Structural basis for the regulatory function of a complex zinc-binding domain in a replicative arterivirus helicase resembling a nonsense-mediated mRNA decay helicase

Deng, Zengqin; Lehmann, Kathleen C.; Li, Xiaorong; Feng, Chong; Wang, Guoqiang; Zhang, Qi; Qi, Xiaoxuan; Yu, Lin; Zhang, Xingliang; Feng, Wenhai; Wu, Wei; Gong, Peng; Tao, Ye; Posthuma, Clara C.; Snijder, Eric J.; Gorbalenya, Alexander E.; Chen, Zhongzhou

If the nidovirus helicase possesses some of the properties of Upf1, this could explain the exclusive conservation of ZBD in nidoviruses, which stand out for their large to very large single-stranded RNA genomes. For instance, by providing post-transcriptional quality control of genomic RNA, i.e. detection of nonsense and/ or other mutations and elimination of defective molecules, the nidovirus helicase could alleviate the consequences of the generally low fidelity of RNA virus genome replication. Such a role of ZBD-HEL1 may have protected an ancestral nidovirus from the mutational meltdown of its expanding genome, similar to the proposed fixation of the proofreading ExoN domain at a later stage of nidovirus evolution (19, 24, 25, 28) . Subsequently, the enzyme would have facilitated expansion to the genome size observed in contemporary arteriviruses, and remained a critical factor in the further ExoN-driven genome expansion to evolve middle-and large-sized nidoviruses. Thus, the proposed Upf1-like role of the nidovirus helicase can be accommodated in a meaningful evolutionary scenario incorporating several of the structural and functional observations made in this study. The structural similarity between nsp10 and Upf1 establishes a new connection between research on viral and cellular helicases, which could be mutually insightful for understanding the evolution and function of this group of vitally important enzymes.