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WIREs RNA
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RNA synthetic mechanisms employed by diverse families of RNA viruses

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Abstract RNA viruses are ubiquitous in nature, infecting every known organism on the planet. These viruses can also be notorious human pathogens with significant medical and economic burdens. Central to the lifecycle of an RNA virus is the synthesis of new RNA molecules, a process that is mediated by specialized virally encoded enzymes called RNA‐dependent RNA polymerases (RdRps). RdRps directly catalyze phosphodiester bond formation between nucleoside triphosphates in an RNA‐templated manner. These enzymes are strikingly conserved in their structural and functional features, even among diverse RNA viruses belonging to different families. During host cell infection, the activities of viral RdRps are often regulated by viral cofactor proteins. Cofactors can modulate the type and timing of RNA synthesis by directly engaging the RdRp and/or by indirectly affecting its capacity to recognize template RNA. High‐resolution structures of RdRps as apoenzymes, bound to RNA templates, in the midst of catalysis, and/or interacting with regulatory cofactor proteins, have dramatically increased our understanding of viral RNA synthetic mechanisms. Combined with elegant biochemical studies, such structures are providing a scientific platform for the rational design of antiviral agents aimed at preventing and treating RNA virus‐induced diseases. WIREs RNA 2013, 4:351–367. doi: 10.1002/wrna.1164 This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes RNA in Disease and Development > RNA in Disease

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Overview of transcription and replication strategies for various types of RNA viruses. (a) Positive‐strand RNA [(+)RNA] viruses. The genomes of (+)RNA viruses are message‐sense (green), and they often contain a 5′ m7G cap (purple circle) and 3′ poly‐A tail (AAAAA). Host cell ribosomes translate the genome into one or more polyproteins, which are cotranslationally and posttranslationally processed by virally encoded proteases. Some of the mature polyprotein processing precursors and products include the RNA‐dependent RNA polymerase (RdRp; blue rectangle) and cofactors (blue squares) that mediate viral RNA synthesis in association with cellular membranes. Other proteins made by the virus include those that will assemble into viral particles (gray squares). The RdRp mediates the synthesis of negative‐strand RNA [(−)RNA] antigenome (red) using the genome as template. The antigenome is then converted into new (+)RNA genome by the RdRp and then packaged into nascent virion particles (gray hexagon). (b) Negative‐strand RNA [(−)RNA] viruses. The genomes of (−)RNA viruses are organized as ribonucleoproteins (RNPs) with their RNA molecules (red) bound by the viral polymerase complex (blue rectangle) and nucleocapsid proteins (N; grey square). Transcription is mediated by the RdRp and cofactor proteins, resulting in the synthesis of 5′ capped (purple circle), 3′ polyadenylated (AAAAA) mRNAs (green). The mRNAs are translated by host ribosomes into polymerase complex proteins (blue) and virion structural components (gray). Genome replication occurs when the RdRp produces a full‐length, antigenome (+)RNA (green) bound by N. This antigenome is then converted into (−)RNA genome (red) and is packaged as a RNP complex into nascent virion particles (gray hexagon). (c) Double‐stranded (ds) RNA viruses. The genomes of dsRNA viruses are maintained inside of particles. The RdRp (blue rectangle) will transcribe (+)RNAs (green) that contain a 5′ cap (purple circle) and serve as protein synthesis templates (mRNAs) or will be packaged into assembling subviral particles (gray hexagon). Once inside the particle, the RdRp will perform (−)RNA synthesis (red) on the (+)RNS template (green) to create the dsRNA genome.

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Rotavirus core‐shell‐RNA‐dependent RNA polymerase (RdRp) interactions. (a) The rotavirus VP2 core shell (PDB#3KZ4) is shown alone, with each of the 120 VP2 monomers depicted in surface representation. Five A‐VP2 and five B‐VP2 monomers of a central decamer are colored dark blue and light blue, respectively. The location of the fivefold axis is depicted with a star. (b) VP1 bound to inner surface of VP2. Two neighboring VP2 monomers (A‐VP2 and B‐VP2) of a decamer unit (side view; PDB#4F5X) are shown in ribbon representation and colored according to panel a. VP1 (light blue) bound to the inner surface of VP2 is also shown in ribbon representation. The structurally resolved portion of the VP2 N‐terminal domain (residues 78–101), which is thought to engage VP1 and aid in enzymatic activation, is shown in gold. No structure yet exists for VP2 N‐terminal residues 1–77, but they, as well as regions of the VP2 principal domain, are also important for VP1 activation.

