| Structural highlights
Function
[POLG_KUNJM] Capsid protein C self-assembles to form an icosahedral capsid about 30 nm in diameter. The capsid encapsulates the genomic RNA (By similarity).[1] [2] [3] [4] prM acts as a chaperone for envelope protein E during intracellular virion assembly by masking and inactivating envelope protein E fusion peptide. prM is matured in the last step of virion assembly, presumably to avoid catastrophic activation of the viral fusion peptide induced by the acidic pH of the trans-Golgi network. After cleavage by host furin, the pr peptide is released in the extracellular medium and small envelope protein M and envelope protein E homodimers are dissociated (By similarity).[5] [6] [7] [8] Envelope protein E binding to host cell surface receptor is followed by virus internalization through clathrin-mediated endocytosis. Envelope protein E is subsequently involved in membrane fusion between virion and host late endosomes. Synthesized as a homodimer with prM which acts as a chaperone for envelope protein E. After cleavage of prM, envelope protein E dissociate from small envelope protein M and homodimerizes (By similarity).[9] [10] [11] [12] Non-structural protein 1 is involved in virus replication and regulation of the innate immune response (By similarity).[13] [14] [15] [16] Non-structural protein 2A may be involved viral RNA replication and capsid assembly (Potential).[17] [18] [19] [20] Non-structural protein 2B is a required cofactor for the serine protease function of NS3 (By similarity).[21] [22] [23] [24] Serine protease NS3 displays three enzymatic activities: serine protease, NTPase and RNA helicase. NS3 serine protease, in association with NS2B, performs its autocleavage and cleaves the polyprotein at dibasic sites in the cytoplasm: C-prM, NS2A-NS2B, NS2B-NS3, NS3-NS4A, NS4A-2K and NS4B-NS5. NS3 RNA helicase binds RNA and unwinds dsRNA in the 3' to 5' direction (By similarity).[25] [26] [27] [28] Non-structural protein 4A induces host endoplasmic reticulum membrane rearrangements leading to the formation of virus-induced membranous vesicles hosting the dsRNA and polymerase, functioning as a replication complex. NS4A might also regulate the ATPase activity of the NS3 helicase (By similarity).[29] [30] [31] [32] Peptide 2k functions as a signal peptide for NS4B and is required for the interferon antagonism activity of the latter (By similarity).[33] [34] [35] [36] Non-structural protein 4B inhibits interferon (IFN)-induced host STAT1 phosphorylation and nuclear translocation, thereby preventing the establishment of cellular antiviral state by blocking the IFN-alpha/beta pathway (By similarity).[37] [38] [39] [40] RNA-directed RNA polymerase NS5 replicates the viral (+) and (-) genome, and performs the capping of genomes in the cytoplasm. NS5 methylates viral RNA cap at guanine N-7 and ribose 2'-O positions. Besides its role in genome replication, also prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) signaling pathway. Inhibits host JAK1 and TYK2 phosphorylation, thereby preventing activation of JAK-STAT signaling pathway.[41] [42] [43] [44]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Flaviviral NS3 is a multifunctional protein displaying N-terminal protease activity in addition to C-terminal helicase, nucleoside 5'-triphosphatase (NTPase), and 5'-terminal RNA triphosphatase (RTPase) activities. NS3 is held to support the separation of RNA daughter and template strands during viral replication. In addition, NS3 assists the initiation of replication by unwinding the RNA secondary structure in the 3' non-translated region (NTR). We report here the three-dimensional structure (at 3.1 A resolution) of the NS3 helicase domain (residues 186-619; NS3:186-619) from Kunjin virus, an Australian variant of the West Nile virus. As for homologous helicases, NS3:186-619 is composed of three domains, two of which are structurally related and held to host the NTPase and RTPase active sites. The third domain (C-terminal) is involved in RNA binding/recognition. The NS3:186-619 construct occurs as a dimer in solution and in the crystals. We show that NS3:186-619 displays both ATPase and RTPase activities, that it can unwind a double-stranded RNA substrate, being however inactive on a double-stranded DNA substrate. Analysis of different constructs shows that full length NS3 displays increased helicase activity, suggesting that the protease domain plays an assisting role in the RNA unwinding process. The structural interaction between the helicase and protease domain has been assessed using small angle X-ray scattering on full length NS3, disclosing that the protease and helicase domains build a rather elongated molecular assembly differing from that observed in the NS3 protein from hepatitis C virus.
