Shanghai Public Health Clinical Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University , Shanghai, China.
J Virol. 2023 Aug 31;97(8):e0074823. doi: 10.1128/jvi.00748-23. Epub 2023 Aug 3.
Proliferating cell nuclear antigen (PCNA) belongs to the DNA sliding clamp family. Via interacting with various partner proteins, PCNA plays critical roles in DNA replication, DNA repair, chromatin assembly, epigenetic inheritance, chromatin remodeling, and many other fundamental biological processes. Although PCNA and PCNA-interacting partner networks are conserved across species, PCNA of a given species is rarely functional in heterologous systems, emphasizing the importance of more representative PCNA studies. Here, we report two crystal structures of PCNA from African swine fever virus (ASFV), which is the only member of the family. Compared to the eukaryotic and archaeal PCNAs and the sliding clamp structural homologs from other viruses, PCNA possesses unique sequences and/or conformations at several regions, such as the J-loop, interdomain-connecting loop (IDCL), P-loop, and C-tail, which are involved in partner recognition or modification of sliding clamps. In addition to double-stranded DNA binding, we also demonstrate that PCNA can modestly enhance the ligation activity of the LIG protein. The unique structural features of PCNA can serve as a potential target for the development of ASFV-specific inhibitors and help combat the deadly virus. IMPORTANCE Two high-resolution crystal structures of African swine fever virus proliferating cell nuclear antigen (PCNA) are presented here. Structural comparison revealed that PCNA is unique at several regions, such as the J-loop, the interdomain-connecting loop linker, and the P-loop, which may play important roles in ASFV-specific partner selection of PCNA. Unlike eukaryotic and archaeal PCNAs, PCNA possesses high double-stranded DNA-binding affinity. Besides DNA binding, PCNA can also modestly enhance the ligation activity of the LIG protein, which is essential for the replication and repair of ASFV genome. The unique structural features make PCNA a potential target for drug development, which will help combat the deadly virus.
增殖细胞核抗原（PCNA）属于 DNA 滑动夹家族。通过与各种伴侣蛋白相互作用，PCNA 在 DNA 复制、DNA 修复、染色质组装、表观遗传遗传、染色质重塑和许多其他基本生物学过程中发挥关键作用。尽管 PCNA 和 PCNA 相互作用的伙伴网络在物种间是保守的，但给定物种的 PCNA 在异源系统中很少具有功能，这强调了更具代表性的 PCNA 研究的重要性。在这里，我们报告了来自非洲猪瘟病毒（ASFV）的 PCNA 的两个晶体结构，ASFV 是该家族的唯一成员。与真核生物和古菌 PCNA 以及来自其他病毒的滑动夹结构同源物相比，PCNA 在几个区域具有独特的序列和/或构象，例如 J 环、结构域间连接环（IDCL）、P 环和 C 尾，这些区域参与伴侣识别或滑动夹的修饰。除了双链 DNA 结合，我们还证明 PCNA 可以适度增强 LIG 蛋白的连接活性。PCNA 的独特结构特征可以作为开发 ASFV 特异性抑制剂的潜在靶标，并有助于对抗致命病毒。
本文呈现了两个高分辨率的非洲猪瘟病毒增殖细胞核抗原（PCNA）晶体结构。结构比较表明，PCNA 在几个区域是独特的，例如 J 环、结构域间连接环接头和 P 环，这可能在 ASFV 特异性 PCNA 伴侣选择中发挥重要作用。与真核生物和古菌 PCNA 不同，PCNA 具有高双链 DNA 结合亲和力。除了 DNA 结合，PCNA 还可以适度增强 LIG 蛋白的连接活性，这对于 ASFV 基因组的复制和修复至关重要。独特的结构特征使 PCNA 成为药物开发的潜在靶点，这将有助于对抗致命病毒。
