♦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)
♦ 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_001474.2 ;  U87411.1 

MNNQRKKARNTPFNMLKRERNRVSTVQQLTKRFSLGMLQGRGPLKLFMALVAFLRFLTIPPTAGILKRWGTIKKSKAINVLRGFRKEIGRMLNILNRRRR
TAGMIIMLIPTVMAFHLTTRNGEPHMIVSRQEKGKSLLFKTEDGVNMCTLMAMDLGELCEDTITYKCPFLKQNEPEDIDCWCNSTSTWVTYGTCTTTGEH
RREKRSVALVPHVGMGLETRTETWMSSEGAWKHAQRIETWILRHPGFTIMAAILAYTIGTTHFQRALIFILLTAVAPSMTMRCIGISNRDFVEGVSGGSW
VDIVLEHGSCVTTMAKNKPTLDFELIETEAKQPATLRKYCIEAKLTNTTTDSRCPTQGEPSLNEEQDKRFVCKHSMVDRGWGNGCGLFGKGGIVTCAMFT
CKKNMKGKVVQPENLEYTIVITPHSGEEHAVGNDTGKHGKEIKITPQSSITEAELTGYGTVTMECSPRTGLDFNEMVLLQMENKAWLVHRQWFLDLPLPW
LPGADTQGSNWIQKETLVTFKNPHAKKQDVVVLGSQEGAMHTALTGATEIQMSSGNLLFTGHLKCRLRMDKLQLKGMSYSMCTGKFKVVKEIAETQHGTI
VIRVQYEGDGSPCKIPFEIMDLEKRHVLGRLITVNPIVTEKDSPVNIEAEPPFGDSYIIIGVEPGQLKLNWFKKGSSIGQMIETTMRGAKRMAILGDTAW
DFGSLGGVFTSIGKALHQVFGAIYGAAFSGVSWIMKILIGVIITWIGMNSRSTSLSVSLVLVGVVTLYLGVMVQADSGCVVSWKNKELKCGSGIFITDNV
HTWTEQYKFQPESPSKLASAIQKAHEEGICGIRSVTRLENLMWKQITPELNHILSENEVKLTIMTGDIKGIMQAGKRSLQPQPTELKYSWKTWGKAKMLS
TESHNQTFLIDGPETAECPNTNRAWNSLEVEDYGFGVFTTNIWLKLREKQDVFCDSKLMSAAIKDNRAVHADMGYWIESALNDTWKIEKASFIEVKSCHW
PKSHTLWSNGVLESEMIIPKNFAGPVSQHNYRPGYHTQTAGPWHLGKLEMDFDFCEGTTVVVTEDCGNRGPSLRTTTASGKLITEWCCRSCTLPPLRYRG
EDGCWYGMEIRPLKEKEENLVNSLVTAGHGQIDNFSLGVLGMALFLEEMLRTRVGTKHAILLVAVSFVTLITGNMSFRDLGRVMVMVGATMTDDIGMGVT
YLALLAAFKVRPTFAAGLLLRKLTSKELMMTTIGIVLLSQSTIPETILELTDALALGMMVLKMVRKMEKYQLAVTIMAILCVPNAVILQNAWKVSCTILA
VVSVSPLFLTSSQQKADWIPLALTIKGLNPTAIFLTTLSRTNKKRSWPLNEAIMAVGMVSILASSLLKNDIPMTGPLVAGGLLTVCYVLTGRSADLELER
AADVKWEDQAEISGSSPILSITISEDGSMSIKNEEEEQTLTILIRTGLLVISGLFPVSIPITAAAWYLWEVKKQRAGVLWDVPSPPPVGKAELEDGAYRI
KQKGILGYSQIGAGVYKEGTFHTMWHVTRGAVLMHKGKRIEPSWADVKKDLISYGGGWKLEGEWKEGEEVQVLALEPGKNPRAVQTKPGLFKTNAGTIGA
VSLDFSPGTSGSPIIDKKGKVVGLYGNGVVTRSGAYVSAIAQTEKSIEDNPEIEDDIFRKRKLTIMDLHPGAGKTKRYLPAIVREAIKRGLRTLILAPTR
VVAAEMEEALRGLPIRYQTPAIRAEHTGREIVDLMCHATFTMRLLSPVRVPNYNLIIMDEAHFTDPASIAARGYISTRVEMGEAAGIFMTATPPGSRDPF
PQSNAPIMDEEREIPERSWSSGHEWVTDFKGKTVWFVPSIKAGNDIAACLRKNGKKVIQLSRKTFDSEYVKTRTNDWDFVVTTDISEMGANFKAERVIDP
RRCMKPVILTDGEERVILAGPMPVTHSSAAQRRGRIGRNPKNENDQYIYMGEPLENDEDCAHWKEAKMLLDNINTPEGIIPSMFEPEREKVDAIDGEYRL
RGEARKTFVDLMRRGDLPVWLAYRVAAEGINYADRRWCFDGIKNNQILEENVEVEIWTKEGERKKLKPRWLDAKIYSDPLALKEFKEFAAGRKSLTLNLI
TEMGRLPTFMTQKARDALDNLAVLHTAEAGGRAYNHALSELPETLETLLLLTLLATVTGGIFLFLMSGRGIGKMTLGMCCIITASILLWYAQIQPHWIAA
SIILEFFLIVLLIPEPEKQRTPQDNQLTYVVIAILTVVAATMANEMGFLEKTKKDLGLGSITTQQPESNILDIDLRPASAWTLYAVATTFVTPMLRHSIE
NSSVNVSLTAIANQATVLMGLGKGWPLSKMDIGVPLLAIGCYSQVNPITLTAALFLLVAHYAIIGPGLQAKATREAQKRAAAGIMKNPTVDGITVIDLDP
IPYDPKFEKQLGQVMLLVLCVTQVLMMRTTWALCEALTLATGPISTLWEGNPGRFWNTTIAVSMANIFRGSYLAGAGLLFSIMKNTTNTRRGTGNIGETL
GEKWKSRLNALGKSEFQIYKKSGIQEVDRTLAKEGIKRGETDHHAVSRGSAKLRWFVERNMVTPEGKVVDLGCGRGGWSYYCGGLKNVREVKGLTKGGPG
HEEPIPMSTYGWNLVRLQSGVDVFFTPPEKCDTLLCDIGESSPNPTVEAGRTLRVLNLVENWLNNNTQFCIKVLNPYMPSVIEKMEALQRKYGGALVRNP
LSRNSTHEMYWLSNASGNIVSSVNMISRMLINRFTMRHKKATYEPDVDLGSGTRNIGIESEIPNLDIIGKRIEKIKQEHETSWHYDQDHPYKTWAYHGSY
ETKQTGSASSMGNGVVRLLTKPWDVVPMVTQMAMTDTTPFGQQRVFKEKVDTRTQEPKEGTKKLMKITAEWLWKELGKKKTPRMCTREEFTRKVRSNAAL
GAIFTDENKWKSAREAVEDSRFWELVDKERNLHLEGKCETCVYNMMGKREKKLGEFGKAKGSRAIWYMWLGARFLEFEALGFLNEDHWFSRENSLSGVEG
EGLHKLGYILRDVSKKEGGAMYADDTAGWDTRITLEDLKNEEMVTNHMEGEHKKLAEAIFKLTYQNKVVRVQRPTPRGTVMDIISRRDQRGSGQVGTYGL
NTFTNMEAQLIRQMEGEGVFKSIQHLTVTEEIAVQNWLARVGRERLSRMAISGDDCVVKPLDDRFASALTALNDMGKVRKDIQQWEPSRGWNDWTQVPFC
SHHFHELIMKDGRVLVVPCRNQDELIGRARISQGAGWSLRETACLGKSYAQMWSLMYFHRRDLRLAANAICSAVPSHWVPTSRTTWSIHAKHEWMTTEDM
LTVWNRVWIQENPWMEDKTPVESWEEIPYLGKREDQWCGSLIGLTSRATWAKNIQTAINQVRSLIGNEEYTDYMPSMKRFRKEEEEAGVLW

