Nature2014-06-26 7:07 PM

HIV-1 Vif蛋白的作用机制 Structural basis for hijacking CBF-β and CUL5 E3 ligase complex by HIV-1 Vif

论文摘要 

在“人免疫缺陷病毒-1”(HIV-1)感染期间,病毒蛋白Vif通过同时劫持“贝塔核心结合因子亚单元”(CBFβ)和E3连接酶复合物CUL5-ELOB-ELOC,来破坏抗病毒宿主因子的活性。但它是怎样做到这一点的此前却一直不清楚。现在,Zhiwei Huang及同事确定了Vif-CBFβ-CUL5-ELOB-ELOC复合物的晶体结构。他们发现,Vif模仿SOCS2的作用来与CUL5和ELOC发生相互作用。Vif蛋白是HIV-1复制绝对需要的,这使其成为抗病毒药物 研发的一个重要目标,而且本文所报告的机制细节应能帮助设计可同时以Vif和上述五聚体复合物为目标的新药。

Abstract 

The human immunodeficiency virus (HIV)-1 protein Vif has a central role in the neutralization of host innate defences by hijacking cellular proteasomal degradation pathways to subvert the antiviral activity of host restriction factors; however, the underlying mechanism by which Vif achieves this remains unclear. Here we report a crystal structure of the Vif–CBF-β–CUL5–ELOB–ELOC complex. The structure reveals that Vif, by means of two domains, organizes formation of the pentameric complex by interacting with CBF-β, CUL5 and ELOC. The larger domain (α/β domain) of Vif binds to the same side of CBF-β as RUNX1, indicating that Vif and RUNX1 are exclusive for CBF-β binding. Interactions of the smaller domain (α-domain) of Vif with ELOC and CUL5 are cooperative and mimic those of SOCS2 with the latter two proteins. A unique zinc-finger motif of Vif, which is located between the two Vif domains, makes no contacts with the other proteins but stabilizes the conformation of the α-domain, which may be important for Vif–CUL5 interaction. Together, our data reveal the structural basis for Vif hijacking of the CBF-β and CUL5 E3 ligase complex, laying a foundation for rational design of novel anti-HIV drugs.

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