Reviewed, UniProtKB/Swiss-Prot P33478 (POLG_DEN1S)

Names and origin

Protein names	Recommended name:     Genome polyprotein Cleaved into the following 14 chains:     1- Recommended name:             Protein C         Alternative name(s):             Core protein             Capsid protein     2- Recommended name:             prM     3- Recommended name:             Peptide pr     4- Recommended name:             Small envelope protein M         Alternative name(s):             Matrix protein     5- Recommended name:             Envelope protein E     6- Recommended name:             Non-structural protein 1                 Short name=NS1     7- Recommended name:             Non-structural protein 2A                 Short name=NS2A     8- Recommended name:             Non-structural protein 2A-alpha                 Short name=NS2A-alpha     9- Recommended name:             Serine protease subunit NS2B         Alternative name(s):             Non-structural protein 2B     10- Recommended name:             Serine protease subunit NS3               EC=3.4.21.91         Alternative name(s):             Non-structural protein 3     11- Recommended name:             Non-structural protein 4A                 Short name=NS4A     12- Recommended name:             Peptide 2k     13- Recommended name:             Non-structural protein 4B                 Short name=NS4B     14- Recommended name:             RNA-directed RNA polymerase NS5               EC=2.7.7.48               EC=2.1.1.56         Alternative name(s):             Non-structural protein 5
Organism	Dengue virus type 1 (strain Singapore/S275/1990) (DENV-1) [Complete proteome]
Taxonomic identifier	33741 [NCBI]
Taxonomic lineage	Viruses › ssRNA positive-strand viruses, no DNA stage › Flaviviridae › Flavivirus › Dengue virus group
Virus host	Aedes aegypti (Yellowfever mosquito) [TaxID: 7159] Homo sapiens (Human) [TaxID: 9606]

Protein attributes

Sequence length	3396 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Inferred from homology.

General annotation (Comments)

Function	Protein C packages viral RNA to form a viral nucleocapsid, and promotes virion budding By similarity. 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. Envelope protein E binds cell surface receptor and is involved in membrane fusion between virion and target cell. Synthesized as an 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. Non-structural protein 1 is slowly secreted from mammalian cells, but not from mosquito cells. Secreted form elicits protective immune response and plays an essential role in RNA replication. Soluble and membrane-associated NS1 may activate human complement and induce host vascular leakage. This effect might explain the clinical manifestations of dengue hemorrhagic fever and dengue shock syndrome By similarity. Non-structural protein 2B is a required cofactor for the serine protease function of NS3 By similarity. Serine protease NS3 displays three enzymatic activities: serine protease, NTPase and RNA helicase. NS3 serine protease, in association with NS2B, 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. Non-structural protein 4A plays a role in RNA replication. Enhances inhibition of cell antiviral response by non-structural protein 4B By similarity. Non-structural protein 4B prevent the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma signaling pathways By similarity. RNA-directed RNA polymerase NS5 replicates the viral (+) and (-) genome, and assure the capping of genomes in the cytoplasm. May be involved in methylation of 5'RNA cap structure By similarity.
Catalytic activity	Selective hydrolysis of -Xaa-Xaa-|-Yaa- bonds in which each of the Xaa can be either Arg or Lys and Yaa can be either Ser or Ala. Nucleoside triphosphate + RNA(n) = diphosphate + RNA(n+1). S-adenosyl-L-methionine + G(5')pppR-RNA = S-adenosyl-L-homocysteine + m(7)G(5')pppR-RNA.
Subunit structure	prM and envelope protein E form heterodimers in the endoplasmic reticulum and Golgi. Envelope protein E forms homodimers. NS1 forms homodimers as well as homohexamers when secreted. NS1 may interact with NS4A. NS3 and NS2B form an heterodimer. NS3 interacts with unphosphorylated NS5 By similarity.
Subcellular location	Protein C: VirionBy similarity. Peptide pr: SecretedBy similarity. Small envelope protein M: Virion membrane; Single-pass type I membrane proteinBy similarity. Envelope protein E: Virion membrane; Single-pass type I membrane proteinBy similarity. Non-structural protein 1: Secreted. Endoplasmic reticulum membrane; Peripheral membrane protein; Lumenal sideBy similarity. Non-structural protein 2A-alpha: Endoplasmic reticulum membraneBy similarity. Non-structural protein 2A: Endoplasmic reticulum membraneBy similarity. Serine protease subunit NS2B: Endoplasmic reticulum membrane; Peripheral membrane protein; Cytoplasmic sideBy similarity. Serine protease subunit NS3: Endoplasmic reticulum membrane; Peripheral membrane protein; Cytoplasmic sideBy similarity. Non-structural protein 4A: Endoplasmic reticulum membrane; Peripheral membrane protein; Cytoplasmic sideBy similarity. Non-structural protein 4B: Endoplasmic reticulum membrane; Multi-pass membrane proteinBy similarity. Note= The C-terminal transmembrane domain of non-structural protein 4B is presumably reoriented after cleavage on the lumenal side By similarity. RNA-directed RNA polymerase NS5: Endoplasmic reticulum membrane; Peripheral membrane protein; Cytoplasmic side. NucleusBy similarity.
Domain	Transmembrane domains of the small envelope protein M and envelope protein E contains an endoplasmic reticulum retention signals By similarity.
Post-translational modification	Specific enzymatic cleavages in vivo yield mature proteins. The nascent protein C contains a C-terminal hydrophobic domain that act as a signal sequence for translocation of prM into the lumen of the ER. Mature protein C is cleaved at a site upstream of this hydrophobic domain by NS3. prM is cleaved in post-Golgi vesicles by a host furin, releasing the mature small envelope protein M, and peptide pr. Non-structural protein 2A-alpha, a C-terminally truncated form of non-structural protein 2A, results from partial cleavage by NS3 By similarity. RNA-directed RNA polymerase NS5 is phosphorylated on serines residues. This phosphorylation may trigger NS5 nuclear localization By similarity. Envelope protein E and non-structural protein 1 are N-glycosylated By similarity.
Miscellaneous	The virion is assembled in the endoplasmic reticulum lumen, transported by vesicles to the Golgi, then transported again to the cell membrane where it is released outside the cell.
Sequence similarities	Contains 1 helicase ATP-binding domain. Contains 1 helicase C-terminal domain. Contains 1 peptidase S7 domain. Contains 1 RdRp catalytic domain.

