小柯机器人

美国加州大学旧金山分校John D. Gross研究小组报道APOBEC3G抗HIV-1 Vif的结构基础。相关论文于2023年2月8日在线发表在《自然》杂志上。

研究人员报道了人APOBE3G（A3G）结合HIV-1 Vif和被劫持的细胞蛋白促进泛素介导的蛋白水解的冷冻电镜结构。一个小表面解释了分子军备竞赛，包括导致HIV-1诞生的跨物种传播事件。出乎意料的是，研究人员发现RNA是Vif-A3G相互作用的分子粘合剂，使Vif通过泛素依赖和独立机制抑制A3G。这些结果提出了一个模型，其中Vif通过拦截A3G的最危险形式来对抗病毒，当它与RNA结合并在包装的过程中，从而防止病毒限制。通过接触限制所需的基本表面，Vif利用了A3G中的一个漏洞，这些结果提出了一种一般机制，即RNA结合有助于定位宿主抗病毒基因的病毒拮抗所必需的关键残基。

研究人员表示，APOBEC3（A3）蛋白是宿主抗病毒细胞蛋白，可使不同病毒家族的病毒基因组高突变。在逆转录病毒主题中，这一过程需要A3包装成病毒颗粒。慢病毒编码一种蛋白Vif，通过靶向A3家族成员进行降解来拮抗它们。A3的多样化允许宿主逃离Vif，而Vif的适应性使灵长类慢病毒能够跨物种传播。这种分子军备竞赛是如何在结构水平上进行的尚不清楚。

附：英文原文

Title: The structural basis for HIV-1 Vif antagonism of human APOBEC3G

Author: Li, Yen-Li, Langley, Caroline A., Azumaya, Caleigh M., Echeverria, Ignacia, Chesarino, Nicholas M., Emerman, Michael, Cheng, Yifan, Gross, John D.

Issue&Volume: 2023-02-08

Abstract: The APOBEC3 (A3) proteins are host antiviral cellular proteins that hypermutate the viral genome of diverse viral families. In retroviruses, this process requires A3 packaging into viral particles1-4. The lentiviruses encode a protein Vif that antagonizes A3 family members by targeting them for degradation. Diversification of A3 allows host escape from Vif whereas adaptations in Vif enable cross-species transmission of primate lentiviruses. How this molecular arms race plays out at the structural level is unknown. Here, we report the cryogenic electron microscopy structure of human APOBE3G (A3G) bound to HIV-1 Vif and hijacked cellular proteins that promote ubiquitin mediated proteolysis. A small surface explains the molecular arms race, including a cross-species transmission event that led to the birth of HIV-1. Unexpectedly, we find RNA is a molecular glue for the Vif-A3G interaction, enabling Vif to repress A3G by ubiquitin dependent and independent mechanisms. Our results suggest a model where Vif antagonizes A3G by intercepting it in its most dangerous form for the virus, when bound to RNA and on pathway to packaging, to prevent viral restriction. By engaging essential surfaces required for restriction, Vif exploits a vulnerability in A3G, suggesting a general mechanism where RNA binding helps position key residues necessary for viral antagonism of a host antiviral gene.

DOI: 10.1038/s41586-023-05779-1

Source: https://www.nature.com/articles/s41586-023-05779-1

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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