♦Genome polyprotein [Cleaved into: Capsid protein C (Core protein)
♦ Protein prM
♦ Peptide pr
♦ Small envelope protein M (Matrix protein)
♦ Envelope protein E
♦ Non-structural protein 1 (NS1)
♦ Non-structural protein 2A (NS2A)
♦ Non-structural protein 2A-alpha (NS2A-alpha)
♦ Serine protease subunit NS2B (Flavivirin protease NS2B regulatory subunit) (Non-structural protein 2B)
♦ Serine protease NS3 (EC 3.4.21.91) (EC 3.6.1.15) (EC 3.6.4.13) (Flavivirin protease NS3 catalytic subunit) (Non-structural protein 3)
♦ Non-structural protein 4A (NS4A)
♦ Peptide 2k
♦ Non-structural protein 4B (NS4B)
♦ RNA-directed RNA polymerase NS5 (EC 2.1.1.56) (EC 2.1.1.57) (EC 2.7.7.48) (Non-structural protein 5)]

NC_002031.1 ;  X03700.1 

MSGRKAQGKTLGVNMVRRGVRSLSNKIKQKTKQIGNRPGPSRGVQGFIFFFLFNILTGKKITAHLKRLWKMLDPRQGLAVLRKVKRVVASLMRGLSSRKR
RSHDVLTVQFLILGMLLMTGGVTLVRKNRWLLLNVTSEDLGKTFSVGTGNCTTNILEAKYWCPDSMEYNCPNLSPREEPDDIDCWCYGVENVRVAYGKCD
SAGRSRRSRRAIDLPTHENHGLKTRQEKWMTGRMGERQLQKIERWFVRNPFFAVTALTIAYLVGSNMTQRVVIALLVLAVGPAYSAHCIGITDRDFIEGV
HGGTWVSATLEQDKCVTVMAPDKPSLDISLETVAIDRPAEVRKVCYNAVLTHVKINDKCPSTGEAHLAEENEGDNACKRTYSDRGWGNGCGLFGKGSIVA
CAKFTCAKSMSLFEVDQTKIQYVIRAQLHVGAKQENWNTDIKTLKFDALSGSQEVEFIGYGKATLECQVQTAVDFGNSYIAEMETESWIVDRQWAQDLTL
PWQSGSGGVWREMHHLVEFEPPHAATIRVLALGNQEGSLKTALTGAMRVTKDTNDNNLYKLHGGHVSCRVKLSALTLKGTSYKICTDKMFFVKNPTDTGH
GTVVMQVKVSKGAPCRIPVIVADDLTAAINKGILVTVNPIASTNDDEVLIEVNPPFGDSYIIVGRGDSRLTYQWHKEGSSIGKLFTQTMKGVERLAVMGD
TAWDFSSAGGFFTSVGKGIHTVFGSAFQGLFGGLNWITKVIMGAVLIWVGINTRNMTMSMSMILVGVIMMFLSLGVGADQGCAINFGKRELKCGDGIFIF
RDSDDWLNKYSYYPEDPVKLASIVKASFEEGKCGLNSVDSLEHEMWRSRADEINAIFEENEVDISVVVQDPKNVYQRGTHPFSRIRDGLQYGWKTWGKNL
VFSPGRKNGSFIIDGKSRKECPFSNRVWNSFQIEEFGTGVFTTRVYMDAVFEYTIDCDGSILGAAVNGKKSAHGSPTFWMGSHEVNGTWMIHTLEALDYK
ECEWPLTHTIGTSVEESEMFMPRSIGGPVSSHNHIPGYKVQTNGPWMQVPLEVKREACPGTSVIIDGNCDGRGKSTRSTTDSGKVIPEWCCRSCTMPPVS
FHGSDGCWYPMEIRPRKTHESHLVRSWVTAGEIHAVPFGLVSMMIAMEVVLRKRQGPKQMLVGGVVLLGAMLVGQVTLLDLLKLTVAVGLHFHEMNNGGD
AMYMALIAAFSIRPGLLIGFGLRTLWSPRERLVLTLGAAMVEIALGGVMGGLWKYLNAVSLCILTINAVASRKASNTILPLMALLTPVTMAEVRLAAMFF
CAVVIIGVLHQNFKDTSMQKTIPLVALTLTSYLGLTQPFLGLCAFLATRIFGRRSIPVNEALAAAGLVGVLAGLAFQEMENFLGPIAVGGLLMMLVSVAG
RVDGLELKKLGEVSWEEEAEISGSSARYDVALSEQGEFKLLSEEKVPWDQVVMTSLALVGAALHPFALLLVLAGWLFHVRGARRSGDVLWDIPTPKIIEE
CEHLEDGIYGIFQSTFLGASQRGVGVAQGGVFHTMWHVTRGAFLVRNGKKLIPSWASVKEDLVAYGGSWKLEGRWDGEEEVQLIAAVPGKNVVNVQTKPS
LFKVRNGGEIGAVALDYPSGTSGSPIVNRNGEVIGLYGNGILVGDNSFVSAISQTEVKEEGKEELQEIPTMLKKGMTTVLDFHPGAGKTRRFLPQILAEC
