Nef

内夫

• 批准号: 7914112
• 负责人: THOMAS C ALBER
• 金额: $ 61.12万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7914112
• 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; 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; protein complex; 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 -网络（彼得林和阿尔伯。项目负责人！ Nef（阴性因子）是一种命名错误的HIV-1、HIV-2和SIV的辅助激活因子， 高水平的病毒血症和艾滋病的进展感染的病人。Nef在其N-末端被肉豆蔻酰化 并通过其C-末端胆固醇识别基序（CRM）结合胆固醇。这些信号使Nef靶向 脂筏（LRs）在细胞膜上。该项目旨在描述Nef与合作伙伴的互动 在两个关键过程中动员的蛋白质-宿主细胞活化和受体内吞作用。这些 研究将测试Nef的大部分表面接触宿主蛋白质的假设， 相互作用不仅将功能性伴侣聚集在一起，而且还通过变构激活靶点。 构象变化介导多种宿主相互作用的Nef表面的鉴定将 提供关于如何同时靶向一个以上Nef功能的新信息， 大药厂 Nef在病毒生命周期的早期组装一个信号体，激活受感染的免疫细胞， 刺激病毒复制。信号体由包括Nef支架在内的六种蛋白质组成。不 已知Nef是否简单地将信号体的宿主成分聚集在一起，或者也激活这些 通过变构相互作用。Nef还通过促进宿主细胞表面的重塑来介导宿主细胞表面的重塑。 细胞受体如CD 4、MHC I类和T细胞抗原受体的内化。调解 Nef在胞吞作用中桥接受体与Armadillo repeat（ARM-重复）形成三元复合物 含有蛋白质，如衔接蛋白（AP）复合物，（3COP），和催化亚基（V1 H）的 液泡ATP酶（V-ATP酶）。这些基本的桥接功能的机制是未知的， Nef结合的协同性还没有被表征。Nef的单体和二聚体结构 已经解决了核磁共振和晶体学，但除了小的复合物之间的脯氨酸丰富的 Nef和SH 3结构域的序列，关于Nef与宿主蛋白结合的信息很少。