Crystal structure and activity of Kunjin virus NS3 helicase; protease and helicase domain assembly in the full length NS3 protein.,Mastrangelo E, Milani M, Bollati M, Selisko B, Peyrane F, Pandini V, Sorrentino G, Canard B, Konarev PV, Svergun DI, de Lamballerie X, Coutard B, Khromykh AA, Bolognesi M J Mol Biol. 2007 Sep 14;372(2):444-55. Epub 2007 Jun 27. PMID:17658551[45]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Leung JY, Pijlman GP, Kondratieva N, Hyde J, Mackenzie JM, Khromykh AA. Role of nonstructural protein NS2A in flavivirus assembly. J Virol. 2008 May;82(10):4731-41. doi: 10.1128/JVI.00002-08. Epub 2008 Mar 12. PMID:18337583 doi:10.1128/JVI.00002-08
- ↑ Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J Virol. 2010 Oct;84(20):10438-47. doi: 10.1128/JVI.00986-10. Epub 2010 Aug 4. PMID:20686019 doi:10.1128/JVI.00986-10
- ↑ Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005 Feb;79(3):1343-50. PMID:15650160 doi:10.1128/JVI.79.3.1343-1350.2005
- ↑ Laurent-Rolle M, Boer EF, Lubick KJ, Wolfinbarger JB, Carmody AB, Rockx B, Liu W, Ashour J, Shupert WL, Holbrook MR, Barrett AD, Mason PW, Bloom ME, Garcia-Sastre A, Khromykh AA, Best SM. The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. J Virol. 2010 Apr;84(7):3503-15. doi: 10.1128/JVI.01161-09. Epub 2010 Jan 27. PMID:20106931 doi:10.1128/JVI.01161-09
- ↑ Leung JY, Pijlman GP, Kondratieva N, Hyde J, Mackenzie JM, Khromykh AA. Role of nonstructural protein NS2A in flavivirus assembly. J Virol. 2008 May;82(10):4731-41. doi: 10.1128/JVI.00002-08. Epub 2008 Mar 12. PMID:18337583 doi:10.1128/JVI.00002-08
- ↑ Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J Virol. 2010 Oct;84(20):10438-47. doi: 10.1128/JVI.00986-10. Epub 2010 Aug 4. PMID:20686019 doi:10.1128/JVI.00986-10
- ↑ Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005 Feb;79(3):1343-50. PMID:15650160 doi:10.1128/JVI.79.3.1343-1350.2005
- ↑ Laurent-Rolle M, Boer EF, Lubick KJ, Wolfinbarger JB, Carmody AB, Rockx B, Liu W, Ashour J, Shupert WL, Holbrook MR, Barrett AD, Mason PW, Bloom ME, Garcia-Sastre A, Khromykh AA, Best SM. The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. J Virol. 2010 Apr;84(7):3503-15. doi: 10.1128/JVI.01161-09. Epub 2010 Jan 27. PMID:20106931 doi:10.1128/JVI.01161-09
- ↑ Leung JY, Pijlman GP, Kondratieva N, Hyde J, Mackenzie JM, Khromykh AA. Role of nonstructural protein NS2A in flavivirus assembly. J Virol. 2008 May;82(10):4731-41. doi: 10.1128/JVI.00002-08. Epub 2008 Mar 12. PMID:18337583 doi:10.1128/JVI.00002-08
- ↑ Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J Virol. 2010 Oct;84(20):10438-47. doi: 10.1128/JVI.00986-10. Epub 2010 Aug 4. PMID:20686019 doi:10.1128/JVI.00986-10
- ↑ Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005 Feb;79(3):1343-50. PMID:15650160 doi:10.1128/JVI.79.3.1343-1350.2005
- ↑ Laurent-Rolle M, Boer EF, Lubick KJ, Wolfinbarger JB, Carmody AB, Rockx B, Liu W, Ashour J, Shupert WL, Holbrook MR, Barrett AD, Mason PW, Bloom ME, Garcia-Sastre A, Khromykh AA, Best SM. The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. J Virol. 2010 Apr;84(7):3503-15. doi: 10.1128/JVI.01161-09. Epub 2010 Jan 27. PMID:20106931 doi:10.1128/JVI.01161-09
- ↑ Leung JY, Pijlman GP, Kondratieva N, Hyde J, Mackenzie JM, Khromykh AA. Role of nonstructural protein NS2A in flavivirus assembly. J Virol. 2008 May;82(10):4731-41. doi: 10.1128/JVI.00002-08. Epub 2008 Mar 12. PMID:18337583 doi:10.1128/JVI.00002-08
- ↑ Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J Virol. 2010 Oct;84(20):10438-47. doi: 10.1128/JVI.00986-10. Epub 2010 Aug 4. PMID:20686019 doi:10.1128/JVI.00986-10
