VE6_HPV18
ID VE6_HPV18 Reviewed; 158 AA.
AC P06463;
DT 01-JAN-1988, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1988, sequence version 1.
DT 03-AUG-2022, entry version 135.
DE RecName: Full=Protein E6 {ECO:0000255|HAMAP-Rule:MF_04006};
GN Name=E6 {ECO:0000255|HAMAP-Rule:MF_04006};
OS Human papillomavirus type 18.
OC Viruses; Monodnaviria; Shotokuvirae; Cossaviricota; Papovaviricetes;
OC Zurhausenvirales; Papillomaviridae; Firstpapillomavirinae;
OC Alphapapillomavirus.
OX NCBI_TaxID=333761;
OH NCBI_TaxID=9606; Homo sapiens (Human).
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=3039146; DOI=10.1016/0022-2836(87)90343-3;
RA Cole S.T., Danos O.;
RT "Nucleotide sequence and comparative analysis of the human papillomavirus
RT type 18 genome. Phylogeny of papillomaviruses and repeated structure of the
RT E6 and E7 gene products.";
RL J. Mol. Biol. 193:599-608(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=3018129; DOI=10.1099/0022-1317-67-9-1909;
RA Matlashewski G., Banks L., Wu-Liao J., Spence P., Pim D., Crawford L.;
RT "The expression of human papillomavirus type 18 E6 protein in bacteria and
RT the production of anti-E6 antibodies.";
RL J. Gen. Virol. 67:1909-1916(1986).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2833614; DOI=10.1128/jvi.62.5.1640-1646.1988;
RA Inagaki Y., Tsunokawa Y., Takebe N., Nawa H., Nakanishi S., Terada M.,
RA Sugimura T.;
RT "Nucleotide sequences of cDNAs for human papillomavirus type 18 transcripts
RT in HeLa cells.";
RL J. Virol. 62:1640-1646(1988).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=3023067; DOI=10.1002/j.1460-2075.1986.tb04496.x;
RA Schneider-Gaedicke A., Schwarz E.;
RT "Different human cervical carcinoma cell lines show similar transcription
RT patterns of human papillomavirus type 18 early genes.";
RL EMBO J. 5:2285-2292(1986).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=3034571; DOI=10.1002/j.1460-2075.1987.tb04731.x;
RA Seedorf K., Oltersdorf T., Kraemer G., Roewekamp W.;
RT "Identification of early proteins of the human papilloma viruses type 16
RT (HPV 16) and type 18 (HPV 18) in cervical carcinoma cells.";
RL EMBO J. 6:139-144(1987).
RN [6]
RP ZINC-BINDING.
RX PubMed=2550872;
RA Grossman S.R., Laimins L.A.;
RT "E6 protein of human papillomavirus type 18 binds zinc.";
RL Oncogene 4:1089-1093(1989).
RN [7]
RP INTERACTION WITH HUMAN TP53 PROTEIN.
RX PubMed=8221889; DOI=10.1016/0092-8674(93)90384-3;
RA Scheffner M., Huibregtse J.M., Vierstra R.D., Howley P.M.;
RT "The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in
RT the ubiquitination of p53.";
RL Cell 75:495-505(1993).
RN [8]
RP INTERACTION WITH HUMAN MPDZ, AND MUTAGENESIS OF 156-THR--VAL-158 AND
RP VAL-158.
RX PubMed=11000240; DOI=10.1128/jvi.74.20.9680-9693.2000;
RA Lee S.S., Glaunsinger B., Mantovani F., Banks L., Javier R.T.;
RT "Multi-PDZ domain protein MUPP1 is a cellular target for both adenovirus
RT E4-ORF1 and high-risk papillomavirus type 18 E6 oncoproteins.";
RL J. Virol. 74:9680-9693(2000).
RN [9]
RP INTERACTION WITH HUMAN FBLN1, AND INHIBITION OF E6-MEDIATED TRANSFORMATION.