ARRRLRTLVLAPTRVVLSEMKEAFHGLDVKFHTQAFSAHGSGREVIDAMCHATLTYRMLEPTRVVNWEVIIMDEAHFLDPASIAARGWAAHRARANESAT
ILMTATPPGTSDEFPHSNGEIEDVQTDIPSEPWNTGHDWILADKRPTAWFLPSIRAANVMAASLRKAGKSVVVLNRKTFEREYPTIKQKKPDFILATDIA
EMGANLCVERVLDCRTAFKPVLVDEGRKVAIKGPLRISASSAAQRRGRIGRNPNRDGDSYYYSEPTSENNAHHVCWLEASMLLDNMEVRGGMVAPLYGVE
GTKTPVSPGEMRLRDDQRKVFRELVRNCDLPVWLSWQVAKAGLKTNDRKWCFEGPEEHEILNDSGETVKCRAPGGAKKPLRPRWCDERVSSDQSALSEFI
KFAEGRRGAAEVLVVLSELPDFLAKKGGEAMDTISVFLHSEEGSRAYRNALSMMPEAMTIVMLFILAGLLTSGMVIFFMSPKGISRMSMAMGTMAGCGYL
MFLGGVKPTHISYVMLIFFVLMVVVIPEPGQQRSIQDNQVAYLIIGILTLVSAVAANELGMLEKTKEDLFGKKNLIPSSASPWSWPDLDLKPGAAWTVYV
GIVTMLSPMLHHWIKVEYGNLSLSGIAQSASVLSFMDKGIPFMKMNISVIMLLVSGWNSITVMPLLCGIGCAMLHWSLILPGIKAQQSKLAQRRVFHGVA
ENPVVDGNPTVDIEEAPEMPALYEKKLALYLLLALSLASVAMCRTPFSLAEGIVLASAALGPLIEGNTSLLWNGPMAVSMTGVMRGNHYAFVGVMYNLWK
MKTGRRGSANGKTLGEVWKRELNLLDKRQFELYKRTDIVEVDRDTARRHLAEGKVDTGVAVSRGTAKLRWFHERGYVKLEGRVIDLGCGRGGWCYYAAAQ
KEVSGVKGFTLGRDGHEKPMNVQSLGWNIITFKDKTDIHRLEPVKCDTLLCDIGESSSSSVTEGERTVRVLDTVEKWLACGVDNFCVKVLAPYMPDVLEK
LELLQRRFGGTVIRNPLSRNSTHEMYYVSGARSNVTFTVNQTSRLLMRRMRRPTGKVTLEADVILPIGTRSVETDKGPLDKEAIEERVERIKSEYMTSWF
YDNDNPYRTWHYCGSYVTKTSGSAASMVNGVIKILTYPWDRIEEVTRMAMTDTTPFGQQRVFKEKVDTRAKDPPAGTRKIMKVVNRWLFRHLAREKNPRL
CTKEEFIAKVRSHAAIGAYLEEQEQWKTANEAVQDPKFWELVDEERKLHQQGRCRTCVYNMMGKREKKLSEFGKAKGSRAIWYMWLGARYLEFEALGFLN
EDHWASRENSGGGVEGIGLQYLGYVIRDLAAMDGGGFYADDTAGWDTRITEADLDDEQEILNYMSPHHKKLAQAVMEMTYKNKVVKVLRPAPGGKAYMDV
ISRRDQRGSGQVVTYALNTITNLKVQLIRMAEAEMVIHHQHVQDCDESVLTRLEAWLTEHGCDRLKRMAVSGDDCVVRPIDDRFGLALSHLNAMSKVRKD
ISEWQPSKGWNDWENVPFCSHHFHELQLKDGRRIVVPCREQDELIGRGRVSPGNGWMIKETACLSKAYANMWSLMYFHKRDMRLLSLAVSSAVPTSWVPQ
GRTTWSIHGKGEWMTTEDMLEVWNRVWITNNPHMQDKTMVKKWRDVPYLTKRQDKLCGSLIGMTNRATWASHIHLVIHRIRTLIGQEKYTDYLTVMDRYS
VDADLQLGELI

♦Capsid protein C: Plays a role in virus budding by binding to the cell membrane and gathering the viral RNA into a nucleocapsid that forms the core of a mature virus particle. During virus entry, may induce genome penetration into the host cytoplasm after hemifusion induced by the surface proteins. Can migrate to the cell nucleus where it modulates host functions.
♦ Capsid protein C: Inhibits RNA silencing by interfering with host Dicer.
♦ Peptide pr: Prevents premature fusion activity of envelope proteins in trans-Golgi by binding to envelope protein E at pH6.0. After virion release in extracellular space, gets dissociated from E dimers.
