Structure-function studies of the membrane-interacting domains of HIV-1 Env spike
HIV-1 Env 刺突膜相互作用域的结构功能研究
基本信息
- 批准号:10326632
- 负责人:
- 金额:$ 83.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-05-20 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Project Summary
The first critical step for enveloped viruses, such as HIV-1, to enter host cells is viral membrane fusion.
Viral fusion proteins are fascinating protein folding machineries capable of adopting completely different
conformations during the fusion process; they are also important vaccine and therapeutic targets. Previous
studies have revealed both pre- and post-fusion conformations of the soluble fragments of many viral fusion
proteins, but less is known for structures of their fusion peptide, transmembrane and membrane-proximal
regions in the context of lipid bilayers. There is strong evidence for functional roles of the membrane-
interacting regions in fusion, and yet mechanistic studies on how they exert their functions remain scarce. We
hypothesize that membrane-interacting regions of other fusion proteins related to HIV-1 envelope
protein (Env) adopt defined oligomeric structures that are critical for the stability, function and
antigenicity of the full-length proteins in membrane. In the studies that we completed during the previous
funding period, we have determined the structures of the TM, membrane proximal external region, and
cytoplasmic tail of HIV-1 Env in bicelles that mimic lipid bilayers using the latest NMR technology. We find that
these regions all form well-ordered trimeric clusters and are conformationally coupled, and that disrupting them
can reduce fusion and alter the antigenic structure of the entire Env. In this application, we propose to apply
our NMR/bicelle technology to investigate the membrane regions of SIV Env and the recently emerged SARS-
CoV-2 spike (S), and to use cryo-electron microscopy to determine structures of the full-length proteins
reconstituted in lipid nanodiscs. We will define roles in membrane fusion of critical structural elements of these
regions by deep mutagenesis and functional assays. We will purse the following specific aims: 1) we will
investigate the membrane-interacting components of SIV Env; 2) we will investigate the membrane-interacting
components in the postfusion arrangement; 3) we will determine structures of the full-length SIV Env and
SARS-CoV-2 S in the context of membrane; 4) we will elucidate roles of the membrane-interacting domains of
HIV/SIV Env and SARS-CoV-2 S in their stability, function and antigenicity.
项目摘要
进入宿主细胞的包裹病毒(例如HIV-1)的第一步是病毒膜融合。
病毒融合蛋白具有令人着迷的蛋白质折叠机器,能够采用完全不同的
融合过程中的构象;它们也是重要的疫苗和治疗靶标。以前的
研究揭示了许多病毒融合的可溶性片段的融合前和融合后构象
蛋白质的融合肽,跨膜和膜 - 蛋白质的结构知之甚少
脂质双层的区域。有充分的证据表明膜的功能作用
融合中的相互作用区域,以及关于它们如何发挥其功能的机械研究仍然很少。我们
假设与HIV-1信封有关的其他融合蛋白的膜相互作用区域
蛋白质(Env)采用定义的寡聚结构,这对于稳定性,功能和功能至关重要
膜中全长蛋白的抗原性。在我们以前完成的研究中
资金期,我们已经确定了TM的结构,膜近端外部区域和
HIV-1 ENV中的细胞质尾部,使用最新的NMR技术模仿脂质双层。我们发现
这些区域都形成了排序良好的三聚合物簇,并在构象上耦合,这破坏了它们
可以减少融合并改变整个ENV的抗原结构。在此应用程序中,我们建议申请
我们的NMR/BICELLE技术研究了SIV Env的膜区域以及最近出现的SARS-
COV-2尖峰(S),并使用冷冻电子显微镜确定全长蛋白的结构
在脂质纳米盘中重构。我们将在这些关键结构元素的膜融合中定义角色
通过深诱变和功能测定的区域。我们将为以下具体目标提取:1)我们将
研究SIV Env的膜相互作用成分; 2)我们将研究膜相互作用
灌注后安排中的组成部分; 3)我们将确定全长SIV环境的结构和
SARS-COV-2在膜的背景下; 4)我们将阐明膜相互作用域的作用
HIV/SIV Env和SARS-COV-2 S的稳定性,功能和抗原性。
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)

暂无数据
数据更新时间:2024-06-01
JAMES Jeiwen CHOU的其他基金
Structural and Functional Roles of the Membrane-Related Components of Single-Pass Membrane Proteins
单程膜蛋白膜相关成分的结构和功能作用
- 批准号:1038087710380877
- 财政年份:2021
- 资助金额:$ 83.42万$ 83.42万
- 项目类别:
CONTROL AND ACTIVATION OF THE TUMOR NECROSIS FACTOR RECEPTORS
肿瘤坏死因子受体的控制和激活
- 批准号:1033810610338106
- 财政年份:2020
- 资助金额:$ 83.42万$ 83.42万
- 项目类别:
CONTROL AND ACTIVATION OF THE TUMOR NECROSIS FACTOR RECEPTORS
肿瘤坏死因子受体的控制和激活
- 批准号:1009295110092951
- 财政年份:2020
- 资助金额:$ 83.42万$ 83.42万
- 项目类别:
Structure-function studies of the membrane-interacting domains of HIV-1 Env spike
HIV-1 Env 刺突膜相互作用域的结构功能研究
- 批准号:92032149203214
- 财政年份:2016
- 资助金额:$ 83.42万$ 83.42万
- 项目类别:
Structure-function studies of the membrane-interacting domains of HIV-1 Env spike
HIV-1 Env 刺突膜相互作用域的结构功能研究
- 批准号:92759219275921
- 财政年份:2016
- 资助金额:$ 83.42万$ 83.42万
- 项目类别:
Structure-function studies of the membrane-interacting domains of HIV-1 Env spike
HIV-1 Env 刺突膜相互作用域的结构功能研究
- 批准号:98991719899171
- 财政年份:2016
- 资助金额:$ 83.42万$ 83.42万
- 项目类别:
Function and mechanism of the HCV p7 channel and its therapeutic potential
HCV p7通道的功能、机制及其治疗潜力
- 批准号:91980399198039
- 财政年份:2016
- 资助金额:$ 83.42万$ 83.42万
- 项目类别:
Function and mechanism of the HCV p7 channel and its therapeutic potential
HCV p7通道的功能、机制及其治疗潜力
- 批准号:88804438880443
- 财政年份:2014
- 资助金额:$ 83.42万$ 83.42万
- 项目类别:
Membrane protein structures by solution NMR
通过溶液 NMR 确定膜蛋白结构
- 批准号:81404708140470
- 财政年份:2010
- 资助金额:$ 83.42万$ 83.42万
- 项目类别:
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