Structural basis of HIV-1 Vif-mediated E3 ligase targeting of host APOBEC3H.
Structural basis of HIV-1 Vif-mediated E3 ligase targeting of host APOBEC3H.
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DOI：
10.1038/s41467-023-40955-x
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发表时间：
2023-08-28
影响因子：
16.6
通讯作者：
Chen XS
中科院分区：
文献类型：
--
作者：
Ito F;Alvarez-Cabrera AL;Kim K;Zhou ZH;Chen XS
人类APOBEC3 （A3）胞苷脱氨酶是抗病毒因子，对逆转录病毒特别有效。作为对策，HIV-1使用病毒感染因子（Vif）靶向特定的人类a3进行蛋白酶体降解。Vif招募细胞转录辅助因子CBF-β和Cullin-5 (CUL5) RING E3泛素连接酶来结合不同的A3s，但由于缺乏复合物的原子结构，这是如何完成的尚不清楚。在这里，我们展示了HIV-1 Vif与人A3H、CBF-β和CUL5泛素连接酶组分（CUL5、ELOB和ELOC）复合物的低温电镜结构。Vif通过直接结合四种人蛋白A3H、CBF-β、CUL5和ELOC使整个复合物成核。该结构揭示了A3H和Vif之间的大界面面积，主要由A3H的α-螺旋侧和Vif的五链β-片介导。这种A3H-Vif界面揭示了这两种蛋白的敏感性调节多态性的基础，包括先前报道的从HIV/AIDS患者分离的Vif的功能获得突变。我们的结构和功能结果为HIV和人类之间显著的相互作用提供了见解，并将为抗HIV治疗的开发工作提供信息。HIV-1 Vif可拮抗多种人类APOBEC3胞苷脱氨酶以逃避免疫。在这里，作者确定了人类APOBEC3H与HIV-1 Vif和E3泛素连接酶结合的结构，为病毒-宿主军备竞赛提供了机制基础。
Human APOBEC3 (A3) cytidine deaminases are antiviral factors that are particularly potent against retroviruses. As a countermeasure, HIV-1 uses a viral infectivity factor (Vif) to target specific human A3s for proteasomal degradation. Vif recruits cellular transcription cofactor CBF-β and Cullin-5 (CUL5) RING E3 ubiquitin ligase to bind different A3s distinctively, but how this is accomplished remains unclear in the absence of the atomic structure of the complex. Here, we present the cryo-EM structures of HIV-1 Vif in complex with human A3H, CBF-β and components of CUL5 ubiquitin ligase (CUL5, ELOB, and ELOC). Vif nucleates the entire complex by directly binding four human proteins, A3H, CBF-β, CUL5, and ELOC. The structures reveal a large interface area between A3H and Vif, primarily mediated by an α-helical side of A3H and a five-stranded β-sheet of Vif. This A3H-Vif interface unveils the basis for sensitivity-modulating polymorphism of both proteins, including a previously reported gain-of-function mutation in Vif isolated from HIV/AIDS patients. Our structural and functional results provide insights into the remarkable interplay between HIV and humans and would inform development efforts for anti-HIV therapeutics. HIV-1 Vif antagonizes multiple human APOBEC3 cytidine deaminases for immune evasion. Here, the authors determine the structure of human APOBEC3H bound to HIV-1 Vif and E3 ubiquitin ligase, providing a mechanistic basis for the virus-host arms race.
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DOI：
10.1107/s2059798318009324
发表时间：
2018-09-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Klaholz BP;Moriarty NW;Poon BK;Sobolev OV;Terwilliger TC;Adams PD;Urzhumtsev A
通讯作者：
Urzhumtsev A
影响因子：
5.6
作者：
Desimmie, Belete A.;Delviks-Frankenberrry, Krista A.;Burdick, Ryan C.;Qi, DongFei;Izumi, Taisuke;Pathak, Vinay K.
通讯作者：
Pathak, Vinay K.
影响因子：
16.6
作者：
Bohn JA;Thummar K;York A;Raymond A;Brown WC;Bieniasz PD;Hatziioannou T;Smith JL
通讯作者：
Smith JL
影响因子：
4.6
作者：
Ito F;Yang H;Xiao X;Li SX;Wolfe A;Zirkle B;Arutiunian V;Chen XS
通讯作者：
Chen XS
影响因子：
64.5
作者：
Harris, RS;Bishop, KN;Malim, MH
通讯作者：
Malim, MH