Summary: Flavivirus RNA-directed RNA polymerase
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RNA-dependent RNA polymerase Edit Wikipedia article
|RNA-directed RNA polymerase, flaviviral|
RNA-dependent RNA polymerase (RdRP), (RDR), or RNA replicase, is an enzyme (EC 220.127.116.11) that catalyzes the replication of RNA from an RNA template. This is in contrast to a typical DNA-dependent RNA polymerase, which catalyzes the transcription of RNA from a DNA template.
RNA-dependent RNA polymerase (RdRp) is an essential protein encoded in the genomes of all RNA-containing viruses with no DNA stage that have sense negative RNA. It catalyses synthesis of the RNA strand complementary to a given RNA template. The RNA replication process is a two-step mechanism. First, the initiation step of RNA synthesis begins at or near the 3' end of the RNA template by means of a primer-independent (de novo), or a primer-dependent mechanism that utilizes a viral protein genome-linked (VPg) primer. The de novo initiation consists in the addition of a nucleotide tri-phosphate (NTP) to the 3'-OH of the first initiating NTP. During the following so-called elongation phase, this nucleotidyl transfer reaction is repeated with subsequent NTPs to generate the complementary RNA product.
A VPg primer mechanism is utilized by the picornavirus (entero- aphtho- and others), additional virus groups (poty-, como-, calici- and others)and picornavirus-like (coronavirus, notavirus, etc.)supergroup of RNA viruses. The mechanism has been best studied for the enteroviruses (which include many human pathogens, such as poliovirus and coxsackie viruses) and the aphthovirus,animal pathogen, Foot and mouth disease (FMDV). In this group, Primer-dependent RNA synthesis utilizes a small 22-25 amino acid long viral protein linked to the genome (VPg) to initiate polymerase activity, where the primer is covalently bound to the 5â end of the RNA template. The uridylylation occurs at a tyrosine residue at the third position of the VPg. A cis-acting replication element (CRE), which is a RNA stem loop structure, serves as a template for the uridylylation of VPg, resulting in the synthesis of VPgpUpUOH. Mutations within the CRE-RNA structure prevent VPg uridylylation, and mutations within the VPg sequence can severely diminish RdRp catalytic activity. While the tyrosine hydroxyl of VPg can prime negative-strand RNA synthesis in a CRE- and VPgpUpUOH-independent manner, CRE-dependent VPgpUpUOH synthesis is absolutely required for positive-strand RNA synthesis. CRE-dependent VPg uridylylation lowers the KmÂ¬ of UTP required for viral RNA replication and CRE-dependent VPgpUpUOH synthesis, and is required for efficient negative-strand RNA synthesis, especially when UTP concentrations are limiting. The VPgpUpUOH primer is transferred to the 3â end of the RNA template for elongation, which can continue by addition of nucleotide bases by RdRp.Partial crystal structures for VPgs of Foot and Mouth Disease Virus  and Coxsackie virus B3  suggest that there may be two sites on the viral polymerase for the small VPgs of the picornaviruses. NMR solution structures of poliovirus VPg  and VPgpU  show that uridylylation stabilizes the structure of the VPg, which is otherwise quite flexible in solution. The second site may be used for uridylylation, after which the VPgpU can initiate RNA synthesis. It should be noted that the VPg primers of caliciviruses, whose structures are only beginning to be revealed, are much larger than those of the picornaviruses. Mechanisms for uridylylation and priming may be quite different in all of these groups.
VPg uridylylation may include the use of precursor proteins, allowing for the determination of a possible mechanism for the location of the diuridylylated, VPg-containing precursor at the 3â end of plus- or minus-strand RNA for production of full-length RNA. Determinants of VPg uridylylation efficiency suggest formation and/or collapse or release of the uridylylated product as the rate-limiting step in vitro depending upon the VPg donor employed. Precursor proteins also have an effect on VPg-CRE specificity and stability. The upper RNA stem loop, to which VPg binds, has a significant impact on both retention, and recruitment, of VPg and Pol. The stem loop of CRE will partially unwind, allowing the precursor components to bind and recruit VPg and Pol4. The CRE loop has a defined consensus sequence to which the initiation components bind, however; there is no consensus sequence for the supporting stem, which suggests that only the structural stability of the CRE is important.
