Summary: HCV NS5a protein C-terminal region
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NS5 (HCV) Edit Wikipedia article
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NS5 is a viral protein found in hepatitis C. NS5B has the key function of replicating the HCVâs viral RNA by using the viral positive RNA strand as its template and catalyzes the polymerization of ribonucleoside triphosphates (rNTP) during RNA replication. Several crystal structures of NS5B polymerase in several crystalline forms have been determined based on the same consensus sequence BK (HCV-BK, genotype 1). The structure can be represented by a right hand shape with fingers, palm, and thumb. The encircled active site, unique to NS5B, is contained within the palm structure of the protein. Recent studies on NS5B protein genotype 1b strain J4âs (HC-J4) structure indicate a presence of an active site where possible control of nucleotide binding occurs and initiation of de-novo RNA synthesis. De-novo adds necessary primers for initiation of RNA replication. Current research attempts to bind structures to this active site to alter its functionality in order to prevent further viral RNA replication.
Nonstructural protein 5A (NS5A) is a zinc-binding and proline-rich hydrophilic phosphoprotein that plays a key role in HCV RNA replication. It appears to be a dimeric form without trans-membrane helices. NS5A is derived from a large polyprotein that is translated from the HCV genome, and continues to be processed by nonstructural protein 3 (NS3) viral protease. Despite no inherent enzymatic activity being attributed to NS5A, its function is mediated through interaction with other nonstructural (NS) viral and cellular proteins. NS5A has two phosphorylated forms: p56 and p58, which differ in the electrophoretic mobility. p56 is basally phosphorylated by host cellular protein kinase at the center and near the C terminus, whereas p58 is a form of hyperphorylated NS5A at the center of the serine-rich region. It has been predicted that the N-terminal 30 aa of NS5A form an amphipathic Î±-helix with a highly preserved feature, which is essential to modulate the association between NS5A and ER membrane. Interestingly, the IFN-sensitivity determining region (ISDR) at the C-terminal of NS5A has been reported to perform strong trans-activating activities, suggesting that NS5A likely functions as a transcriptional activator.
NS5A has three structurally different domains: domain I was demonstrated to be an alternative dimeric structure by Crystallography, while domain II and III remained unfolded. Furthermore, the conformational flexibility of NS5A plays an important role in multiple HCV infection stages. It is also possible that NS5A is a critical component during HCV replication and subcellular localization, which may shed light on the poorly understood HCV life cycle. Additionally, NS5A has been shown to modulate the polymerase activity of NS5B, an RNA-dependent RNA polymerase (RdRp). Intriguingly, NS5A may be a RNA binding protein due to the fact that it is able to bind to the 3âUTR of the plus and minus HCV RNA strands. Moreover, NS5A is a key mediator in regulating host cell function and activity upon HCV infection. Therefore, NS5A has been extensively studied in HCV research also due to its capability to regulate the interferon (IFN) response of the host cells. Because NS5A exerts functionally essential effects in regulation of viral replication, assembly and egress, it has been considered a potential drug target for antiviral therapeutic intervention. Indeed, small molecule drugs efficiently targeting NS5A displayed a much higher potency in controlling HCV infection than other drugs. Therefore, NS5A related researches would have important implications in single molecule drug design and pegIFN-free direct-acting antiviral (DAA) combination therapies.
- Gehring S, Gregory SH, Wintermeyer P, Aloman C, Wands JR (December 2008). "Generation of Immune Responses Against HCV Using Dendritic Cells Containing NS5 Protein-Coated Microparticles". Clin. Vaccine Immunol. 16 (2): 163â71. doi:10.1128/CVI.00287-08. PMC 2643538. PMID 19091993.
