Summary: HCV NS5a protein C-terminal region
Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.
This is the Wikipedia entry entitled "NS5 (HCV)". More...
NS5 (HCV) Edit Wikipedia article
 |
This article needs more links to other articles to help integrate it into the encyclopedia. (March 2013) |
NS5 is a viral protein found in hepatitis C.[1] 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.[2][3] Several crystal structures of NS5B polymerase in several crystalline forms have been determined based on the same consensus sequence BK (HCV-BK, genotype 1).[4] 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.[5] Current research attempts to bind structures to this active site to alter its functionality in order to prevent further viral RNA replication.[6]
Nonstructural protein 5A (NS5A) is a zinc-binding and proline-rich hydrophilic phosphoprotein that plays a key role in HCV RNA replication.[7][8] It appears to be a dimeric form without trans-membrane helices.[9] 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.[10] Despite no inherent enzymatic activity being attributed to NS5A, its function is mediated through interaction with other nonstructural (NS) viral and cellular proteins.[8][10] NS5A has two phosphorylated forms: p56 and p58, which differ in the electrophoretic mobility.[9] 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.[9] It has been predicted that the N-terminal 30 aa of NS5A form an amphipathic α-helix with a highly preserved feature, which is essential to modulate the association between NS5A and ER membrane.[9][10] 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.[9]
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.[7] Furthermore, the conformational flexibility of NS5A plays an important role in multiple HCV infection stages.[7] 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.[7][10] Additionally, NS5A has been shown to modulate the polymerase activity of NS5B, an RNA-dependent RNA polymerase (RdRp).[9] 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.[9] Moreover, NS5A is a key mediator in regulating host cell function and activity upon HCV infection.[10] 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.[7][10] Indeed, small molecule drugs efficiently targeting NS5A displayed a much higher potency in controlling HCV infection than other drugs.[7] Therefore, NS5A related researches would have important implications in single molecule drug design and pegIFN-free direct-acting antiviral (DAA) combination therapies.[7]
[edit] References
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ a b c d e f g 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.
- ^ a b 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.
- ^ a b c d e f g 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.
- ^ a b c d e f 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.
|
|||||||||||||||||||||||||||||||||||||||||||||||||
 |
This virus-related article is a stub. You can help Wikipedia by expanding it. |
This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.
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
| PANDIT: | PF12941 |
| Pseudofam: | PF12941 |
| SYSTERS: | HCV_NS5a_C |
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].
Domain organisation
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
Loading domain graphics...
Alignments
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...
View options
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.
| Seed (17) |
Full (15967) |
Representative proteomes | NCBI (9643) |
Meta (0) |
||||
|---|---|---|---|---|---|---|---|---|
| RP15 (0) |
RP35 (0) |
RP55 (0) |
RP75 (0) |
|||||
| Jalview | ||||||||
| HTML | ||||||||
| PP/heatmap | 1 | |||||||
| Pfam viewer | ||||||||
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key:
available,
not generated,
— not available.
Format an alignment
Download options
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.
| Seed (17) |
Full (15967) |
Representative proteomes | NCBI (9643) |
Meta (0) |
||||
|---|---|---|---|---|---|---|---|---|
| RP15 (0) |
RP35 (0) |
RP55 (0) |
RP75 (0) |
|||||
| Raw Stockholm | ||||||||
| Gzipped | ||||||||
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
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 HMMER3.
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'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.
Curation
| Seed source: | jackhmmer:A1YSL9 |
| Previous IDs: | DUF3838; |
| Type: | Family |
| 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 information
| HMM build commands: |
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|
||||||||||||
| Model details: |
|
||||||||||||
| Model length: | 244 | ||||||||||||
| Family (HMM) version: | 2 | ||||||||||||
| Download: | download the raw HMM for this family |
Species distribution
Sunburst controls
Show
Archea
Eukaryota
Bacteria
Other sequences
Viruses
Unclassified
Viroids
Unclassified sequence
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...
Tree controls
HideThe tree shows the occurrence of this domain across different species. More...
Loading...
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.
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 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.
Loading structure mapping...