RX PubMed=12200142; DOI=10.1016/s0006-291x(02)02041-7;
RA Du M., Fan X., Hong E., Chen J.J.;
RT "Interaction of oncogenic papillomavirus E6 proteins with fibulin-1.";
RL Biochem. Biophys. Res. Commun. 296:962-969(2002).
RN [10]
RP INTERACTION WITH HUMAN MAGI3.
RX PubMed=12140759; DOI=10.1038/sj.onc.1205668;
RA Thomas M., Laura R., Hepner K., Guccione E., Sawyers C., Lasky L.,
RA Banks L.;
RT "Oncogenic human papillomavirus E6 proteins target the MAGI-2 and MAGI-3
RT proteins for degradation.";
RL Oncogene 21:5088-5096(2002).
RN [11]
RP INTERACTION WITH HUMAN MAGI3.
RX PubMed=15507623; DOI=10.1128/jvi.78.22.12366-12377.2004;
RA Lee C., Laimins L.A.;
RT "Role of the PDZ domain-binding motif of the oncoprotein E6 in the
RT pathogenesis of human papillomavirus type 31.";
RL J. Virol. 78:12366-12377(2004).
RN [12]
RP INTERACTION WITH HUMAN MAGI3.
RX PubMed=15378012; DOI=10.1038/sj.onc.1207977;
RA Massimi P., Gammoh N., Thomas M., Banks L.;
RT "HPV E6 specifically targets different cellular pools of its PDZ domain-
RT containing tumour suppressor substrates for proteasome-mediated
RT degradation.";
RL Oncogene 23:8033-8039(2004).
CC -!- FUNCTION: Plays a major role in the induction and maintenance of
CC cellular transformation. Acts mainly as an oncoprotein by stimulating
CC the destruction of many host cell key regulatory proteins. E6
CC associates with host UBE3A/E6-AP ubiquitin-protein ligase, and
CC inactivates tumor suppressors TP53 and TP73 by targeting them to the
CC 26S proteasome for degradation. In turn, DNA damage and chromosomal
CC instabilities increase and lead to cell proliferation and cancer
CC development. The complex E6/E6AP targets several other substrates to
CC degradation via the proteasome including host DLG1 or NFX1, a repressor
CC of human telomerase reverse transcriptase (hTERT). The resulting
CC increased expression of hTERT prevents the shortening of telomere
CC length leading to cell immortalization. Other cellular targets
CC including BAK1, Fas-associated death domain-containing protein (FADD)
CC and procaspase 8, are degraded by E6/E6AP causing inhibition of
CC apoptosis. E6 also inhibits immune response by interacting with host
CC IRF3 and TYK2. These interactions prevent IRF3 transcriptional
CC activities and inhibit TYK2-mediated JAK-STAT activation by interferon
CC alpha resulting in inhibition of the interferon signaling pathway.
CC {ECO:0000255|HAMAP-Rule:MF_04006}.
CC -!- SUBUNIT: Forms homodimers. Interacts with ubiquitin-protein ligase
CC UBE3A/E6-AP and thus forms a complex with human TP53. Interacts with
CC human NFX1 and MAGI3. Interacts with human IRF3; this interaction
CC inhibits the establishment of antiviral state. Interacts with human
CC TYK2; this interaction inhibits JAK-STAT activation by interferon
CC alpha. Interacts with host DLG1; this interaction leads to the
CC proteasomal degradation of DLG1. {ECO:0000255|HAMAP-Rule:MF_04006,
CC ECO:0000269|PubMed:11000240, ECO:0000269|PubMed:12140759,
CC ECO:0000269|PubMed:12200142, ECO:0000269|PubMed:15378012,
CC ECO:0000269|PubMed:15507623, ECO:0000269|PubMed:8221889}.
