Vif

维夫

• 批准号: 7914110
• 负责人: Boris Matija PETERLIN
• 金额: $ 40.98万
• 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/7914110
• 关键词: Architecture; Binding; Boxing; Cells; Complementary DNA; Complex; Crystallography; Cullin 5 Protein; Cytidine; Cytidine Deaminase; DNA lesion; Deaminase; Enzymes; Family; HIV; HIV-1; HIV-1 load; HIV-2; Maps; Mutation; N-terminal; Oligonucleotides; Primate Lentiviruses; Proteins; RNA; Recruitment Activity; Resolution; Reverse Transcription; Role; SIV; Structure; Transcription Process; Ubiquitin-Protein Ligase Complexes; Ubiquitination; Viral; Virus; acrosome stabilizing factor; apolipoprotein B mRNA editing enzyme; in vivo; member; multicatalytic endopeptidase complex; particle; polypeptide; reconstruction; ubiquitin-protein ligase; viral DNA

PROJECT 4 - Vif (PETERLIN AND GROSS. PROJECT LEADERS) The viral infectivity factor Vif is an essential accessory protein of primate lentiviruses, HIV-1, HIV-2, and SIV. Without Vif, these viruses do not replicate in non-permissive cells or in the host. Vif inactivates the cellular cytidine deaminases ASF and A3G, which are members of the APOBEC3 (apolipoprotein B mRNA-editing enzyme catalytic-polypeptides 3) family. In the absence of Vif, these APOBEC3 proteins are incorporated into new viral particles where they deaminate cytidines in the minus-strand cDNA during reverse transcription. These DNA lesions result in viral DNA degradation or introduction of deleterious mutations. In addition, the APOBEC3 proteins can inhibit viral replication in the absence of their enzymatic activity, possibly by altering the reverse transcription process itself. Thus, APOBEC proteins protect cells against HIV, and Vif has evolved to provide an essential viral counter defense. A key role for Vif is to promote ubiquitination and subsequent destruction of A3G and ASF by the proteosome. Vif recruits A3G and ASF to a cellular ubiquitin protein ligase that includes Cullin-5, Ring-box 2, and Elongins B and C (EloBC). Even modest inhibition of Vif function, either by interfering with binding to A3G and/or ASF or by blocking recruitment of the EloBC/Cul5/Rbx2 E3 ligase, might significantly reduce HIV-1 loads in vivo. Therefore, a major objective of this project is to determine the architecture of the Vif/EloBC/Cul5/Rbx2 complex and subcomplexes with A3G.

项目 4 - Vif（PETERLIN 和总项目负责人） 病毒感染因子 Vif 是灵长类慢病毒、HIV-1、HIV-2、 和SIV。如果没有 Vif，这些病毒就不会在不受许可的细胞或宿主中复制。 Vif 失活 细胞胞苷脱氨酶 ASF 和 A3G，它们是 APOBEC3（载脂蛋白 B mRNA 编辑酶催化多肽 3) 家族。在没有 Vif 的情况下，这些 APOBEC3 蛋白 被整合到新的病毒颗粒中，在过程中它们使负链 cDNA 中的胞苷脱氨 逆转录。这些 DNA 损伤导致病毒 DNA 降解或引入有害物质 突变。此外，APOBEC3 蛋白在缺乏酶促作用的情况下可以抑制病毒复制。 活性，可能是通过改变逆转录过程本身。因此，APOBEC 蛋白可以保护细胞 对抗 HIV，Vif 已进化为提供重要的病毒防御。 Vif 的一个关键作用是促进 A3G 和 ASF 的泛素化和随后的破坏 蛋白酶体。 Vif 将 A3G 和 ASF 募集到细胞泛素蛋白连接酶（包括 Cullin-5、Ring-box） 2、Elongins B 和 C (EloBC)。即使是通过干扰结合来适度抑制 Vif 功能 A3G 和/或 ASF 或通过阻断 EloBC/Cul5/Rbx2 E3 连接酶的招募，可能会显着减少 HIV-1在体内负载。因此，该项目的一个主要目标是确定 Vif/EloBC/Cul5/Rbx2 复合物和具有 A3G 的子复合物。