- ↑ Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005 Feb;79(3):1343-50. PMID:15650160 doi:10.1128/JVI.79.3.1343-1350.2005
- ↑ Laurent-Rolle M, Boer EF, Lubick KJ, Wolfinbarger JB, Carmody AB, Rockx B, Liu W, Ashour J, Shupert WL, Holbrook MR, Barrett AD, Mason PW, Bloom ME, Garcia-Sastre A, Khromykh AA, Best SM. The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. J Virol. 2010 Apr;84(7):3503-15. doi: 10.1128/JVI.01161-09. Epub 2010 Jan 27. PMID:20106931 doi:10.1128/JVI.01161-09
- ↑ Leung JY, Pijlman GP, Kondratieva N, Hyde J, Mackenzie JM, Khromykh AA. Role of nonstructural protein NS2A in flavivirus assembly. J Virol. 2008 May;82(10):4731-41. doi: 10.1128/JVI.00002-08. Epub 2008 Mar 12. PMID:18337583 doi:10.1128/JVI.00002-08
- ↑ Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J Virol. 2010 Oct;84(20):10438-47. doi: 10.1128/JVI.00986-10. Epub 2010 Aug 4. PMID:20686019 doi:10.1128/JVI.00986-10
- ↑ Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005 Feb;79(3):1343-50. PMID:15650160 doi:10.1128/JVI.79.3.1343-1350.2005
- ↑ Laurent-Rolle M, Boer EF, Lubick KJ, Wolfinbarger JB, Carmody AB, Rockx B, Liu W, Ashour J, Shupert WL, Holbrook MR, Barrett AD, Mason PW, Bloom ME, Garcia-Sastre A, Khromykh AA, Best SM. The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. J Virol. 2010 Apr;84(7):3503-15. doi: 10.1128/JVI.01161-09. Epub 2010 Jan 27. PMID:20106931 doi:10.1128/JVI.01161-09
- ↑ Leung JY, Pijlman GP, Kondratieva N, Hyde J, Mackenzie JM, Khromykh AA. Role of nonstructural protein NS2A in flavivirus assembly. J Virol. 2008 May;82(10):4731-41. doi: 10.1128/JVI.00002-08. Epub 2008 Mar 12. PMID:18337583 doi:10.1128/JVI.00002-08
- ↑ Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J Virol. 2010 Oct;84(20):10438-47. doi: 10.1128/JVI.00986-10. Epub 2010 Aug 4. PMID:20686019 doi:10.1128/JVI.00986-10
- ↑ Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005 Feb;79(3):1343-50. PMID:15650160 doi:10.1128/JVI.79.3.1343-1350.2005
- ↑ Laurent-Rolle M, Boer EF, Lubick KJ, Wolfinbarger JB, Carmody AB, Rockx B, Liu W, Ashour J, Shupert WL, Holbrook MR, Barrett AD, Mason PW, Bloom ME, Garcia-Sastre A, Khromykh AA, Best SM. The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. J Virol. 2010 Apr;84(7):3503-15. doi: 10.1128/JVI.01161-09. Epub 2010 Jan 27. PMID:20106931 doi:10.1128/JVI.01161-09
- ↑ Leung JY, Pijlman GP, Kondratieva N, Hyde J, Mackenzie JM, Khromykh AA. Role of nonstructural protein NS2A in flavivirus assembly. J Virol. 2008 May;82(10):4731-41. doi: 10.1128/JVI.00002-08. Epub 2008 Mar 12. PMID:18337583 doi:10.1128/JVI.00002-08
- ↑ Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J Virol. 2010 Oct;84(20):10438-47. doi: 10.1128/JVI.00986-10. Epub 2010 Aug 4. PMID:20686019 doi:10.1128/JVI.00986-10
- ↑ Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005 Feb;79(3):1343-50. PMID:15650160 doi:10.1128/JVI.79.3.1343-1350.2005
- ↑ Laurent-Rolle M, Boer EF, Lubick KJ, Wolfinbarger JB, Carmody AB, Rockx B, Liu W, Ashour J, Shupert WL, Holbrook MR, Barrett AD, Mason PW, Bloom ME, Garcia-Sastre A, Khromykh AA, Best SM. The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. J Virol. 2010 Apr;84(7):3503-15. doi: 10.1128/JVI.01161-09. Epub 2010 Jan 27. PMID:20106931 doi:10.1128/JVI.01161-09
- ↑ Leung JY, Pijlman GP, Kondratieva N, Hyde J, Mackenzie JM, Khromykh AA. Role of nonstructural protein NS2A in flavivirus assembly. J Virol. 2008 May;82(10):4731-41. doi: 10.1128/JVI.00002-08. Epub 2008 Mar 12. PMID:18337583 doi:10.1128/JVI.00002-08
- ↑ Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J Virol. 2010 Oct;84(20):10438-47. doi: 10.1128/JVI.00986-10. Epub 2010 Aug 4. PMID:20686019 doi:10.1128/JVI.00986-10