- Moradpour, D.; Penin, F.; Rice, C.M. Replication of hepatitis C virus. Nat Rev Microbiol. 2007, 5, 453-63.. PMID 17487147. Citation has no title
- Rigat, K.; Wang, Y.; Hudyma, T.W.; Ding, M.; Zheng, X.; Gentles, R.G.; Beno, B.R.; Gao, M.; Roberts, S.B. Ligand-induced changes in hepatitis C virus NS5B polymerase structure. Antiviral Res. 2010, 88, 197-206.. PMID 20813137. Citation has no title
- Biswal, B.K.; Cherney, M.M.; Wang, M.; Chan, L.; Yannopoulos, C.G.; Bilimoria, D.; Nicolas, O.; Bedard, J.; James, M.N. Crystal structures of the RNA-dependent RNA polymerase genotype 2a of hepatitis C virus reveal two conformations and suggest mechanisms of inhibition by non-nucleoside inhibitors. J Biol Chem. 2005, 280, 18202-10.. PMID 15746101. Citation has no title
- OâFarrell, D.; Trowbridge, R.; Rowlands, D.; Jager, J. Substrate complexes of hepatitis C virus RNA polymerase (HC-J4); structural evidence for nucleotide import and de-novo initiation. J Mol Biol. 2003, 326, 1025-35.. PMID 12589751. Citation has no title
- Biswal, B.K.; Wang, M.; Cherney, M.M.; Chan, L.; Yannopoulos, C.G.; Bilimoria, D.; Bedard, J.; James, M.N. Non-nucleoside inhibitors binding to helpatitis C virus NS5B polymerase reveal a novel mechanism of inhibition. J Mol Biol. 2006. 361. 33-45.. PMID 16828488. Citation has no title
- Belda, O. and P. Targett-Adams, Small molecule inhibitors of the hepatitis C virus-encoded NS5A protein. Virus Research. 2012. 170(1-2): p. 1-14.. PMID 23009750. Citation has no title
- Huang, Y., et al., Phosphorylation of hepatitis C virus NS5A nonstructural protein: a new paradigm for phosphorylation-dependent viral RNA replication? Virology. 2007. 364(1): p. 1-9.. PMID 17400273. Citation has no title
- Macdonald, A. and M. Harris, Hepatitis C virus NS5A: tales of a promiscuous protein. Journal of General Virology. 2004. 85(9): p. 2485-502.. PMID 15302943. Citation has no title
- He, Y., K.A. Staschke, and S.L. Tan, HCV NS5A: A Multifunctional Regulator of Cellular Pathways and Virus Replication, in Hepatitis C Viruses: Genomes and Molecular Biology, S.L. Tan, Editor 2006: Norfolk (UK). . PMID 21250384. Citation has no title
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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.
HCV NS5a protein C-terminal region Provide feedback
This is a family of proteins found in the hepatitis C virus. This family contains the C-terminal region of the NS5A protein. CC The molecular function of the non-structural 5a protein is uncertain. The NS5a protein is phosphorylated when expressed in mammalian cells. It is thought to interact with the ds RNA dependent (interferon inducible) kinase PKR, P19525.
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR024350
This entry represents the C-terminal region of the Hepatitus C virus, NS5a protein. The molecular function of the non-structural 5a protein is uncertain. The NS5a protein is phosphorylated when expressed in mammalian cells. It is thought to interact with the dsRNA dependent (interferon inducible) kinase PKR [PUBMED:9710605, PUBMED:9143277].
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
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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 using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
- Pfam viewer
- an HTML-based viewer that uses DAS to retrieve alignment fragments on request
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
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.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
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 HMMER3.
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...
If you find these logos useful in your own work, please consider citing the following article:
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.
Note: You can also download the data file for the tree.
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.
|Author:||Mistry J, Bateman A|
|Number in seed:||17|
|Number in full:||15967|
|Average length of the domain:||185.50 aa|
|Average identity of full alignment:||77 %|
|Average coverage of the sequence by the domain:||38.13 %|
|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:||2|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
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:
Colouring and labels
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.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
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.
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 HCV_NS5a_C domain has been found. There are 2 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.
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