteinsReportingResearch ProposalsRoleSIVSeminalSignal TransductionSiteSorting - Cell MovementStructureTailViralViral AntigensVirionVirusVirus Latencybasedesignfollow-upinsightmemberpreventprotein complexreactivation from latencyreceptorreconstitutiontrans-Golgi Networkviral fitness
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
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{{ truncateString('James H Hurley', 18)}}的其他基金
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:
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: