A Dimerization-Dependent Mechanism Drives the Endoribonuclease Function of Porcine Reproductive and Respiratory Syndrome Virus nsp11.
Bottom Line: The PRRSV nsp11 endoribonuclease plays a vital role in arterivirus replication, but its precise roles and mechanisms of action are poorly understood.Structural and biochemical experiments demonstrated that nsp11 exists mainly as a dimer in solution and that nsp11 may be fully active as a dimer.Mutagenesis and structural analysis revealed NendoU active site residues, which are conserved throughout the order Nidovirales(families Arteriviridae and Coronaviridae) and the major determinants of dimerization (Ser74 and Phe76) in Arteriviridae Importantly, these findings may provide a new structural basis for antiviral drug development.
Affiliation: State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.Show MeSH
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Mentions: Our crystal structure indicates that nsp11 assembles into dimers, which is different from coronavirus nsp15 (19, 21). The monomer structure of SARS-CoV nsp15 includes three domains, the N-terminal domain (NTD), the middle domain, and the catalytic domain (23) (Fig. 3C); the NTD is critical for hexamerization and interactions with the middle domain and the catalytic domain of an adjacent monomer (19, 23). However, the NTD structure (approximately 61 N-terminal residues) of coronavirus nsp15 is missing in nsp11, and the NTD of nsp11 superimposes onto the middle domain of coronavirus nsp15 (Fig. 4). Moreover, the major determinants of dimerization (Ser74 and Phe76) are significantly different from the key residues involved in the oligomerization of SARS-CoV nsp15 (Fig. 4; Fig. 5), which indicates why the active form of nsp11 is a dimer rather than a hexamer.
Affiliation: State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.