Assembly and organization of the picornavirus VPg ribonucleoprotein complex. Step 1: Two 3CD (VPg complex) molecules bind to CRE with the 3C domains (VPg domain) contacting the upper stem and the 3D domains (VPg domain) contacting the lower stem. Step 2: The 3C dimer opens the RNA stem by forming a more stable interaction with single strands forming the stem. Step 3: 3Dpol is recruited to and retained in this complex by a physical interaction between the back of the thumb subdomain of 3Dpol and a surface of one or both 3C subdomains of 3CD.
VPg may also play an important role in specific recognition of viral genome by movement protein (MP). Movement proteins are non-structural proteins encoded by many, if not all, plant viruses to enable their movement from one infected cell to neighboring cells. MP and VPg interact to provide specificity for the transport of viral RNA from cell to cell. To fulfill energy requirements, MP also interacts with P10, which is a cellular ATPase.
Viral RdRPs were discovered in the early 1960s from studies on mengovirus and polio virus when it was observed that these viruses were not sensitive to actinomycin D, a drug that inhibits cellular DNA-directed RNA synthesis. This lack of sensitivity suggested that there is a virus-specific enzyme that could copy RNA from an RNA template and not from a DNA template.
The most famous example of RdRP is that of the polio virus. The viral genome is composed of RNA, which enters the cell through receptor-mediated endocytosis. From there, the RNA is able to act as a template for complementary RNA synthesis, immediately. The complementary strand is then, itself, able to act as a template for the production of new viral genomes that are further packaged and released from the cell ready to infect more host cells. The advantage of this method of replication is that there is no DNA stage; replication is quick and easy. The disadvantage is that there is no 'back-up' DNA copy.
Many RdRPs are associated tightly with membranes and are, therefore, difficult to study. The best-known RdRPs are polioviral 3Dpol, vesicular stomatitis virus L, and hepatitis C virus NS5b protein.
Many eukaryotes also have RdRPs involved in an amplification of RNA interference. By binding of the RISC-complex to its mRNA target, RdRP is recruited. It then transcribes secondary- siRNAs which in turn are bound by class 3 Argonauts (SAGO) to repress target RNA. In fact these same RdRPs that are used in the defense mechanisms can be usurped by RNA viruses for their benefit.
Deep sequencing of seawater has shown that RdRps are highly conserved throughout viruses and is even related to telomerase, though the reason for such high conservation in such diverse organisms is an ongoing question as of 2009. The similarity has led to speculation that viral RdRps are ancestral to human telomerase.
 3D structure
All the RNA-directed RNA polymerases, and many DNA-directed polymerases, employ a fold whose organization has been likened to the shape of a right hand with three subdomains termed fingers, palm, and thumb. Only the palm subdomain, composed of a four-stranded antiparallel beta-sheet with two alpha-helices, is well conserved among all of these enzymes. In RdRp, the palm subdomain comprises three well-conserved motifs (A, B, and C). Motif A (D-x(4,5)-D) and motif C (GDD) are spatially juxtaposed; the Asp residues of these motifs are implied in the binding of Mg2+ and/or Mn2+. The Asn residue of motif B is involved in selection of ribonucleoside triphosphates over dNTPs and, thus, determines whether RNA rather than DNA is synthesized. The domain organization and the 3D structure of the catalytic centre of a wide range of RdPps, even those with a low overall sequence homology, are conserved. The catalytic centre is formed by several motifs containing a number of conserved amino acid residues.
There are 4 superfamilies of viruses that cover all RNA-containing viruses with no DNA stage:
- Viruses containing positive-strand RNA or double-strand RNA, except retroviruses and Birnaviridae: viral RNA-directed RNA polymerases including all positive-strand RNA viruses with no DNA stage, double-strand RNA viruses, and the Cystoviridae, Reoviridae, Hypoviridae, Partitiviridae, Totiviridae families
- Mononegavirales (negative-strand RNA viruses with non-segmented genomes)
- Negative-strand RNA viruses with segmented genomes, i.e., Orthomyxoviruses (including influenza A, B, and C viruses, Thogotoviruses, and the infectious salmon anemia virus), Arenaviruses, Bunyaviruses, Hantaviruses, Nairoviruses, Phleboviruses, Tenuiviruses and Tospoviruses
- Birnaviridae family of dsRNA viruses.
