Structural analysis of viral ExoN domains reveals polyphyletic hijacking events

Abstract

Nidoviruses and arenaviruses are the only known RNA viruses encoding a 3’-5’ exonuclease domain (ExoN). The proofreading activity of the ExoN domain has played a key role in the growth of nidoviral genomes, while in arenaviruses this domain partakes in the suppression of the host innate immune signaling. Sequence and structural homology analyses suggest that these proteins have been hijacked from cellular hosts many times. Analysis of the available nidoviral ExoN sequences reveals a high conservation level comparable to that of the viral RNA-dependent RNA polymerases (RdRp), which are the most conserved viral proteins. Two highly preserved zinc fingers are present in all nidoviral exonucleases, while in the arenaviral protein only one zinc finger can be identified. This is in sharp contrast with the reported lack of zinc fingers in cellular ExoNs, and opens the possibility of therapeutic strategies in the struggle against COVID-19.

The Antiviral Effect of the Chemical Compounds Targeting DED/EDh Motifs of the Viral Proteins on Lymphocytic Choriomeningitis Virus and SARS-CoV-2

“…In conclusion, this study proved that the DED/EDh motif of two different virus families, arenavirus and coronavirus, could be a drug target. Although ExoNs are also expressed in the host, targeting slight differences in these ExoNs between the host and viral ExoNs, such as the existence of the zinc finger motif, could lead to develop a specific drug [ 31 ]. In addition, treating these viral infections with dual and/or triple drugs could increase the antiviral effect and reduce the possible appearance of drug-resistant viruses.…”

Structural Analysis of Monomeric RNA-Dependent Polymerases Revisited

“…However, the works summarized here show that the right-hand polymerases’ substrate- and product specificities are far from absolute, and that minor changes allow them to use both RNA and DNA. Hence, it is likely that the earliest forms of the monomeric right-hand polymerases lacked absolute specificity, as has been suggested for other possible paramount ancient nucleic acid-associated enzymes such as the exonucleases (Zuckerkandl and Villet 1988 ; Dworkin et al 2003 ; Cruz-González et al 2021 ).…”

“…The comparison of tertiary structures has proven quite successful for studying the evolutionary history of RNA viruses, whose extremely high mutation rates have erased the footprints within their primary structure. Analyses of tertiary structures have shown the wide array of evolutionary strategies exploited by RNA viruses such as gene duplications (Cisneros-Martínez et al 2021 ) and hijacking events (Mönttinen et al 2019 ; Cruz-González et al 2021 ), underpinning the mosaic-nature of these biological entities’ genomes. The development and the advances of cryo-EM have been critical in the obtention of a more diverse spectrum of viral tertiary structures, and it is expected that this diversity will continue to increase, which might allow to answer some of the current evolutionary unknowns.…”

Adaptive convergent evolution of genome proofreading in SARS-CoV2: insights into the Eigen’s paradox

“…ExoN belongs to DEDDh family of exonucleases present across all kingdoms of life including DNA viruses, and constitute enzymes involved in DNA proof-reading as well as RNA metabolism (Zuo and Deutscher 2001;Cruz-González et al 2021). Multiple sequence alignment of ExoN with diverse homologs suggested conservation of core catalytic motif involved in exonuclease activity (Robson et al 2020).…”