Ontologies

Keywords
Biological process	RNA replication Transcription Transcription regulation
Cellular component	Capsid protein Endoplasmic reticulum Envelope protein Membrane Nucleus Secreted Virion
Domain	Transmembrane
Ligand	ATP-binding Metal-binding Nucleotide-binding RNA-binding Viral nucleoprotein
Molecular function	Helicase Hydrolase Nucleotidyltransferase Protease RNA-directed RNA polymerase Ribonucleoprotein Serine protease Transferase
PTM	Cleavage on pair of basic residues Glycoprotein Phosphoprotein
Technical term	Complete proteome Multifunctional enzyme
Gene Ontology (GO)
Biological process	regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW transcription, RNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW viral genome replication Inferred from electronic annotation. Source: InterPro
Cellular component	endoplasmic reticulum membrane Inferred from electronic annotation. Source: UniProtKB-SubCell extracellular region Inferred from electronic annotation. Source: UniProtKB-KW integral to membrane Inferred from electronic annotation. Source: InterPro nucleus Inferred from electronic annotation. Source: UniProtKB-KW ribonucleoprotein complex Inferred from electronic annotation. Source: UniProtKB-KW viral capsid Inferred from electronic annotation. Source: InterPro viral envelope Inferred from electronic annotation. Source: InterPro
Molecular function	ATP binding Inferred from electronic annotation. Source: InterPro ATP-dependent helicase activity Inferred from electronic annotation. Source: InterPro RNA helicase activity Inferred from electronic annotation. Source: InterPro RNA-directed RNA polymerase activity Inferred from electronic annotation. Source: InterPro double-stranded RNA binding Inferred from electronic annotation. Source: InterPro mRNA (guanine-N7-)-methyltransferase activity Inferred from electronic annotation. Source: EC metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW serine-type endopeptidase activity Inferred from electronic annotation. Source: InterPro structural molecule activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 100	100	Protein C		PRO_0000037894
	Propeptide	101 – 114	14	ER anchor for the protein C, removed in mature form by serine protease NS3		PRO_0000037895
	Chain	115 – 280	166	prM		PRO_0000264654
	Chain	115 – 205	91	Peptide pr		PRO_0000264655
	Chain	206 – 280	75	Small envelope protein M		PRO_0000037896
	Chain	281 – 774	494	Envelope protein E		PRO_0000037897
	Chain	775 – 1126	352	Non-structural protein 1		PRO_0000037898
	Chain	1127 – 1344	218	Non-structural protein 2A		PRO_0000037899
	Chain	1127 – 1315	189	Non-structural protein 2A-alpha		PRO_0000264656
	Chain	1345 – 1474	130	Serine protease subunit NS2B		PRO_0000037900
	Chain	1475 – 2093	619	Serine protease subunit NS3		PRO_0000037901
	Chain	2094 – 2220	127	Non-structural protein 4A		PRO_0000037902
	Peptide	2221 – 2243	23	Peptide 2k		PRO_0000264657
