Do NSm Virulence Factors in the Viral Order Originate from Gn Gene Duplication?

One-third of the nine WHO shortlisted pathogens prioritized for research and development in public health emergencies belong to the order. Several species carry an NSm protein that acts as a virulence factor. We predicted the structures of these NSm proteins and unexpectedly found that in two families, their cytosolic domain was inferred to have a similar fold to that of the cytosolic domain of the viral envelope-forming glycoprotein N (Gn) encoded on the same genome fragment. We show that although the sequence identity between the NSm and the Gn domains is low, the conservation of the two zinc finger-forming CysCysHisCys motifs explains the predicted structural conservation. Importantly, our predictions provide a first glimpse into the long-unknown structure of NSm. Also, these predictions suggest that NSm is the result of a gene duplication event in the and families and that such events may be common in the recent evolutionary history of RNA viruses.