CC -!- INTERACTION:
CC P06463; Q12959: DLG1; Xeno; NbExp=4; IntAct=EBI-1186926, EBI-357481;
CC P06463; Q811D0: Dlg1; Xeno; NbExp=2; IntAct=EBI-1186926, EBI-514290;
CC P06463; Q96QZ7: MAGI1; Xeno; NbExp=4; IntAct=EBI-1186926, EBI-924464;
CC P06463; P33993: MCM7; Xeno; NbExp=2; IntAct=EBI-1186926, EBI-355924;
CC P06463; P26045: PTPN3; Xeno; NbExp=4; IntAct=EBI-1186926, EBI-1047946;
CC P06463; Q14160: SCRIB; Xeno; NbExp=4; IntAct=EBI-1186926, EBI-357345;
CC P06463; P04637: TP53; Xeno; NbExp=3; IntAct=EBI-1186926, EBI-366083;
CC P06463; Q05086: UBE3A; Xeno; NbExp=7; IntAct=EBI-1186926, EBI-954357;
CC -!- SUBCELLULAR LOCATION: Host cytoplasm {ECO:0000255|HAMAP-Rule:MF_04006}.
CC Host nucleus {ECO:0000255|HAMAP-Rule:MF_04006}.
CC -!- MISCELLANEOUS: Belongs to the high risk human alphapapillomavirus
CC family. The cancer-causing human papillomavirus E6 protein has a unique
CC carboxy terminal PDZ domain containing substrate. {ECO:0000255|HAMAP-
CC Rule:MF_04006}.
CC -!- SIMILARITY: Belongs to the papillomaviridae E6 protein family.
CC {ECO:0000305}.
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DR EMBL; X04354; CAA27879.1; -; Genomic_DNA.
DR EMBL; X05015; CAA28664.1; -; Genomic_DNA.
DR EMBL; M20325; AAA99514.1; -; mRNA.
DR EMBL; M26798; AAA46946.1; -; Genomic_DNA.
DR EMBL; X04773; CAA28466.1; -; Genomic_DNA.
DR PIR; A26165; W6WL18.
DR RefSeq; NP_040310.1; NC_001357.1.
DR PDB; 2I04; X-ray; 2.15 A; C/D=152-158.
DR PDB; 2I0I; X-ray; 2.80 A; D/E/F=152-158.
DR PDB; 2I0L; X-ray; 2.31 A; C/D=152-158.
DR PDB; 4JOR; X-ray; 1.34 A; C/D=149-158.
DR PDB; 5IC3; X-ray; 1.70 A; C/D=149-158.
DR PDB; 5K4F; X-ray; 1.36 A; C/D=149-158.
DR PDB; 6SJV; X-ray; 2.03 A; A=1-152.
DR PDB; 6ZFD; X-ray; 1.90 A; A/B=152-158.
DR PDB; 6ZFG; X-ray; 1.85 A; A/B=152-158.
DR PDBsum; 2I04; -.
DR PDBsum; 2I0I; -.
DR PDBsum; 2I0L; -.
DR PDBsum; 4JOR; -.
DR PDBsum; 5IC3; -.
DR PDBsum; 5K4F; -.
DR PDBsum; 6SJV; -.
DR PDBsum; 6ZFD; -.
DR PDBsum; 6ZFG; -.
DR SMR; P06463; -.
DR DIP; DIP-44730N; -.
DR ELM; P06463; -.
DR IntAct; P06463; 112.
DR MINT; P06463; -.
DR ChEMBL; CHEMBL4630868; -.
DR PRIDE; P06463; -.
DR DNASU; 1489088; -.
DR GeneID; 1489088; -.
DR KEGG; vg:1489088; -.
DR EvolutionaryTrace; P06463; -.
DR Proteomes; UP000009109; Genome.
DR GO; GO:0030430; C:host cell cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0042025; C:host cell nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-UniRule.
DR GO; GO:0030165; F:PDZ domain binding; IEA:UniProtKB-UniRule.
DR GO; GO:0008270; F:zinc ion binding; IDA:BHF-UCL.
DR GO; GO:0039526; P:modulation by virus of host apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0039649; P:modulation by virus of host ubiquitin-protein ligase activity; IEA:UniProtKB-UniRule.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:CACAO.
