A Structure-Function Diversity Survey of the RNA-Dependent RNA Polymerases From the Positive-Strand RNA Viruses

Jia, Hengxia; Gong, Peng

Three-dimensional RdRPs structures have been reported for about 20 positive-strand RNA virus species (Hansen et al., 1997; Lesburg et al., 1999; Ng et al., 2002 Ng et al., , 2004 Choi et al., 2004; Ferrer-Orta et al., 2004; Love et al., 2004; Fullerton et al., 2007; Malet et al., 2007; Yap et al., 2007; Campagnola et al., 2008; Takeshita and Tomita, 2010; Wu et al., 2010; Lu and Gong, 2013; Vives-Adrian et al., 2014; Ferrero et al., 2015; Bi et al., 2017; Upadhyay et al., 2017; Wang et al., 2017; Liu et al., 2018) . However, these species only cover five virus families (Picornaviridae, Caliciviridae, Flaviviridae, Leviviridae, and Permutotetraviridae) (Figures 1, 3) . Among structure-available RdRPs in each virus family, only the RdRPs from the Flaviviridae exhibit apparent global structure diversity and have three distinct structural forms. Therefore, a total of seven RdRP structures, including three from the Flaviviridae, were chosen as representatives for a schematic illustration of RdRP global structure diversity in positive-strand RNA viruses (Figure 3) . Among these seven structures, five of them do not contain functional regions beyond the polymerase catalytic module (Lesburg et al., 1999; Ng et al., 2002; Thompson and Peersen, 2004; Takeshita and Tomita, 2010; Ferrero et al., 2015) , although the full-length Thosea asigna virus (TaV) RdRP does contain a large C-terminal region (discussed below). While the structural details are quite different, all these structures are composed of the palm, fingers, and thumb domains and share similar global architecture. The flavivirus NS5 and the pestivirus NS5B, both from the Flaviviridae family, are the only RdRP structures contain additional functional regions (Lu and Gong, 2013; Liu et al., 2018) . The N-terminal ∼260 residues of the flavivirus NS5 is a methyltransferase (MTase) that participates in the 5 -capping process of the virus RNA genome (Egloff et al., 2002; Koonin, 1993) . Based on full-length NS5 crystal structures solved in Japanese encephalitis virus (JEV), dengue virus (DENV), and Zika virus (ZIKV), the MTase adopts the Rossmann fold and interacts with the RdRP fingers domain intra-molecularly in two different modes, one represented by the JEV and ZIKV structures and the other represented by the DENV structures (Lu and Gong, 2013; Upadhyay et al., 2017; Zhao et al., 2015) . The N-terminal ∼90 residues of the pestivirus NS5B folds into a small α/β globular domain (namely NTD). The NTD forms intra-molecular interactions with the RdRP palm domain (Li et al., 2018; Liu et al., 2018) . Collectively, only a couple of representative RdRP structural forms contain functional regions beyond the RdRP catalytic module. However, the following primary structure analysis suggest that numerous representative RdRPs may have functional regions fused to the catalytic module, in particular to the N-terminus.