Vif

维夫

• 批准号: 7914107
• 负责人: John D Gross
• 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/7914107
• 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（彼得林和格罗斯）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，这些病毒不会在非允许细胞或宿主中复制。Vif失活 细胞胞苷脱氨酶ASF和A3 G，它们是APOBEC 3（载脂蛋白B）的成员 mRNA编辑酶催化多肽3）家族。在Vif不存在的情况下，这些APOBEC 3蛋白 被整合到新的病毒颗粒中，在那里它们在负链cDNA中脱氨基胞苷， 逆转录这些DNA损伤导致病毒DNA降解或引入有害的 突变。此外，APOBEC 3蛋白可以在不存在其酶促作用的情况下抑制病毒复制。 活性，可能是通过改变逆转录过程本身。因此，APOBEC蛋白保护细胞 Vif已经进化为提供一种重要的病毒对抗防御。 Vif的一个关键作用是促进A3 G和ASF的泛素化和随后的破坏。 蛋白体Vif将A3 G和ASF募集到包括Cullin-5、Ring-box 2，以及延伸蛋白B和C（EloBC）。即使是适度抑制Vif功能，无论是通过干扰结合 A3 G和/或ASF或通过阻断EloBC/Cul 5/Rbx 2 E3连接酶的募集，可以显著降低 体内HIV-1载量。因此，本项目的一个主要目标是确定 Vif/EloBC/Cul 5/Rbx 2复合物和具有A3 G的亚复合物。