- ↑ Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005 Feb;79(3):1343-50. PMID:15650160 doi:10.1128/JVI.79.3.1343-1350.2005
- ↑ Laurent-Rolle M, Boer EF, Lubick KJ, Wolfinbarger JB, Carmody AB, Rockx B, Liu W, Ashour J, Shupert WL, Holbrook MR, Barrett AD, Mason PW, Bloom ME, Garcia-Sastre A, Khromykh AA, Best SM. The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. J Virol. 2010 Apr;84(7):3503-15. doi: 10.1128/JVI.01161-09. Epub 2010 Jan 27. PMID:20106931 doi:10.1128/JVI.01161-09
- ↑ Leung JY, Pijlman GP, Kondratieva N, Hyde J, Mackenzie JM, Khromykh AA. Role of nonstructural protein NS2A in flavivirus assembly. J Virol. 2008 May;82(10):4731-41. doi: 10.1128/JVI.00002-08. Epub 2008 Mar 12. PMID:18337583 doi:10.1128/JVI.00002-08
- ↑ Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J Virol. 2010 Oct;84(20):10438-47. doi: 10.1128/JVI.00986-10. Epub 2010 Aug 4. PMID:20686019 doi:10.1128/JVI.00986-10
- ↑ Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005 Feb;79(3):1343-50. PMID:15650160 doi:10.1128/JVI.79.3.1343-1350.2005
- ↑ Laurent-Rolle M, Boer EF, Lubick KJ, Wolfinbarger JB, Carmody AB, Rockx B, Liu W, Ashour J, Shupert WL, Holbrook MR, Barrett AD, Mason PW, Bloom ME, Garcia-Sastre A, Khromykh AA, Best SM. The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. J Virol. 2010 Apr;84(7):3503-15. doi: 10.1128/JVI.01161-09. Epub 2010 Jan 27. PMID:20106931 doi:10.1128/JVI.01161-09
- ↑ Leung JY, Pijlman GP, Kondratieva N, Hyde J, Mackenzie JM, Khromykh AA. Role of nonstructural protein NS2A in flavivirus assembly. J Virol. 2008 May;82(10):4731-41. doi: 10.1128/JVI.00002-08. Epub 2008 Mar 12. PMID:18337583 doi:10.1128/JVI.00002-08
- ↑ Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J Virol. 2010 Oct;84(20):10438-47. doi: 10.1128/JVI.00986-10. Epub 2010 Aug 4. PMID:20686019 doi:10.1128/JVI.00986-10
- ↑ Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005 Feb;79(3):1343-50. PMID:15650160 doi:10.1128/JVI.79.3.1343-1350.2005
- ↑ Laurent-Rolle M, Boer EF, Lubick KJ, Wolfinbarger JB, Carmody AB, Rockx B, Liu W, Ashour J, Shupert WL, Holbrook MR, Barrett AD, Mason PW, Bloom ME, Garcia-Sastre A, Khromykh AA, Best SM. The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. J Virol. 2010 Apr;84(7):3503-15. doi: 10.1128/JVI.01161-09. Epub 2010 Jan 27. PMID:20106931 doi:10.1128/JVI.01161-09
- ↑ Leung JY, Pijlman GP, Kondratieva N, Hyde J, Mackenzie JM, Khromykh AA. Role of nonstructural protein NS2A in flavivirus assembly. J Virol. 2008 May;82(10):4731-41. doi: 10.1128/JVI.00002-08. Epub 2008 Mar 12. PMID:18337583 doi:10.1128/JVI.00002-08
- ↑ Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J Virol. 2010 Oct;84(20):10438-47. doi: 10.1128/JVI.00986-10. Epub 2010 Aug 4. PMID:20686019 doi:10.1128/JVI.00986-10
- ↑ Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005 Feb;79(3):1343-50. PMID:15650160 doi:10.1128/JVI.79.3.1343-1350.2005
- ↑ Laurent-Rolle M, Boer EF, Lubick KJ, Wolfinbarger JB, Carmody AB, Rockx B, Liu W, Ashour J, Shupert WL, Holbrook MR, Barrett AD, Mason PW, Bloom ME, Garcia-Sastre A, Khromykh AA, Best SM. The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. J Virol. 2010 Apr;84(7):3503-15. doi: 10.1128/JVI.01161-09. Epub 2010 Jan 27. PMID:20106931 doi:10.1128/JVI.01161-09
- ↑ Mastrangelo E, Milani M, Bollati M, Selisko B, Peyrane F, Pandini V, Sorrentino G, Canard B, Konarev PV, Svergun DI, de Lamballerie X, Coutard B, Khromykh AA, Bolognesi M. Crystal structure and activity of Kunjin virus NS3 helicase; protease and helicase domain assembly in the full length NS3 protein. J Mol Biol. 2007 Sep 14;372(2):444-55. Epub 2007 Jun 27. PMID:17658551 doi:10.1016/j.jmb.2007.06.055
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