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Review
. 2017 Nov;8(6):10.1002/wrna.1437.
doi: 10.1002/wrna.1437. Epub 2017 Aug 16.

Organization of the Flavivirus RNA replicase complex

Carolin Brand  1 , Martin Bisaillon  1 , Brian J Geiss  2   3
Affiliations
Review

Organization of the Flavivirus RNA replicase complex

Carolin Brand et al. Wiley Interdiscip Rev RNA. 2017 Nov.

Abstract

Flaviviruses, such as dengue, Japanese encephalitis, West Nile, yellow fever, and Zika viruses, are serious human pathogens that cause significant morbidity and mortality globally each year. Flaviviruses are single-stranded, positive-sense RNA viruses, and encode two multidomain proteins, NS3 and NS5, that possess all enzymatic activities required for genome replication and capping. NS3 and NS5 interact within virus-induced replication compartments to form the RNA genome replicase complex. Although the individual enzymatic activities of both proteins have been extensively studied and are well characterized, there are still gaps in our understanding of how they interact to efficiently coordinate their respective activities during positive-strand RNA synthesis and capping. Here, we discuss what is known about the structures and functions of the NS3 and NS5 proteins and propose a preliminary NS3:NS5:RNA interaction model based on a large body of literature about how the viral enzymes function, physical restraints between NS3 and NS5, as well as critical steps in the replication process. WIREs RNA 2017, 8:e1437. doi: 10.1002/wrna.1437 For further resources related to this article, please visit the WIREs website.

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Figures

Figure 1
Figure 1. Structure of the NS3 helicase domain
The crystal structure of the DENV NS3 helicase domain bound to ssRNA (pdb 2jlu) is shown. Subdomains 1, 2 and 3 are colored in red, purple and orange, respectively, and RNA is colored in blue. The 5’ end of the (−) ssRNA is close to the helical gate where dsRNA is separated into individual strands and the negative strand enters the RNA binding tunnel. The 3’ end of the (−) ssRNA is in proximity to the RNA exit site, from where it will be fed into the NS5 RdRp for replication.
Figure 2
Figure 2. Structure of the NS5 capping enzyme domain
The crystal structure of the YFV NS5 capping enzyme domain bound to GTP and SAH (pdb 3evd) is shown. The capping enzyme domain is colored in light blue, the catalytic tetrad in violet, and GTP and SAH are colored by element. The RNA entry site and substrate binding pockets are indicated.
Figure 3
Figure 3. Structure of the NS5 RNA-dependent RNA polymerase domain
(A) The crystal structure of the JEV NS5 RdRp (pdb 4k6m) is shown. The fingers, palm and thumb subdomains are colored in blue, yellow and green, respectively. In the cartoon representation, the priming loop is colored in purple and the two catalytic aspartic acid residues are shown as magenta colored sticks. In the surface representations, the RNA template tunnel and the NTP entry channel / dsRNA exit channel are indicated. (B) The structure of the poliovirus RdRp elongation complex after multiple nucleotide addition cycles is shown (pdb 3ola). (C) The negative strand from the poliovirus RdRp structure was modelled into the JEV RdRp structure. As expected, the 5’ end of the (−) ssRNA is close to the entry of the RNA template tunnel and the 3’ end is exiting the active site through the dsRNA exit channel.
Figure 4
Figure 4. Model of the replicase complex formed by NS3, NS5 and viral RNA during positive strand synthesis
(A) Front view. (B) Top view. The incoming dsRNA replication intermediate is denatured by the NS3 helicase. The 5’ end of the positive strand is guided into the NS5 capping enzyme domain active site for the synthesis of the 5’ cap structure. The 3’ end of the negative strand flows through the NS3 RNA binding tunnel and then into the NS5 RdRp active site to serve as template for the synthesis of a new positive strand.
Figure 4
Figure 4. Model of the replicase complex formed by NS3, NS5 and viral RNA during positive strand synthesis
(A) Front view. (B) Top view. The incoming dsRNA replication intermediate is denatured by the NS3 helicase. The 5’ end of the positive strand is guided into the NS5 capping enzyme domain active site for the synthesis of the 5’ cap structure. The 3’ end of the negative strand flows through the NS3 RNA binding tunnel and then into the NS5 RdRp active site to serve as template for the synthesis of a new positive strand.
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