A Crystal Structure of the Dengue Virus NS5 Protein Reveals a Novel Inter-domain Interface Essential for Protein Flexibility and Virus Replication
Fig 6
A schematic model for the divergent evolution of flaviviral NS5 proteins.
The same color scheme as in Fig. 1 is used: MTase is in yellow, RdRp fingers in green, palm in blue, thumb in salmon. The linker region 310 helix (residues 263–266) between the two domains is in orange. Active sites for MTase and RdRp are labelled with dotted tetragon and pentagon respectively. Linker residues and interface residues are labeled. A possible evolutionary pathway is presented: the MTase domain and RdRp domain originally existing as two separate proteins (left) became linked together to form the NS5 protein from an ancestral Flavivirus, possibly through gene fusion. This fusion promoted colocalization of both enzymatic activities and effectively increased the effective concentration of the proteins with respect to each other (middle panel). Following further (divergent) evolution, NS5 acquired different adaptive mutations and gave rise to the NS5 proteins now observed for various viruses, including DENV, JEV and possibly other flaviviruses) (right panel). Thus NS5 proteins from DENV and JEV may have different conformations and different allosteric mechanisms, in which the MTase and RdRp domain cross-talk to each other through unique interfaces specific to either DENV or JEV [72].