Summary: Flavivirus RNA-directed RNA polymerase
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RNA-dependent RNA polymerase Edit Wikipedia article
|RNA-dependent RNA polymerase|
Stalled HCV RNA replicase (NS5B), in complex with sofosbuvir (PDB 4WTG).
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / QuickGO|
|RNA dependent RNA polymerase[a]|
|SCOPe||2jlg / SUPFAM|
|Bunyavirus RNA replicase[b]|
|RNA-dependent RNA polymerase, eukaryotic-type|
RNA-dependent RNA polymerase (RdRP), (RDR), or RNA replicase, is an enzyme 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 i.e. only RNA viruses. 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 nucleoside triphosphate (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.
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.
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.
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 RNA interference; these amplify microRNAs and small temporal RNAs and produce double-stranded RNA using small interfering RNAs as primers. In fact these same RdRPs that are used in the defense mechanisms can be usurped by RNA viruses for their benefit. Their evolutionary history has been reviewed.
Viral/prokaryotic RNA-directed RNA polymerases, and many single-subunit 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.
Eukaryotic RNA interference requires a cellular RNA-dependent RNA polymerase (cRdRP). Unlike the "hand" polymerases, they resemble simplified multi-subunit DdRPs, specifically in the catalytic Î²/Î²' subunits, in that they use two sets of double-psi Î²-barrels in the active site. QDE1 in Neurospora crassa, which forms a homodimer, is an example of such an enzyme. Bacteriophage homologs, including yonO, appear to be closer to cRdRPs than DdRPs are. yonO is a DNA-dependent RNA polymerase.
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
- 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)
- dsRNA virus family Reoviridae, Totiviridae, Hypoviridae, Partitiviridae
- Mononegavirales (negative-strand RNA viruses with non-segmented genomes; InterPro: IPR016269)
- Negative-strand RNA viruses with segmented genomes (InterPro: IPR007099), i.e., Orthomyxoviruses (including influenza A, B, and C viruses, Thogotoviruses, and the infectious salmon anemia virus), Bunyavirales (Arenaviruses, Bunyaviruses, Hantaviruses, Nairoviridae, Phleboviruses, Tenuiviruses and Tospoviruses)
- dsRNA virus family Birnaviridae (InterPro: IPR007100)
RNA transcription is similar to[how?] but not the same as DNA replication.
Flaviviruses produce a polyprotein from the ssRNA genome. The polyprotein is cleaved to a number of products, one of which is NS5, an RNA-dependent RNA polymerase. This RNA-directed RNA polymerase possesses a number of short regions and motifs homologous to other RNA-directed RNA polymerases.
RNA replicase found in positive-strand ssRNA viruses are related to each other, forming three large superfamilies. Birnaviral RNA replicase is unique in that it lacks motif C (GDD) in the palm. Mononegaviral RdRP (PDB 5A22) has been automatically classified as similar to (+)-ssRNA RdRPs, specifically one from Pestivirus and one from Leviviridae. Bunyaviral RdRP monomer (PDB 5AMQ) resembles the heterotrimeric complex of Orthomyxoviral (Influenza; PDB 4WSB) RdRP.
- See Pfam clan for other (+)ssRNA/dsRNA families.
- A (-)ssRNA polymerase.
- 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 Letters. 252 (1â€“2): 42â€“6. 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". Journal of Virology. 70 (9): 6083â€“96. PMC 190630. PMID 8709232.
- Jin Z, Leveque V, Ma H, Johnson KA, Klumpp K (March 2012). "Assembly, purification, and pre-steady-state kinetic analysis of active RNA-dependent RNA polymerase elongation complex". The Journal of Biological Chemistry. 287 (13): 10674â€“83. doi:10.1074/jbc.M111.325530. PMC 3323022. PMID 22303022.
- Kao CC, Singh P, Ecker DJ (September 2001). "De novo initiation of viral RNA-dependent RNA synthesis". Virology. 287 (2): 251â€“60. doi:10.1006/viro.2001.1039. PMID 11531403.
- Suttle CA (September 2005). "Viruses in the sea". Nature. 437 (7057): 356â€“61. Bibcode:2005Natur.437..356S. doi:10.1038/nature04160. PMID 16163346.
- Timm C, Gupta A, Yin J (August 2015). "Robust kinetics of an RNA virus: Transcription rates are set by genome levels". Biotechnology and Bioengineering. 112 (8): 1655â€“62. doi:10.1002/bit.25578. PMC 5653219. PMID 25726926.