♦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. Overcomes the anti-viral effects of host EXOC1 by sequestering and degrading the latter through the proteasome degradation pathway.
♦ 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 1: Disrupts the host endothelial glycocalyx layer of host pulmonary microvascular endothelial cells, inducing degradation of sialic acid and shedding of heparan sulfate proteoglycans. NS1 induces expression of sialidases, heparanase, and activates cathepsin L, which activates heparanase via enzymatic cleavage. These effects are probably linked to the endothelial hyperpermeability observed in severe dengue disease.
♦ 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.
♦ Non-structural protein 4A: Regulates the ATPase activity of the NS3 helicase activity. NS4A allows NS3 helicase to conserve energy during unwinding. Plays a role in the inhibition of the host innate immune response. Interacts with host MAVS and thereby prevents the interaction between DDX58 and MAVS. In turn, IFN-beta production is impaired.
♦ 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.
♦ RNA-directed RNA polymerase NS5: Replicates the viral (+) and (-) RNA 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 RNA genome replication, also prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) signaling pathway. Inhibits host TYK2 and STAT2 phosphorylation, thereby preventing activation of JAK-STAT signaling pathway.

♦ Capsid protein C: Virion . Host nucleus . Host cytoplasm . Host cytoplasm, host perinuclear region .
♦ Peptide pr: Secreted .
♦ Small envelope protein M: Virion membrane
♦ Multi-pass membrane protein . Host endoplasmic reticulum membrane
♦ Multi-pass membrane protein .
♦ Envelope protein E: Virion membrane
♦ Multi-pass membrane protein . Host endoplasmic reticulum membrane
♦ Multi-pass membrane protein .
♦ 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 . Host mitochondrion . Note=Located in RE-associated vesicles hosting the replication complex. Interacts with host MAVS in the mitochondrion-associated endoplasmic reticulum membranes. .
♦ 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, especially in the DENV 2, 3, 4 serotypes. .

♦DOMAIN 1476 1653 Peptidase S7.
♦ DOMAIN 1655 1811 Helicase ATP-binding.
♦ DOMAIN 1821 1988 Helicase C-terminal.
♦ DOMAIN 2493 2755 mRNA cap 0-1 NS5-type MT.
♦ DOMAIN 3019 3168 RdRp catalytic.

♦ACT_SITE 1526 1526 Charge relay system
♦ for serine protease NS3 activity.
♦ ACT_SITE 1550 1550 Charge relay system
♦ for serine protease NS3 activity.
♦ ACT_SITE 1610 1610 Charge relay system
♦ for serine protease NS3 activity.
♦ ACT_SITE 2552 2552 For 2'-O-MTase activity.
♦ ACT_SITE 2637 2637 For 2'-O-MTase activity.
♦ ACT_SITE 2672 2672 For 2'-O-MTase activity.
♦ ACT_SITE 2708 2708 For 2'-O-MTase activity.