The RNA-directed RNA polymerases in the first of the above superfamilies can be divided into the following three subgroups:
- All positive-strand RNA eukaryotic viruses with no DNA stage
- All RNA-containing bacteriophages -there are two families of RNA-containing bacteriophages: Leviviridae (positive ssRNA phages) and Cystoviridae (dsRNA phages)
- Reoviridae family of dsRNA viruses.
Flaviviruses produce a polyprotein from the ssRNA genome. The polyprotein is cleaved to a number of products, one of which is NS5. Recombinant dengue type 1 virus NS5 protein expressed in Escherichia coli exhibits RNA-dependent RNA polymerase activity. This RNA-directed RNA polymerase possesses a number of short regions and motifs homologous to other RNA-directed RNA polymerases.
 See also
- Koonin EV, Gorbalenya AE, Chumakov KM (July 1989). "Tentative identification of RNA-dependent RNA polymerases of dsRNA viruses and their relationship to positive strand RNA viral polymerases". FEBS Lett. 252 (1â2): 42â6. doi:10.1016/0014-5793(89)80886-5. PMID 2759231.
- Zanotto PM, Gibbs MJ, Gould EA, Holmes EC (September 1996). "A reevaluation of the higher taxonomy of viruses based on RNA polymerases". J. Virol. 70 (9): 6083â96. PMC 190630. PMID 8709232.
- Kao CC, Singh P, Ecker DJ (September 2001). "De novo initiation of viral RNA-dependent RNA synthesis". Virology 287 (2): 251â60. doi:10.1006/viro.2001.1039. PMID 11531403.
- Flanegan JB, Baltimore D. Poliovirus-specific primer-dependent RNA polymerase able to copy poly(A). Proc Natl Acad Sci USA. 1977;74(9):3677-80
- Ambros V, Baltimore D. Protein is linked to the 5' end of poliovirus RNA by a phosphodiester linkage to tyrosine. J Biol Chem. 1978;253(15):5263-6
- Gu C, Zeng T, Li Y, Xu Z, Mo Z, Zheng C (October 2009). "Structure-function analysis of mutant RNA-dependent RNA polymerase complexes with VPg". Biochemistry Mosc. 74 (10): 1132â41. doi:10.1134/S0006297909100095. PMID 19916926.
- Steil BP, Barton DJ (October 2008). "Poliovirus cis-Acting Replication Element-Dependent VPg Uridylylation Lowers the Km of the Initiating Nucleoside Triphosphate for Viral RNA Replication". J. Virol. 82 (19): 9400â8. doi:10.1128/JVI.00427-08. PMC 2546976. PMID 18653453.
- Ferrer-Orta C, Arias A, Agudo R, Perez-Luque R, Escarmis C, Domingo E, Verdaguer N. The structure of a protein primer-polymerase complex in the initiation of genome replication. Embo Journal. 2006;25(4):880-8
- Gruez A, Selisko B, Roberts M, Bricogne G, Bussetta C, Jabafi I, Coutard B, De Palma AM, Neyts J, Canard B. The crystal structure of coxsackievirus B3 RNA-dependent RNA polymerase in complex with its protein primer VPg confirms the existence of a second VPg binding site on Picornaviridae polymerases. J Virol. 2008;82(19):9577-90
- Schein CH, Oezguen N, Volk DE, Garimella R, Paul A, Braun W. NMR structure of the viral peptide linked to the genome (VPg) of poliovirus. Peptides. 2006;27(7):1676-84. PMCID: 1629084
- Schein CH, Oezguen N, van der Heden van Noort GJ, Filippov DV, Paul A, Kumar E, Braun W. NMR solution structure of poliovirus uridylyated peptide linked to the genome (VPgpU). Peptides. 2010;31(8):1441-8. PMCID: 2905501
- Schein CH, Volk DE, Oezguen N, Paul A. Novel, structure-based mechanism for uridylylation of the genome-linked peptide (VPg) of picornaviruses. Proteins. 2006;63(4):719-26
- Leen EN, Kwok KYR, Birtley JR, Simpson PJ, Subba-Reddy CV, Chaudhry Y, Sosnovtsev SV, Green KY, Prater SN, Young JC, Chung LMW, Marchant J, Roberts LO, Kao CC, Matthews S, Goodfellow IG, Curry S. Structures of the Compact Helical Core Domains of Feline Calicivirus and Murine Norovirus VPg proteins. J Virol. 2013.
