DENV-2 E

Dengue virus (DENV) in one of four serotypes is the cause of dengue fever. It is a mosquito-borne single positive-stranded RNA virus of the family Flaviviridae; genus Flavivirus. All four serotypes can cause the full spectrum of disease. Its genome is about 11000 bases that codes for three structural proteins, capsid protein C, membrane protein M, envelope protein E; seven nonstructural proteins, NS1, NS2a, NS2b, NS3, NS4a, NS4b, NS5; and short non-coding regions on both the 5 and 3 ends. Further classification of each serotype into genotypes often relates to the region where particular strains are commonly found or were first found.

DENV- 2 Envelope protein

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 (PubMed:23522008).

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 (PubMed:19272179).

Envelope protein is synthesized in the endoplasmic reticulum in the form of heterodimer with protein prM (By similarity).

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 (By similarity).

The virion is transported to the Golgi apparatus where the low pH causes dissociation of PrM-E heterodimers and formation of E homodimers (By similarity).

prM-E cleavage is inefficient, and many virions are only partially matured. These uncleaved prM would play a role in immune evasion (By similarity).

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. Antagonizing the complement function. Binds to the host macrophages and dendritic cells. Inhibits signal transduction originating from Toll-like receptor 3 (TLR3).

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 (By similarity).

Mediates complement activation, which may contribute to the pathogenesis of the vascular leakage that occurs in severe dengue disease (PubMed:16544248).

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. Interacts with host AUP1 which mediates induction of lipophagy in host cells and facilitates production of virus progeny particles (By similarity).

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 (By similarity).

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:15944325).

Inhibits host TYK2 and STAT2 phosphorylation, thereby preventing activation of JAK-STAT signaling pathway (PubMed:19754307).

May reduce immune responses by preventing the recruitment of the host PAF1 complex to interferon-responsive genes (PubMed:30550790).

Clathrin-dependent endocytosis of virus by host cell Source: UniProtKB-KW
Fusion of virus membrane with host endosome membrane Source: UniProtKB-KW
Induction by virus of host autophagy Source: UniProtKB
Pore formation by virus in membrane of host cell Source: UniProtKB-KW
Protein complex oligomerization Source: UniProtKB-KW
Suppression by virus of host MAVS activity Source: UniProtKB-KW
Suppression by virus of host STAT2 activity Source: UniProtKB-KW
Suppression by virus of host transcription Source: UniProtKB
Suppression by virus of host TYK2 activity Source: UniProtKB-KW
Suppression by virus of host type I interferon-mediated signaling pathway Source: UniProtKB-KW
Viral RNA genome replication Source: InterPro
Virion attachment to host cell Source: UniProtKB-KW

Capsid protein C: Virion; Host nucleus; Host cytoplasm; Host perinuclear region.
Peptide pr&Envelope protein E: Secreted
Small envelope protein M: Virion membrane; Host endoplasmic reticulum membrane
Non-structural protein 1: Secreted; Host endoplasmic reticulum membrane. Located in RE-derived vesicles hosting the replication complex.
Non-structural protein 2A&Serine protease subunit NS2B: Host endoplasmic reticulum membrane
Serine protease NS3: Host endoplasmic reticulum membrane; Host nucleus. Remains non-covalently associated to serine protease subunit NS2B.
Non-structural protein 4A: Host endoplasmic reticulum membrane; Host mitochondrion. 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. Located in RE-derived vesicles hosting the replication complex.
RNA-directed RNA polymerase NS5: Host endoplasmic reticulum membrane; Host nucleus. 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.

Cytoplasmic: 1-101
Helical: 102-119
Extracellular: 120-242
Helical: 243-260
Cytoplasmic: 261
Helical: 262-280
Extracellular: 281-725
Helical: 726-746
Cytoplasmic: 747-752
Helical: 753-773
Extracellular: 774-1195
Helical: 1196-1220
Cytoplasmic: 1221-1226
Helical: 1227-1245
Lumenal: 1246-1269
Helical: 1270-1290
Cytoplasmic: 1291
Helical: 1292-1310
Lumenal: 1311-1317
Helical: 1318-1338
Cytoplasmic: 1339-1346
Helical: 1347-1367
Lumenal: 1368-1370
Helical: 1371-1391
Cytoplasmic: 1392-1447
Helical: 1448-1468
Cytoplasmic: 1469-2147
Helical: 2148-2168
Lumenal: 2169-2170
Helical: 2171-2191
Lumenal: 2192
Helical: 2193-2213
Cytoplasmic: 2214-2228
Helical: 2229-2249
Lumenal: 2250-2274
Helical: 2275-2295
Lumenal: 2296-2316
Helical: 2317-2337
Lumenal: 2338-2347
Helical: 2348-2368
Cytoplasmic: 2369-2413
Helical: 2414-2434
Lumenal: 2435-2459
Helical: 2460-2480
Cytoplasmic: 2481-3391

Genome polyprotein:
Specific enzymatic cleavages in vivo yield mature proteins. Cleavages in the lumen of endoplasmic reticulum are performed by host signal peptidase, whereas cleavages in the cytoplasmic side are performed by serine protease NS3. Signal cleavage at the 2K-4B site requires a prior NS3 protease-mediated cleavage at the 4A-2K site.
Protein prM:
Cleaved in post-Golgi vesicles by a host furin, releasing the mature small envelope protein M, and peptide pr. This cleavage is incomplete as up to 30% of viral particles still carry uncleaved prM.
Envelope protein E:
N-glycosylated.
Non-structural protein 1:
N-glycosylated. The excreted form is glycosylated and this is required for efficient secretion of the protein from infected cells.
RNA-directed RNA polymerase NS5:
Sumoylation of RNA-directed RNA polymerase NS5 increases NS5 protein stability allowing proper viral RNA replication.
RNA-directed RNA polymerase NS5:
Phosphorylated on serines residues. This phosphorylation may trigger NS5 nuclear localization.