Nef

内夫

• 批准号: 7480010
• 负责人: THOMAS C ALBER
• 金额: $ 40.76万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7480010
• 关键词: Acquired Immunodeficiency Syndrome; Adaptor Signaling Protein; Armadillo Repeat; Binding; C-terminal; CDC42 gene; Catalytic Domain; Cell surface; Cells; Cellular Membrane; Cholesterol; Complex; Crystallography; Cytoplasmic Tail; Endocytosis; HIV-1; HIV-2; Immune; Integration Host Factors; Life Cycle Stages; MHC Class I Genes; Mediating; Membrane Microdomains; Patients; Pharmacologic Substance; Proline; Proteins; Reaction; Reading; Receptor Activation; SH3 Domains; SIV; Signal Transduction; Structure; Surface; T-Cell Receptor; Testing; Viral; Viremia; cdc42 GTP-Binding Protein; receptor; receptor mediated endocytosis; scaffold; vacuolar H+-ATPase

PROJECT 5 - Net (PETERLIN AND ALBER. PROJECT LEADERS! Nef (negative factor) is a misnamed, accessory activator of HIV-1, HIV-2, and SIV that is essential for high-level viremia and progression to AIDS in infected patients. Nef is myristylated at its N-terminus and binds cholesterol via its C-terminal cholesterol recognition motif (CRM). These signals target Nef to lipid rafts (LRs) in cellular membranes. This project aims to characterize Nef interactions with partner proteins that are mobilized in two crucial processes¿host-cell activation and receptor endocytosis. These studies will test the hypotheses that much of the surface of Nef contacts host proteins, and these interactions not only bring together functional partners but also activate targets through allosteric conformational changes. The identification of surfaces of Nef that mediate multiple host interactions will provide new information about how to simultaneously target more than one Nef function with new Pharmaceuticals. Nef assembles a signalosome early in the viral life cycle that activates infected immune cells, stimulating viral replication. The signalosome consists of six proteins including the Nef scaffold. It is not known if Nef simply brings together the host components of the signalosome or also activates these factors through allosteric interactions. Nef also mediates remodeling of the host cell surface by promoting internalization of cellular receptors, such as CD4, MHC class I, and T cell antigen receptor. To mediate endocytosis, Nef bridges the receptors in ternary complexes with armadillo repeat (ARM-repeat) containing proteins such as adaptor protein (AP) complexes, (3COP, and the catalytic subunit (V1H) of the vacuolar ATPase (V-ATPase). The mechanisms of these essential bridging functions are unknown and the cooperativity of Nef binding has not been characterized. Monomeric and dimeric structures of Nef have been solved by NMR and crystallography, but except for small complexes between the proline-rich sequence of Nef and SH3 domains, little information is available about Nef bound to host proteins.

项目5--网(Peterlin和Alber.项目负责人！ NEF(负性因子)是一种命名错误的HIV-1、HIV-2和SIV的辅助激活剂，是必不可少的 用于感染患者的高水平病毒血症和进展为艾滋病。NEF在其N-末端是肉豆蔻化的 并通过其C末端胆固醇识别基序(CRM)与胆固醇结合。这些信号针对Nef到 细胞膜中的脂筏(LRs)。该项目旨在描述Nef与合作伙伴的互动 在宿主细胞激活和受体内吞作用这两个关键过程中被动员的蛋白质。这些 研究将测试Nef表面的大部分接触宿主蛋白质的假设，以及这些 相互作用不仅将功能伙伴聚集在一起，而且还通过变构激活靶标 构象变化。识别调节多个宿主相互作用的Nef表面将 提供有关如何同时以多个Nef函数为目标的新信息 制药公司。 NEF在病毒生命周期的早期组装了一个信号体，激活受感染的免疫细胞， 刺激病毒复制。信号体由六种蛋白质组成，其中包括Nef支架。它不是 已知Nef是否只是将信号体的宿主组件聚集在一起，或者也激活了这些组件 通过变构相互作用产生的因子。NEF也通过促进宿主细胞表面的重塑来调节 细胞受体的内化，如CD4、MHC I类和T细胞抗原受体。调停 内吞作用，Nef将受体桥接在带有手臂重复序列(Arm-Repeat)的三元复合体中 含有蛋白质，如接合蛋白(AP)复合体(3COP)和 液泡型ATPase(V-ATPase)。这些基本的桥接功能的机制是未知的 Nef结合的协作性还没有被表征。Nef的单体和二聚体结构 已经被核磁共振和结晶学所解决，但除了小的富含脯氨酸的络合物 关于Nef和SH3结构域的序列，关于Nef与宿主蛋白结合的信息很少。