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The MTase domain is involved in 5’ capping of the newly synthesized RNA as well as methylation of certain guanine and adenine residues which contributes to evasion from host defence mechanisms. It catalyzes RNA cap methylation at both the N7 position on the cap guanosine and the 2’O on the first nucleotide of the newly synthesized (+) RNA strand. The MTase domain contains five parallel beta sheets.
The MTase domain is involved in 5’ capping of the newly synthesized RNA as well as methylation of certain guanine and adenine residues which contributes to evasion from host defence mechanisms. It catalyzes RNA cap methylation at both the N7 position on the cap guanosine and the 2’O on the first nucleotide of the newly synthesized (+) RNA strand. The MTase domain contains five parallel beta sheets.
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The linker connects the two domains and is responsible for their flexible orientation relative to each other. Residues 262-266 are key in this regard, which fold into a compact 310 helix and allow for a large interface interaction between the two domains giving the protein its globular shape. (GREEN LINK)This flexibility is a key aspect as it has been demonstrated that the linker residues N-terminal to the RdRp region enhance stability and polymerase activity and is further evidenced by results showing superior activity in the complete NS5 protein as compared to the RdRp alone, suggesting that MTase-RdRp interactions are required to maintain RNA synthesis.
+
The linker connects the two domains and is responsible for their flexible orientation relative to each other. Residues 262-266 are key in this regard, which fold into a compact 310 helix and allow for a large interface interaction between the two domains giving the protein its globular shape. (GREEN LINK)This flexibility is a key aspect as it has been demonstrated that the linker residues N-terminal to the RdRp region enhance stability and polymerase activity and is further evidenced by results showing superior activity in the complete NS5 protein as compared to the RdRp alone, further corroborating that MTase-RdRp interactions are required to maintain RNA synthesis.
The inter-domain interface is stabilized by several polar contacts between residues projecting from the MTase and RdRp domains of NS5. These interactions are as follows
The inter-domain interface is stabilized by several polar contacts between residues projecting from the MTase and RdRp domains of NS5. These interactions are as follows

Revision as of 10:52, 22 April 2015

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Dengue Virus Non-Structural Protein NS5

The dengue virus (DENV) belongs to genus Flavivirus, which also includes the West Nile Virus, Japanese Encephalitis Virus and Yellow Fever Virus. The mosquito-borne DENV causes dengue fever which can then progress to dengue hemorrhagic fever and dengue shock syndrome. Endemic to the tropics and subtropics. It is mainly transmitted by Aedes mosquitoes. Although there are 390 million dengue infections reported annually, no specific antiviral drug or vaccine has been developed yet.

There are four serotypes of the virus (DEN-1 – DEN-4). The viral genome encodes three structural proteins (capsid, membrane and envelope) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5). By associating with host cofactors and each other, NS proteins form multi-protein replication complexes, which comprise the viral replication machinery. The NS5 primary sequence is generally well conserved across serotypes and also shares some similarity with the NS5 protein of other flaviviruses.

[1]


[2]

Structure

DENV NS5 (4V0Q)

Cartoon view of NS5

Drag the structure with the mouse to rotate

References

  1. ↑ Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, Drake JM, Brownstein JS, Hoen AG, Sankoh O, Myers MF, George DB, Jaenisch T, Wint GR, Simmons CP, Scott TW, Farrar JJ, Hay SI. The global distribution and burden of dengue. Nature. 2013 Apr 25;496(7446):504-7. doi: 10.1038/nature12060. Epub 2013 Apr 7. PMID:23563266 doi:http://dx.doi.org/10.1038/nature12060
  2. ↑ Potisopon S, Priet S, Collet A, Decroly E, Canard B, Selisko B. The methyltransferase domain of dengue virus protein NS5 ensures efficient RNA synthesis initiation and elongation by the polymerase domain. Nucleic Acids Res. 2014 Oct;42(18):11642-56. doi: 10.1093/nar/gku666. Epub 2014, Sep 10. PMID:25209234 doi:http://dx.doi.org/10.1093/nar/gku666
  3. ↑ Zhao Y, Soh TS, Zheng J, Chan KW, Phoo WW, Lee CC, Tay MY, Swaminathan K, Cornvik TC, Lim SP, Shi PY, Lescar J, Vasudevan SG, Luo D. A Crystal Structure of the Dengue Virus NS5 Protein Reveals a Novel Inter-domain Interface Essential for Protein Flexibility and Virus Replication. PLoS Pathog. 2015 Mar 16;11(3):e1004682. doi: 10.1371/journal.ppat.1004682., eCollection 2015 Mar. PMID:25775415 doi:http://dx.doi.org/10.1371/journal.ppat.1004682
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