VE6_HPV16
ID VE6_HPV16 Reviewed; 158 AA.
AC P03126; Q71BI7;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 21-JUL-1986, sequence version 1.
DT 23-FEB-2022, entry version 156.
DE RecName: Full=Protein E6 {ECO:0000255|HAMAP-Rule:MF_04006};
GN Name=E6 {ECO:0000255|HAMAP-Rule:MF_04006};
OS Human papillomavirus type 16.
OC Viruses; Monodnaviria; Shotokuvirae; Cossaviricota; Papovaviricetes;
OC Zurhausenvirales; Papillomaviridae; Firstpapillomavirinae;
OC Alphapapillomavirus.
OX NCBI_TaxID=333760;
OH NCBI_TaxID=9606; Homo sapiens (Human).
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2990099; DOI=10.1016/0042-6822(85)90214-4;
RA Seedorf K., Krammer G., Durst M., Suhai S., Rowekamp W.G.;
RT "Human papillomavirus type 16 DNA sequence.";
RL Virology 145:181-185(1985).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=Isolate European German 131;
RA Terai M., Fu L., Ma Z., Burk R.D.;
RT "Cloning and sequencing of non-European human papillomavirus (HPV) variant
RT complete genomes from cervicovaginal cells by an overlapping PCR method.";
RL Submitted (AUG-2002) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 31-50.
RX PubMed=2157796; DOI=10.1099/0022-1317-71-4-809;
RA Schneider-Maunoury S., Pehau-Arnaudet G., Breitburd F., Orth G.;
RT "Expression of the human papillomavirus type 16 genome in SK-v cells, a
RT line derived from a vulvar intraepithelial neoplasia.";
RL J. Gen. Virol. 71:809-817(1990).
RN [4]
RP FUNCTION.
RX PubMed=8598912; DOI=10.1038/380079a0;
RA Klingelhutz A.J., Foster S.A., McDougall J.K.;
RT "Telomerase activation by the E6 gene product of human papillomavirus type
RT 16.";
RL Nature 380:79-82(1996).
RN [5]
RP FUNCTION, AND INTERACTION WITH HOST DLG1.
RX PubMed=9326658; DOI=10.1073/pnas.94.21.11612;
RA Kiyono T., Hiraiwa A., Fujita M., Hayashi Y., Akiyama T., Ishibashi M.;
RT "Binding of high-risk human papillomavirus E6 oncoproteins to the human
RT homologue of the Drosophila discs large tumor suppressor protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:11612-11616(1997).
RN [6]
RP FUNCTION, AND INTERACTION WITH HOST IRF3.
RX PubMed=9649509; DOI=10.1101/gad.12.13.2061;
RA Ronco L.V., Karpova A.Y., Vidal M., Howley P.M.;
RT "Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory
RT factor-3 and inhibits its transcriptional activity.";
RL Genes Dev. 12:2061-2072(1998).
RN [7]
RP FUNCTION.
RX PubMed=10523825; DOI=10.1038/sj.onc.1202920;
RA Gardiol D., Kuehne C., Glaunsinger B., Lee S.S., Javier R., Banks L.;
RT "Oncogenic human papillomavirus E6 proteins target the discs large tumour
RT suppressor for proteasome-mediated degradation.";
RL Oncogene 18:5487-5496(1999).
RN [8]
RP FUNCTION, AND INTERACTION WITH HOST TYK2.
RX PubMed=10523853; DOI=10.1038/sj.onc.1202960;
RA Li S., Labrecque S., Gauzzi M.C., Cuddihy A.R., Wong A.H., Pellegrini S.,
RA Matlashewski G.J., Koromilas A.E.;
RT "The human papilloma virus (HPV)-18 E6 oncoprotein physically associates
RT with Tyk2 and impairs Jak-STAT activation by interferon-alpha.";
RL Oncogene 18:5727-5737(1999).
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 NFX1.
