Structures and implications of the nuclease domain of human parvovirus B19 NS1 protein

Yixi Zhang; Zhiwei Shao; Yanqing Gao; Boming Fan; Jie Yang; Xi Chen; Xin Zhao; Qiyuan Shao; Weizhen Zhang; Chulei Cao; Hehua Liu; Jianhua Gan

doi:10.1016/j.csbj.2022.08.047

Structures and implications of the nuclease domain of human parvovirus B19 NS1 protein

Comput Struct Biotechnol J. 2022 Aug 27:20:4645-4655. doi: 10.1016/j.csbj.2022.08.047. eCollection 2022.

Authors

Yixi Zhang¹, Zhiwei Shao¹, Yanqing Gao¹, Boming Fan¹, Jie Yang¹, Xi Chen¹, Xin Zhao¹, Qiyuan Shao¹, Weizhen Zhang¹, Chulei Cao¹, Hehua Liu¹, Jianhua Gan¹

Affiliation

¹ Shanghai Public Health Clinical Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Department of Biochemistry and Biophysics, School of Life Sciences, Fudan University, Shanghai 200438, China.

Abstract

Infection of human parvovirus B19 (B19V) can cause a variety of diseases, such as hydrops fetalis, erythema infectiosum in children and acute arthropathy in women. Although B19V infection mainly occurs during childhood, about 50 % of adults are still susceptible to B19V infection. As the major replication protein of B19V, deletion of NS1 completely abolishes the infectivity of the virus. The nuclease domain of NS1 (NS1_Nuc) is responsible for DNA Ori binding and nicking that is critical for B19V viral DNA replication. NS1 has various variants, the structure and function for the majority of the variants are poorly studied. Here, we report two high-resolution crystal structures of NS1_Nuc, revealed the detailed conformations of many key residues. Structural comparison indicates that these residues are important for ssDNA or dsDNA binding by NS1. NS1 belongs to the HUH-endonuclease superfamily and it shares conserved ssDNA cleavage mechanism with other HUH-endonuclease members. However, our structural analyses, mutagenesis and in vitro assay results all suggested that NS1_Nuc utilizes one unique model in ssDNA binding.

Keywords: AAV5, Adeno-associated virus type 5; B19V; B19V, Human parvovirus B19; Crystal structure; DNA binding; DNA cleavage; Human parvovirus B19; ITR, identical terminal repeat; NS1 nuclease domain; NS1_Nuc, Nuclease domain of NS1; NSBE, NS1-binding element; PCV2, Porcine circovirus 2; TRS, terminal resolution site; WDV, Wheat dwarf virus; dsDNA, double -stranded DNA; ssDNA, single -stranded DNA.