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Mechanical regulation of the helicase activity of Zika virus NS3
Biophysical Journal ( IF 3.4 ) Pub Date : 2022-08-02 , DOI: 10.1016/j.bpj.2022.07.030
Xiaocong Cao 1 , Kaixian Liu 2 , Shannon Yan 3 , Sai Li 4 , Yajuan Li 5 , Tengchuan Jin 6 , Shixin Liu 4
Affiliation  

Zika virus (ZIKV) is a positive-sense single-stranded RNA virus that infects humans and can cause birth defects and neurological disorders. Its non-structural protein 3 (NS3) contains a protease domain and a helicase domain, both of which play essential roles during the viral life cycle. However, it has been shown that ZIKV NS3 has an inherently weak helicase activity, making it unable to unwind long RNA duplexes alone. How this activity is stimulated to process the viral genome and whether the two domains of NS3 are functionally coupled remain unclear. Here, we used optical tweezers to characterize the RNA-unwinding properties of ZIKV NS3—including its processivity, velocity, and step size—at the single-molecule level. We found that external forces that weaken the stability of the duplex RNA substrate significantly enhance the helicase activity of ZIKV NS3. On the other hand, we showed that the protease domain increases the binding affinity of NS3 to RNA but has only a minor effect on unwinding per se. Our findings suggest that the ZIKV NS3 helicase is activated on demand in the context of viral replication, a paradigm that may be generalizable to other flaviviruses.



中文翻译:

寨卡病毒 NS3 解旋酶活性的机械调控

寨卡病毒 (ZIKV) 是一种正义单链 RNA 病毒,可感染人类并可导致出生缺陷和神经系统疾病。其非结构蛋白 3 (NS3) 包含一个蛋白酶结构域和一个解旋酶结构域,这两者在病毒生命周期中都发挥着重要作用。然而,已表明 ZIKV NS3 具有固有的弱解旋酶活性,使其无法单独解开长 RNA 双链体。如何刺激这种活性来处理病毒基因组以及 NS3 的两个结构域是否在功能上耦合仍不清楚。在这里,我们使用光学镊子在单分子水平上表征 ZIKV NS3 的 RNA 解旋特性,包括其持续合成能力、速度和步长。我们发现削弱双链 RNA 底物稳定性的外力显着增强 ZIKV NS3 的解旋酶活性。另一方面,我们发现蛋白酶结构域增加了 NS3 与 RNA 的结合亲和力,但对解旋本身只有很小的影响。我们的研究结果表明,ZIKV NS3 解旋酶在病毒复制的背景下按需激活,这种范例可以推广到其他黄病毒。

更新日期:2022-08-02
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