Summary

Flavivirus RNA-directed RNA polymerase

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 [2].

Literature references

Marin MS, Zanotto PM, Gritsun TS, Gould EA; , Virology 1995;206:1133-1139.: Phylogeny of TYU, SRE, and CFA virus: different evolutionary rates in the genus Flavivirus. PUBMED:7856087
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
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
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

InterPro entry IPR000208

RNA-directed RNA polymerase (RdRp) () 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 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.

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 PUBMED:8607261.

Clan

This family is a member of clan RdRP (CL0027), which contains the following 8 members:

Flavi_NS5 Mitovir_RNA_pol RdRP_1 RdRP_2 RdRP_3 RdRP_4 RVT_1 RVT_2

Gene Ontology

Molecular function	ATP binding (GO:0005524)
	RNA-directed RNA polymerase activity (GO:0003968)

External database links

PANDIT:	PF00972
SCOP:	1l9k
SYSTERS:	Flavi_NS5

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Alignments

There are various ways to view or download the sequence alignments that we store. You can use a sequence viewer to look at either the seed or full alignment for the family, or you can look at a plain text version of the sequence in a variety of different formats. More...

View options

Alignment:	Seed (7) Full (3131) NCBI (3685) Metagenomics
Viewer:

Formatting options

Alignment:	Seed (7) Full (3131)
Format:
Order:	Tree Alphabetical
Sequence:	Inserts lower case All upper case
Gaps:
Download/view:	Download View

Download options

Very large alignments can often cause problems for the formatting tool above. If you find that downloading or viewing a large alignment is problematic, you can also download a gzip-compressed, Stockholm-format file containing the seed or full alignment for this family.

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

The main seed and full alignments are generated using sequences from the UniProt sequence database. However, we also generate alignments using sequences from the NCBI sequence database and the "metaseq" metagenomics dataset.

You can view alignments from these two additional datasets using the form above, or you can download alignments of NCBI or metagenomics sequences, as gzip-compressed files.

Pfam alignments:	Seed (7) Full (3131) NCBI (3685) Metagenomics
Full length sequences	Full-sequences (3131)

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER2.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family. 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 or full alignments.

Note: You can also download the data files for the seed, full, NCBI or metagenomics trees.

Curation and family details

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.

Curation

Seed source:

Pfam-B_200 (release 3.0)

Previous IDs:

none

Type:

Family

Author:

Finn RD, Bateman A

Number in seed:

7

Number in full:

3131

Average length of the domain:

474.80 aa

Average identity of full alignment:

68 %

Average coverage of the sequence by the domain:

21.23 %

HMM information

HMM build commands:

build method: hmmbuild -o /dev/null HMM SEED

search method: hmmsearch -Z 9421015 -E 1000 HMM pfamseq

Model details:

Parameter	Sequence	Domain
Gathering cut-off	19.0	19.0
Trusted cut-off	19.0	19.1
Noise cut-off	18.9	18.9

Model length:

649

Family (HMM) version:

13

Download:

download the raw HMM for this family

Species distribution

Tree controls

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The tree shows the occurrence of this domain across different species. More...

Species trees

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.

Interactive tree

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

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Structures

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.

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Family: Flavi_NS5 (PF00972)

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