DR GO; GO:0039502; P:suppression by virus of host type I interferon-mediated signaling pathway; IEA:UniProtKB-UniRule.
DR GO; GO:0039548; P:suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity; IEA:UniProtKB-UniRule.
DR GO; GO:0006351; P:transcription, DNA-templated; IEA:UniProtKB-UniRule.
DR Gene3D; 3.30.240.40; -; 2.
DR HAMAP; MF_04006; HPV_E6; 1.
DR InterPro; IPR001334; E6.
DR InterPro; IPR038575; E6_sf.
DR Pfam; PF00518; E6; 1.
DR SUPFAM; SSF161229; SSF161229; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Activator; DNA-binding; Early protein; Host cytoplasm;
KW Host nucleus; Host-virus interaction;
KW Inhibition of host innate immune response by virus;
KW Inhibition of host IRF3 by virus; Inhibition of host RLR pathway by virus;
KW Metal-binding; Modulation of host cell apoptosis by virus; Oncogene;
KW Reference proteome; Transcription; Transcription regulation;
KW Viral immunoevasion; Zinc; Zinc-finger.
FT CHAIN 1..158
FT /note="Protein E6"
FT /id="PRO_0000133338"
FT ZN_FING 32..68
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04006"
FT ZN_FING 105..141
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04006"
FT MOTIF 156..158
FT /note="PDZ-binding domain"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04006"
FT MUTAGEN 156..158
FT /note="TQV->DQA: Complete loss of binding to MPDZ protein."
FT /evidence="ECO:0000269|PubMed:11000240"
FT MUTAGEN 158
FT /note="V->A: Complete loss of binding to MPDZ protein."
FT /evidence="ECO:0000269|PubMed:11000240"
FT CONFLICT 22
FT /note="N -> S (in Ref. 4; AAA46946)"
FT /evidence="ECO:0000305"
FT HELIX 3..5
FT /evidence="ECO:0007829|PDB:6SJV"
FT TURN 7..9
FT /evidence="ECO:0007829|PDB:6SJV"
FT HELIX 14..20
FT /evidence="ECO:0007829|PDB:6SJV"
FT TURN 25..27
FT /evidence="ECO:0007829|PDB:6SJV"
FT TURN 33..35
FT /evidence="ECO:0007829|PDB:6SJV"
FT HELIX 41..49
FT /evidence="ECO:0007829|PDB:6SJV"
FT STRAND 55..57
FT /evidence="ECO:0007829|PDB:6SJV"
FT STRAND 60..63
FT /evidence="ECO:0007829|PDB:6SJV"
FT HELIX 66..79
FT /evidence="ECO:0007829|PDB:6SJV"
FT STRAND 81..85
FT /evidence="ECO:0007829|PDB:6SJV"
FT HELIX 87..94
FT /evidence="ECO:0007829|PDB:6SJV"
FT TURN 98..100
FT /evidence="ECO:0007829|PDB:6SJV"
FT TURN 106..108
FT /evidence="ECO:0007829|PDB:6SJV"
FT HELIX 114..122
FT /evidence="ECO:0007829|PDB:6SJV"
FT STRAND 127..130
FT /evidence="ECO:0007829|PDB:6SJV"
FT STRAND 133..136
FT /evidence="ECO:0007829|PDB:6SJV"
FT HELIX 139..142
FT /evidence="ECO:0007829|PDB:6SJV"
FT STRAND 155..158
FT /evidence="ECO:0007829|PDB:4JOR"
SQ SEQUENCE 158 AA; 18872 MW; 5BCF13CF43D157FA CRC64;
MARFEDPTRR PYKLPDLCTE LNTSLQDIEI TCVYCKTVLE LTEVFEFAFK DLFVVYRDSI
PHAACHKCID FYSRIRELRH YSDSVYGDTL EKLTNTGLYN LLIRCLRCQK PLNPAEKLRH
LNEKRRFHNI AGHYRGQCHS CCNRARQERL QRRRETQV