- Pathak HB, Oh HS, Goodfellow IG, Arnold JJ, Cameron CE (November 2008). "Picornavirus Genome Replication: ROLES OF PRECURSOR PROTEINS AND RATE-LIMITING STEPS IN oriI-DEPENDENT VPg URIDYLYLATION". J. Biol. Chem. 283 (45): 30677â88. doi:10.1074/jbc.M806101200. PMC 2576561. PMID 18779320.
- Shen M, Wang Q, Yang Y, Pathak HB, Arnold JJ, Castro C, Lemon SM, Cameron CE (November 2007). "Human Rhinovirus Type 14 Gain-of-Function Mutants for oriI Utilization Define Residues of 3C(D) and 3Dpol That Contribute to Assembly and Stability of the Picornavirus VPg Uridylylation Complex". J. Virol. 81 (22): 12485â95. doi:10.1128/JVI.00972-07. PMC 2169002. PMID 17855535.
- Yang Y, Rijnbrand R, McKnight KL, Wimmer E, Paul A, Martin A, Lemon SM (August 2002). "Sequence Requirements for Viral RNA Replication and VPg Uridylylation Directed by the Internal cis-Acting Replication Element (cre) of Human Rhinovirus Type 14". J. Virol. 76 (15): 7485â94. doi:10.1128/JVI.76.15.7485-7494.2002. PMC 136355. PMID 12097561.
- Roy Chowdhury S, Savithri HS (2011). "Interaction of Sesbania Mosaic Virus Movement Protein with VPg and P10: Implication to Specificity of Genome Recognition". In Pfeffer, Sebastien. PLoS ONE 6 (1): e15609. doi:10.1371/journal.pone.0015609. PMC 3016346. PMID 21246040.
- Iyer LM, Koonin EV, Aravind L (January 2003). "Evolutionary connection between the catalytic subunits of DNA-dependent RNA polymerases and eukaryotic RNA-dependent RNA polymerases and the origin of RNA polymerases". BMC Struct. Biol. 3: 1. doi:10.1186/1472-6807-3-1. PMC 151600. PMID 12553882.
- Suttle CA (September 2005). "Viruses in the sea". Nature 437 (7057): 356â61. doi:10.1038/nature04160. PMID 16163346.
- Hansen JL, Long AM, Schultz SC (August 1997). "Structure of the RNA-dependent RNA polymerase of poliovirus". Structure 5 (8): 1109â22. doi:10.1016/S0969-2126(97)00261-X. PMID 9309225.
- Gohara DW, Crotty S, Arnold JJ, Yoder JD, Andino R, Cameron CE (August 2000). "Poliovirus RNA-dependent RNA polymerase (3Dpol): structural, biochemical, and biological analysis of conserved structural motifs A and B". J. Biol. Chem. 275 (33): 25523â32. doi:10.1074/jbc.M002671200. PMID 10827187.
- O'Reilly EK, Kao CC (December 1998). "Analysis of RNA-dependent RNA polymerase structure and function as guided by known polymerase structures and computer predictions of secondary structure". Virology 252 (2): 287â303. doi:10.1006/viro.1998.9463. PMID 9878607.
- Tan BH, Fu J, Sugrue RJ, Yap EH, Chan YC, Tan YH (February 1996). "Recombinant dengue type 1 virus NS5 protein expressed in Escherichia coli exhibits RNA-dependent RNA polymerase activity". Virology 216 (2): 317â25. doi:10.1006/viro.1996.0067. PMID 8607261.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Flavivirus RNA-directed RNA polymerase Provide feedback
Flaviviruses produce a polyprotein from the ssRNA genome. This protein is also known as NS5. This RNA-directed RNA polymerase possesses a number of short regions and motifs homologous to other RNA-directed RNA polymerases .
