Structural basis for hijacking CBF-β and CUL5 E3 ligase complex by HIV-1 Vif
Structural basis for hijacking CBF-β and CUL5 E3 ligase complex by HIV-1 Vif
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DOI：
10.1038/nature12884
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发表时间：
2014-01-09
期刊：
影响因子：
64.8
通讯作者：
Huang, Zhiwei
中科院分区：
文献类型：
--
作者：
Guo, Yingying;Dong, Liyong;Huang, Zhiwei
人类免疫缺陷病毒（HIV）-1蛋白Vif通过劫持细胞蛋白酶体降解途径破坏宿主限制性因子的抗病毒活性，在中和宿主先天性防御中发挥核心作用（1-6）;然而，Vif实现这一点的潜在机制仍不清楚。在这里，我们报告的Vif-CBF-β-CUL 5-β-CULB-β-CULC复合物的晶体结构。该结构揭示了Vif通过两个结构域，通过与CBF-β、CUL 5和CUL 2C相互作用来组织五聚体复合物的形成。Vif的较大结构域（α/β结构域）与RUNX 1结合到CBF-β的同一侧，表明Vif和RUNX 1是CBF-β结合的唯一结构域。Vif的较小结构域（α-结构域）与CUL 5和CUL 5的相互作用是协同的，并且模拟SOCS 2与后两种蛋白的相互作用。Vif的一个独特的锌指基序位于两个Vif结构域之间，不与其他蛋白质接触，但稳定了α结构域的构象，这可能对Vif-CUL 5相互作用很重要。总之，我们的数据揭示了Vif劫持CBF-beta和CUL 5 E3连接酶复合物的结构基础，为合理设计新型抗HIV药物奠定了基础。
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(1-6); however, the underlying mechanism by which Vif achieves this remains unclear. Here we report a crystal structure of the Vif-CBF-beta-CUL5-ELOB-ELOC complex. The structure reveals that Vif, by means of two domains, organizes formation of the pentameric complex by interacting with CBF-beta, CUL5 and ELOC. The larger domain (alpha/beta domain) of Vif binds to the same side of CBF-beta as RUNX1, indicating that Vif and RUNX1 are exclusive for CBF-beta binding. Interactions of the smaller domain (alpha-domain) of Vif with ELOCand 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 alpha-domain, which may be important for Vif-CUL5 interaction. Together, our data reveal the structural basis for Vif hijacking of the CBF-beta and CUL5 E3 ligase complex, laying a foundation for rational design of novel anti-HIV drugs.