♦ Protein prM: Acts as a chaperone for envelope protein E during intracellular virion assembly by masking and inactivating envelope protein E fusion peptide. prM is the only viral peptide matured by host furin in the trans-Golgi network probably to avoid catastrophic activation of the viral fusion activity in acidic Golgi compartment prior to virion release. prM-E cleavage is inefficient, and many virions are only partially matured. These uncleaved prM would play a role in immune evasion.
♦ Small envelope protein M: May play a role in virus budding. Exerts cytotoxic effects by activating a mitochondrial apoptotic pathway through M ectodomain. May display a viroporin activity.
♦ Envelope protein E: Binds to host cell surface receptor and mediates fusion between viral and cellular membranes. Envelope protein is synthesized in the endoplasmic reticulum in the form of heterodimer with protein prM. They play a role in virion budding in the ER, and the newly formed immature particle is covered with 60 spikes composed of heterodimer between precursor prM and envelope protein E. The virion is transported to the Golgi apparatus where the low pH causes dissociation of PrM-E heterodimers and formation of E homodimers. prM-E cleavage is inefficient, and many virions are only partially matured. These uncleaved prM would play a role in immune evasion.
♦ Non-structural protein 1: Involved in immune evasion, pathogenesis and viral replication. Once cleaved off the polyprotein, is targeted to three destinations: the viral replication cycle, the plasma membrane and the extracellular compartment. Essential for viral replication. Required for formation of the replication complex and recruitment of other non-structural proteins to the ER-derived membrane structures. Excreted as a hexameric lipoparticle that plays a role against host immune response. Antagonizing the complement function. Binds to the host macrophages and dendritic cells. Inhibits signal transduction originating from Toll-like receptor 3 (TLR3).
♦ Non-structural protein 2A: Component of the viral RNA replication complex that functions in virion assembly and antagonizes the host immune response.
♦ Serine protease subunit NS2B: Required cofactor for the serine protease function of NS3. May have membrane-destabilizing activity and form viroporins (By similarity).
♦ 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. Also plays a role in virus assembly (PubMed:18199634).
♦ Non-structural protein 4A: Regulates the ATPase activity of the NS3 helicase activity. NS4A allows NS3 helicase to conserve energy during unwinding.
