STRUCTURE/FUNCTION ANALYSIS OF THE HIV ENV GENE PRODUCT

HIV ENV 基因产物的结构/功能分析

• 批准号: 8172360
• 负责人: Eric Hunter
• 金额: $ 5.48万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172360
• 关键词: Amino Acids; Area; Arginine; Biological Process; C-terminal; Cell fusion; Cell membrane; Cells; Charge; Complex; Computer Retrieval of Information on Scientific Projects Database; Cytoplasmic Tail; Funding; Glycine; Glycoproteins; Grant; HIV; Head; Human; Institution; Intracellular Transport; Investigation; Lipids; Lysine; Mediating; Membrane; Membrane Fusion; Modeling; Play; Proteins; Research; Research Personnel; Resources; Role; SIV; Series; Side; Source; Structure; Terminator Codon; Tryptophan; United States National Institutes of Health; Viral; Viral Pathogenesis; Virion; Virus; Virus Assembly; Virus Diseases; base; env Gene Products; mutant

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Three broad areas of investigation have been pursued: + Characterizing the role of the tryptophan-rich membrane-proximal (TRMP) domain of gp41 in Env-mediated membrane fusion and glycoprotein incorporation into virus. + Analyzing the topology and structural requirements of the gp41 membrane-spanning domain for virus assembly and entry. + Determining the role of sequences within the cytoplasmic domain (CD) of HIV Env in intracellular transport, and viral pathogenesis. The membrane-spanning domain (MSD) of the envelope (Env) glycoprotein from human (HIV) and simian immunodeficiency viruses plays a key role in anchoring the Env complex into the viral membrane but also contributes to its biological function in fusion and virus entry. In HIV type 1 (HIV-1), it has been predicted to span 27 amino acids, from lysine residue 681 to arginine 707, and encompasses an internal arginine at residue 694. By examining a series of C-terminal-truncation mutants of the HIV-1 gp41 glycoprotein that substituted termination codons for amino acids 682 to 708, we have shown that this entire region is required for efficient viral infection of target cells. Truncation to the arginine at residue 694 resulted in an Env complex that was secreted from the cells. In contrast, a region from residues 681 to 698, which contains highly conserved hydrophobic residues and glycine motifs and extends 4 amino acids beyond 694R, can effectively anchor the protein in the membrane, allow efficient transport to the plasma membrane, and mediate wild-type levels of cell-cell fusion. However, these fusogenic truncated Env mutants are inefficiently incorporated into budding virions. Based on the analysis of these mutants, a "snorkeling" model, in which the flanking charged amino acid residues at 681 and 694 are buried in the lipid while their side chains interact with polar head groups, is proposed for the HIV-1 MSD.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 已在三个广泛的领域进行调查： + 表征gp 41的富含色氨酸的膜近端（TRMP）结构域在Env介导的膜融合和糖蛋白掺入病毒中的作用。 + 分析gp 41跨膜结构域对病毒组装和进入的拓扑结构和结构要求。 + 确定HIV Env胞质结构域（CD）内序列在细胞内转运和病毒发病机制中的作用。 来自人类（HIV）和猿猴免疫缺陷病毒的包膜（Env）糖蛋白的跨膜结构域（MSD）在将Env复合物锚定到病毒膜中中起关键作用，但也有助于其在融合和病毒进入中的生物学功能。在HIV 1型（HIV-1）中，预测其跨越27个氨基酸，从赖氨酸残基681至精氨酸707，并包括残基694处的内部精氨酸。通过研究一系列的C-末端截短突变体的HIV-1 gp 41糖蛋白取代终止密码子的氨基酸682至708，我们已经表明，这整个区域是需要有效的病毒感染的靶细胞。在残基694处截断精氨酸导致从细胞分泌的Env复合物。 相比之下，残基681至698的区域，其含有高度保守的疏水残基和甘氨酸基序，并延伸4个氨基酸超过694 R，可以有效地将蛋白质锚在膜中，允许有效运输到质膜，并介导野生型水平的细胞-细胞融合。然而，这些融合性截短的Env突变体无效地掺入到出芽的病毒体中。 基于对这些突变体的分析，提出了HIV-1 MSD的“浮潜”模型，其中侧翼681和694处的带电氨基酸残基被埋在脂质中，而它们的侧链与极性头部基团相互作用。