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Influenza A virus RNA‐dependent RNA polymerase (RdRp)–cofactor interfaces. (a) Each of the (−)RNA genome segments of influenza A virus is bound by nucleocapsid protein (not shown, for simplicity) and organized as a corkscrew‐like ribonucleoprotein (RNP). The viral polymerase complex resides at the RNP terminus (made by 5′–3′ base‐pair interactions) and is comprised of three proteins, shown as light blue circles: PA (endonuclease), PB1 (RdRp), and PB2 (cap‐binding). The interfaces between PA–PB1 and PB1–PB2 for which structure is known are shown in gold. (b) Structure of PB–cofactor interfaces. Left: Ribbon representations of the C‐terminal domain of PA (blue) with a small portion of the PB1 N‐terminus (gold) (PDB#3CM8). Right: Ribbon representation of very small regions of the PB2 N‐terminus (light blue) in complex with the PB1 C‐terminus (gold) (PDB#3A1G).

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Rhabdoviridae RNA‐dependent RNA polymerase (RdRp)–phosphoprotein interactions. (a) The (−)RNA genome of Rhabdoviridae members is bound by nucleocapsid protein (N) and organized as an ribonucleoprotein (RNP). The viral polymerase complex is comprised of a phosphoprotein (P) dimer and the large protein (L). P is able to bind to L and N‐RNA simultaneously via distinct N‐ and C‐terminal domains. It is thought that engagement of L by P is required for template recognition by the RdRp. (b) Structure of rabies virus P. The top of this panel shows a cartoon schematic of a P dimer with protein– protein interaction regions labeled. Ribbon representations of the central dimerization domains (PDB# 3L32) and C‐terminal domains of a P protein dimer (PDB#1VYI) are shown. The structure of the N‐terminal domain of P is not known, nor is the structure of connecting regions between the three ordered domains. (c) Electron micrographs of L and L‐P. The images show recombinant L protein of vesicular stomatitis virus in the presence or absence of phosphoprotein. Dramatic rearrangements are seen in L following P binding, particularly in the regions of the protein associated with RNA capping. (Reprinted with permission from Ref . Copyright 2012 National Academy of Science, USA)

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Proteolytic activation of the poliovirus RNA‐dependent RNA polymerase (RdRp). (a) The poliovirus genome is message‐sense (green), and they often contain a 5′ VPg (blue circle) and 3′ poly‐A tail (AAAAA). Host cell ribosomes translate the genome into three polyproteins (P1, P2, and P3), which are cotranslationally and posttranslationally processed by virally encoded proteases (2A, 3C, and 3CD). The polymerase activity of 3D is triggered following cleavage of 3CD. (b) Structure of 3CD. Ribbon representation of poliovirus 3CD (PDB#1VYI) is shown. The flexible linker between the two domains is shown in gold. Upon cleavage, this gold region becomes the N‐terminus of 3D and becomes buried inside the RdRp where it helps position the catalytic aspartates.

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Initiation mechanisms utilized by diverse viral RNA‐dependent RNA polymerases (RdRps). Ribbon representations of the catalytic centers of RdRps with different mechanisms of initiation. In all images, the fingers, palm, and thumb subdomains are colored light blue, red, and light green, respectively. (a) De novo initiation by the bovine diarrheal virus RdRp (PDB#1S49) as a model for the Flaviviridae family. In this image, the special GTP that stabilizes the initiating nucleotide is shown as element sticks and the C‐terminal loop is shown in gold and labeled. (b) De novo initiation by the reovirus RdRp (PDB#1N1H) as a model for the Reoviridae family. In this image, the RNA template and nucleoside triphosphates (NTPs) are shown as element sticks and the priming loop is shown in gold. Two divalent cations are shown as lavender spheres. (c) VPg‐primed initiation by the foot‐and‐mouth disease virus RdRp (PDB#2F8E) as a model for Picornaviridae and Caliciviridae. In this image, VPg‐UMP is shown in gold and a cation is shown in green.

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Unique structural features of the Reoviridae RNA‐dependent RNA polymerases (RdRps). Left: Ribbon representation of the entire rotavirus RdRp (PDB#2R7Q). The central polymerase domain of the enzyme contains fingers (light blue), palm (red), and thumb (light green) subdomains. This canonical region is surrounded by a C‐terminal bracelet‐like domain (pink) and an N‐terminal domain (yellow). Right: Surface representation of the rotavirus RdRp turned 90° to the left compared to the ribbon representation. This image is also computationally sliced, so as to view the four tunnels involved in RNA template entry, RNA template and product exit, and nucleoside triphosphate (NTP) entry.

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Structural motifs of the RNA‐dependent RNA polymerase (RdRp) catalytic center. Ribbon representations of the poliovirus (PDB#1RA6) and rotavirus (PDB#2R7Q) RdRp are shown. Motifs are labeled and colored as follows: motif A (red), motif B (green), motif C (gold), motif D (purple), motif E (cyan), and motif F (blue).

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Conserved three‐dimensional architecture of RNA‐dependent RNA polymerases (RdRps) from disparate RNA viruses. Ribbon representations of the poliovirus RdRp (PDB#1RA6), the Norwalk virus RdRp (PDB#1SH0), the hepatitis C virus RdRp (PDB#1C2P), and the central domain of the rotavirus RdRP (PDB#2R7Q). The fingers, palm, and thumb subdomains are shown in light blue, red, and light green, respectively.

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