♦ Peptide 2k: Functions as a signal peptide for NS4B and is required for the interferon antagonism activity of the latter.
♦ Non-structural protein 4B: Induces the formation of ER-derived membrane vesicles where the viral replication takes place. 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 (PubMed:15956546).
♦ RNA-directed RNA polymerase NS5: Replicates the viral (+) and (-) RNA genome, and performs the capping of genomes in the cytoplasm (PubMed:19850911). NS5 methylates viral RNA cap at guanine N-7 and ribose 2'-O positions (PubMed:19850911). Besides its role in RNA genome replication, also prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) signaling pathway (PubMed:25211074). IFN-I induces binding of NS5 to host IFN-activated transcription factor STAT2, preventing its transcriptional activity. Host TRIM23 is the E3 ligase that interacts with and polyubiquitinates NS5 to promote its binding to STAT2 and trigger IFN-I signaling inhibition (PubMed:25211074).

♦ Capsid protein C: Virion . Host nucleus . Host cytoplasm, host perinuclear region . Host cytoplasm .
♦ Peptide pr: Secreted .
♦ Small envelope protein M: Virion membrane
♦ Multi-pass membrane protein . Host endoplasmic reticulum membrane
♦ Multi-pass membrane protein . Note=ER membrane retention is mediated by the transmembrane domains. .
♦ Envelope protein E: Virion membrane
♦ Multi-pass membrane protein . Host endoplasmic reticulum membrane
♦ Multi-pass membrane protein . Note=ER membrane retention is mediated by the transmembrane domains. .
♦ Non-structural protein 1: Secreted . Host endoplasmic reticulum membrane
♦ Peripheral membrane protein
♦ Lumenal side . Note=Located in RE-derived vesicles hosting the replication complex. Q6P4.
♦ Non-structural protein 2A: Host endoplasmic reticulum membrane
♦ Multi-pass membrane protein .
♦ Serine protease subunit NS2B: Host endoplasmic reticulum membrane
♦ Multi-pass membrane protein .
♦ Serine protease NS3: Host endoplasmic reticulum membrane PROSITE-ProRule:PRU00860
♦ Peripheral membrane protein PROSITE-ProRule:PRU00860
♦ Cytoplasmic side PROSITE-ProRule:PRU00860. Note=Remains non-covalently associated to serine protease subunit NS2B. PROSITE-ProRule:PRU00860.
♦ Non-structural protein 4A: Host endoplasmic reticulum membrane
♦ Multi-pass membrane protein . Note=Located in RE-associated vesicles hosting the replication complex. .
♦ Non-structural protein 4B: Host endoplasmic reticulum membrane
♦ Multi-pass membrane protein . Note=Located in RE-derived vesicles hosting the replication complex. Q6P4.
♦ RNA-directed RNA polymerase NS5: Host endoplasmic reticulum membrane
♦ Peripheral membrane protein
♦ Cytoplasmic side. Host nucleus . Note=Located in RE-associated vesicles hosting the replication complex. NS5 protein is mainly localized in the nucleus rather than in ER vesicles. .

♦DOMAIN 1485 1665 Peptidase S7.
♦ DOMAIN 1669 1825 Helicase ATP-binding.
♦ DOMAIN 1820 1997 Helicase C-terminal.
♦ DOMAIN 2507 2771 mRNA cap 0-1 NS5-type MT.
♦ DOMAIN 3035 3187 RdRp catalytic.

♦ACT_SITE 1537 1537 Charge relay system
♦ for serine protease NS3 activity.
♦ ACT_SITE 1561 1561 Charge relay system
♦ for serine protease NS3 activity.
♦ ACT_SITE 1622 1622 Charge relay system
♦ for serine protease NS3 activity.
♦ ACT_SITE 2567 2567 For 2'-O-MTase activity.
♦ ACT_SITE 2652 2652 For 2'-O-MTase activity.
♦ ACT_SITE 2688 2688 For 2'-O-MTase activity.
♦ ACT_SITE 2724 2724 For 2'-O-MTase activity.