	Chain	2244 – 2492	249	Non-structural protein 4B		PRO_0000037903
	Chain	2493 – 3396	904	RNA-directed RNA polymerase NS5		PRO_0000037904
Regions
	Topological domain	1 – 101	101	Cytoplasmic Potential
	Transmembrane	102 – 122	21	Potential
	Topological domain	123 – 238	116	Extracellular Potential
	Transmembrane	239 – 259	21	Potential
	Topological domain	260 – 265	6	Cytoplasmic Potential
	Transmembrane	266 – 286	21	Potential
	Topological domain	287 – 724	438	Extracellular Potential
	Transmembrane	725 – 745	21	Potential
	Topological domain	746 – 751	6	Cytoplasmic Potential
	Transmembrane	752 – 772	21	Potential
	Topological domain	773 – 1155	383	Extracellular Potential
	Transmembrane	1156 – 1176	21	Potential
	Topological domain	1177 – 1446	270	Cytoplasmic Potential
	Transmembrane	1447 – 1467	21	Potential
	Topological domain	1468 – 2192	725	Lumenal Potential
	Transmembrane	2193 – 2213	21	Potential
	Topological domain	2214 – 2220	7	Cytoplasmic Potential
	Transmembrane	2221 – 2240	20	Potential
	Topological domain	2241 – 2348	108	Lumenal Potential
	Transmembrane	2349 – 2369	21	Potential
	Topological domain	2370 – 2414	45	Cytoplasmic Potential
	Transmembrane	2415 – 2435	21	Potential
	Topological domain	2436 – 2460	25	Lumenal Potential
	Transmembrane	2461 – 2481	21	Potential
	Topological domain	2482 – 3391	910	Cytoplasmic Potential
	Domain	1655 – 1811	157	Helicase ATP-binding
	Domain	1821 – 1988	168	Helicase C-terminal
	Domain	3019 – 3168	150	RdRp catalytic
	Nucleotide binding	1668 – 1675	8	ATP Potential
	Motif	1759 – 1762	4	DEAH box By similarity
Sites
	Active site	1525	1	Charge relay system; for serine protease NS3 activity By similarity
	Active site	1549	1	Charge relay system; for serine protease NS3 activity By similarity
	Active site	1609	1	Charge relay system; for serine protease NS3 activity By similarity
	Site	100 – 101	2	Cleavage; by serine protease NS3 By similarity
	Site	114 – 115	2	Cleavage; by host signal peptidase By similarity
	Site	205 – 206	2	Cleavage; by host furin By similarity
	Site	280 – 281	2	Cleavage; by host signal peptidase By similarity
	Site	774 – 775	2	Cleavage; by host signal peptidase By similarity
	Site	1126 – 1127	2	Cleavage; by host By similarity
	Site	1314 – 1315	2	Cleavage; by serine protease NS3 By similarity
	Site	1474 – 1475	2	Cleavage; by serine protease NS3 By similarity
	Site	2220 – 2221	2	Cleavage; by host signal peptidase By similarity
	Site	2243 – 2244	2	Cleavage; by serine protease NS3 By similarity
	Site	2492 – 2493	2	Cleavage; by serine protease NS3 By similarity
Amino acid modifications
	Glycosylation	183	1	N-linked (GlcNAc...) Potential
	Glycosylation	347	1	N-linked (GlcNAc...) Potential
	Glycosylation	433	1	N-linked (GlcNAc...) Potential
	Glycosylation	981	1	N-linked (GlcNAc...) Potential
	Glycosylation	2302	1	N-linked (GlcNAc...) Potential
	Glycosylation	2306	1	N-linked (GlcNAc...) Potential
	Glycosylation	2458