Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.
J Mol Biol. 2018 Mar 30;430(7):948-962. doi: 10.1016/j.jmb.2018.02.006. Epub 2018 Feb 15.
Recently, Zika virus (ZIKV) emerged as a global public health concern and is distinct from other flaviviruses in many aspects, for example, causing transplacental infection, fetal abnormalities and vector-independent transmission through body fluids in humans. The capsid (C) protein is a multifunctional protein, since it binds to viral RNA in the process of nucleocapsid assembly and plays important roles in virus infection processes by interacting with cellular proteins, modulating cellular metabolism, apoptosis and immune response. Here we solved the crystal structure of ZIKV C protein at a resolution of 1.9Å. The ZIKV C protein structure contains four α helices with a long pre-α1 loop and forms dimers. The unique long pre-α1 loop in ZIKV C contributes to the tighter association of dimeric assembly and renders a divergent hydrophobic feature at the lipid bilayer interface in comparison with the known C structures of West Nile and dengue viruses. We reported the interaction between the ZIKV C protein and lipid droplets through confocal microscopy analysis. Substitutions of key amino acids in the pre-α1 loop of ZIKV C disrupted the interaction with lipid droplets, indicating that the loop is critical for membrane association. We also recognized that ZIKV C protein possesses broad binding capability to different nucleotide types, including single-stranded and double-stranded RNAs or DNAs. Furthermore, the highly positively charged interface, mainly formed by α4 helix, is proposed to be responsible for nucleotide binding. These findings will greatly enhance our understanding of ZIKV C protein, providing information for anti-ZIKV drug design targeting the C protein.
最近，寨卡病毒（ZIKV）成为全球公共卫生关注的焦点，它在许多方面与其他黄病毒不同，例如引起胎盘感染、胎儿畸形和通过人体体液的媒介独立传播。衣壳（C）蛋白是一种多功能蛋白，因为它在核衣壳组装过程中与病毒 RNA 结合，并通过与细胞蛋白相互作用、调节细胞代谢、凋亡和免疫反应，在病毒感染过程中发挥重要作用。在这里，我们解决了分辨率为 1.9Å 的 ZIKV C 蛋白的晶体结构。ZIKV C 蛋白结构包含四个α螺旋，带有一个长的 pre-α1 环，并形成二聚体。ZIKV C 中的独特长 pre-α1 环有助于二聚体组装的更紧密结合，并在脂质双层界面处呈现出与西尼罗河和登革热病毒的已知 C 结构不同的发散疏水性特征。我们通过共聚焦显微镜分析报告了 ZIKV C 蛋白与脂滴之间的相互作用。ZIKV C 中 pre-α1 环关键氨基酸的取代破坏了与脂滴的相互作用，表明该环对于膜结合至关重要。我们还认识到，ZIKV C 蛋白对不同核苷酸类型具有广泛的结合能力，包括单链和双链 RNA 或 DNA。此外，主要由α4 螺旋形成的高度带正电荷的界面被认为负责核苷酸结合。这些发现将极大地增强我们对 ZIKV C 蛋白的理解，为针对 C 蛋白的抗 ZIKV 药物设计提供信息。