- 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 Structural Biology. 3: 1. doi:10.1186/1472-6807-3-1. PMC 151600. PMID 12553882.
- Zong J, Yao X, Yin J, Zhang D, Ma H (November 2009). "Evolution of the RNA-dependent RNA polymerase (RdRP) genes: duplications and possible losses before and after the divergence of major eukaryotic groups". Gene. 447 (1): 29â€“39. doi:10.1016/j.gene.2009.07.004. PMID 19616606.
- Hansen JL, Long AM, Schultz SC (August 1997). "Structure of the RNA-dependent RNA polymerase of poliovirus". Structure. 5 (8): 1109â€“22. 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". The Journal of Biological Chemistry. 275 (33): 25523â€“32. 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): 287â€“303. doi:10.1006/viro.1998.9463. PMID 9878607.
- Werner F, Grohmann D (February 2011). "Evolution of multisubunit RNA polymerases in the three domains of life". Nature Reviews. Microbiology. 9 (2): 85â€“98. doi:10.1038/nrmicro2507. PMID 21233849.
- 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 Structural Biology. 3: 1. doi:10.1186/1472-6807-3-1. PMC 151600. PMID 12553882.
- Forrest D, James K, Yuzenkova Y, Zenkin N (June 2017). "Single-peptide DNA-dependent RNA polymerase homologous to multi-subunit RNA polymerase". Nature Communications. 8: 15774. Bibcode:2017NatCo...815774F. doi:10.1038/ncomms15774. PMC 5467207. PMID 28585540.
- 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): 317â€“25. doi:10.1006/viro.1996.0067. PMID 8607261.
- Koonin EV (September 1991). "The phylogeny of RNA-dependent RNA polymerases of positive-strand RNA viruses" (PDF). The Journal of General Virology. 72 ( Pt 9) (9): 2197â€“206. doi:10.1099/0022-1317-72-9-2197. PMID 1895057.
- Shwed PS, Dobos P, Cameron LA, Vakharia VN, Duncan R (May 2002). "Birnavirus VP1 proteins form a distinct subgroup of RNA-dependent RNA polymerases lacking a GDD motif". Virology. 296 (2): 241â€“50. doi:10.1006/viro.2001.1334. PMID 12069523.
- Structural Similarities for the Entities in PDB 5A22.
- Gerlach P, Malet H, Cusack S, Reguera J (June 2015). "Structural Insights into Bunyavirus Replication and Its Regulation by the vRNA Promoter". Cell. 161 (6): 1267â€“79. doi:10.1016/j.cell.2015.05.006. PMC 4459711. PMID 26004069.
- Wolf YI, Kazlauskas D, Iranzo J, LucÃa-Sanz A, Kuhn JH, Krupovic M, Dolja VV, Koonin EV (November 2018). "Origins and Evolution of the Global RNA Virome". mBio. 9 (6). doi:10.1128/mBio.02329-18. PMC 6282212. PMID 30482837.
- Venkataraman S, Prasad BV, Selvarajan R (February 2018). "RNA Dependent RNA Polymerases: Insights from Structure, Function and Evolution". Viruses. 10 (2): 76. doi:10.3390/v10020076. PMC 5850383. PMID 29439438.
- ÄŒernÃ½ J, ÄŒernÃ¡ BolfÃkovÃ¡ B, ValdÃ©s JJ, Grubhoffer L, RÅ¯Å¾ek D (2014). "Evolution of tertiary structure of viral RNA dependent polymerases". PLOS ONE. 9 (5): e96070. Bibcode:2014PLoSO...996070C. doi:10.1371/journal.pone.0096070. PMC 4015915. PMID 24816789.
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.
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 [PUBMED:8607261].
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 5'-3' RNA polymerase activity (GO:0003968)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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This clan represents the replicative RNA dependent RNA polymerase. from a variety of RNA viruses .
The clan contains the following 10 members:Birna_RdRp Flavi_NS5 Mitovir_RNA_pol RdRP_1 RdRP_2 RdRP_3 RdRP_4 RVT_1 RVT_2 Viral_RdRp_C
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
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This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Seed source:||Pfam-B_200 (release 3.0)|
|Author:||Finn RD , Bateman A|
|Number in seed:||3|
|Number in full:||14|
|Average length of the domain:||429.70 aa|
|Average identity of full alignment:||31 %|
|Average coverage of the sequence by the domain:||33.85 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 47079205 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||21|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
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Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
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Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
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.
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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.
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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.
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There are 2 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
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 192 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 sequence.
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