Tan BH, Fu J, Sugrue RJ, Yap EH, Chan YC, Tan YH; , Virology 1996;216:317-325.: Recombinant dengue type 1 virus NS5 protein expressed in Escherichia coli exhibits RNA-dependent RNA polymerase activity. PUBMED:8607261 EPMC:8607261
Koonin EV; , J Gen Virol 1993;74:733-740.: Computer-assisted identification of a putative methyltransferase domain in NS5 protein of flaviviruses and lambda 2 protein of reovirus. PUBMED:8385698 EPMC:8385698
Koonin EV, Dolja VV; , Crit Rev Biochem Mol Biol 1993;28:375-430.: Evolution and taxonomy of positive-strand RNA viruses: implications of comparative analysis of amino acid sequences. PUBMED:8269709 EPMC:8269709
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR000208
RNA-directed RNA polymerase (RdRp) (EC) is an essential protein encoded in the genomes of all RNA containing viruses with no DNA stage [PUBMED:2759231, PUBMED:8709232]. It catalyses synthesis of the RNA strand complementary to a given RNA template, but the precise molecular mechanism remains unclear. The postulated RNA replication process is a two-step mechanism. First, the initiation step of RNA synthesis begins at or near the 3' end of the RNA template by means of a primer-independent (de novo) mechanism. The de novo initiation consists in the addition of a nucleotide tri-phosphate (NTP) to the 3'-OH of the first initiating NTP. During the following so-called elongation phase, this nucleotidyl transfer reaction is repeated with subsequent NTPs to generate the complementary RNA product [PUBMED:11531403].
All the RNA-directed RNA polymerases, and many DNA-directed polymerases, employ a fold whose organisation has been likened to the shape of a right hand with three subdomains termed fingers, palm and thumb [PUBMED:9309225]. Only the catalytic palm subdomain, composed of a four-stranded antiparallel beta-sheet with two alpha-helices, is well conserved among all of these enzymes. In RdRp, the palm subdomain comprises three well conserved motifs (A, B and C). Motif A (D-x(4,5)-D) and motif C (GDD) are spatially juxtaposed; the Asp residues of these motifs are implied in the binding of Mg2+ and/or Mn2+. The Asn residue of motif B is involved in selection of ribonucleoside triphosphates over dNTPs and thus determines whether RNA is synthesised rather than DNA [PUBMED:10827187]. The domain organisation [PUBMED:9878607] and the 3D structure of the catalytic centre of a wide range of RdPp's, even those with a low overall sequence homology, are conserved. The catalytic centre is formed by several motifs containing a number of conserved amino acid residues.
There are 4 superfamilies of viruses that cover all RNA containing viruses with no DNA stage:
- Viruses containing positive-strand RNA or double-strand RNA, except retroviruses and Birnaviridae: viral RNA-directed RNA polymerases including all positive-strand RNA viruses with no DNA stage, double-strand RNA viruses, and the Cystoviridae, Reoviridae, Hypoviridae, Partitiviridae, Totiviridae families.
- Mononegavirales (negative-strand RNA viruses with non-segmented genomes).
- Negative-strand RNA viruses with segmented genomes, i.e. Orthomyxoviruses (including influenza A, B, and C viruses, Thogotoviruses, and the infectious salmon anemia virus), Arenaviruses, Bunyaviruses, Hantaviruses, Nairoviruses, Phleboviruses, Tenuiviruses and Tospoviruses.
- Birnaviridae family of dsRNA viruses.
- All positive-strand RNA eukaryotic viruses with no DNA stage.
- All RNA-containing bacteriophages -there are two families of RNA-containing bacteriophages: Leviviridae (positive ssRNA phages) and Cystoviridae (dsRNA phages).
- Reoviridae family of dsRNA viruses.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||ATP binding (GO:0005524)|
|RNA-directed RNA polymerase activity (GO:0003968)|
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|Seed source:||Pfam-B_200 (release 3.0)|
|Author:||Finn RD, Bateman A|
|Number in seed:||7|
|Number in full:||5252|
|Average length of the domain:||449.30 aa|
|Average identity of full alignment:||66 %|
|Average coverage of the sequence by the domain:||21.01 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||15|
|Download:||download the raw HMM for this family|
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Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Flavi_NS5 domain has been found. There are 49 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
Loading structure mapping...