RX PubMed=15371341; DOI=10.1101/gad.1214704;
RA Gewin L., Myers H., Kiyono T., Galloway D.A.;
RT "Identification of a novel telomerase repressor that interacts with the
RT human papillomavirus type-16 E6/E6-AP complex.";
RL Genes Dev. 18:2269-2282(2004).
RN [11]
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 [12]
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 [13]
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).
RN [14]
RP REVIEW.
RX PubMed=19081541; DOI=10.1016/s1937-6448(08)01202-1;
RA Kisseljov F., Sakharova O., Kondratjeva T.;
RT "Cellular and molecular biological aspects of cervical intraepithelial
RT neoplasia.";
RL Int. Rev. Cytol. 271:35-95(2008).
RN [15]
RP ROLE AS ANTIGEN IN HEAD AND NECK SQUAMOUS CELL CARCINOMA.
RX PubMed=33208941; DOI=10.1038/s41586-020-2931-3;
RA Wieland A., Patel M.R., Cardenas M.A., Eberhardt C.S., Hudson W.H.,
RA Obeng R.C., Griffith C.C., Wang X., Chen Z.G., Kissick H.T., Saba N.F.,
RA Ahmed R.;
RT "Defining HPV-specific B cell responses in patients with head and neck
RT cancer.";
RL Nature 597:274-278(2021).
RN [16]
RP ROLE AS ANTIGEN IN HEAD AND NECK SQUAMOUS CELL CARCINOMA.
RX PubMed=34471285; DOI=10.1038/s41586-021-03862-z;
RA Eberhardt C.S., Kissick H.T., Patel M.R., Cardenas M.A., Prokhnevska N.,
RA Obeng R.C., Nasti T.H., Griffith C.C., Im S.J., Wang X., Shin D.M.,
RA Carrington M., Chen Z.G., Sidney J., Sette A., Saba N.F., Wieland A.,
RA Ahmed R.;
RT "Functional HPV-specific PD-1+ stem-like CD8 T cells in head and neck
RT cancer.";
RL Nature 597:279-284(2021).
RN [17]
RP STRUCTURE BY NMR OF 87-158, DNA-BINDING, INTERACTION WITH HOST UBE3A, AND
RP SUBCELLULAR LOCATION.
RX PubMed=16507364; DOI=10.1016/j.molcel.2006.01.024;
RA Nomine Y., Masson M., Charbonnier S., Zanier K., Ristriani T.,
RA Deryckere F., Sibler A.P., Desplancq D., Atkinson R.A., Weiss E.,
RA Orfanoudakis G., Kieffer B., Trave G.;
RT "Structural and functional analysis of E6 oncoprotein: insights in the
RT molecular pathways of human papillomavirus-mediated pathogenesis.";
RL Mol. Cell 21:665-678(2006).
RN [18]
RP STRUCTURE BY NMR OF 148-157.
RX PubMed=21238461; DOI=10.1016/j.jmb.2011.01.015;
RA Charbonnier S., Nomine Y., Ramirez J., Luck K., Chapelle A., Stote R.H.,
RA Trave G., Kieffer B., Atkinson R.A.;
RT "The structural and dynamic response of MAGI-1 PDZ1 with noncanonical
RT domain boundaries to the binding of human papillomavirus E6.";
RL J. Mol. Biol. 406:745-763(2011).
RN [19]
RP STRUCTURE BY NMR OF 7-158, SUBUNIT, AND SUBCELLULAR LOCATION.
RX PubMed=22483108; DOI=10.1016/j.str.2012.02.001;
RA Zanier K., ould M'hamed ould Sidi A., Boulade-Ladame C., Rybin V.,
RA Chappelle A., Atkinson A., Kieffer B., Trave G.;
RT "Solution structure analysis of the HPV16 E6 oncoprotein reveals a self-
RT association mechanism required for E6-mediated degradation of p53.";
RL Structure 20:604-617(2012).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.55 ANGSTROMS) OF 9-150, AND INTERACTION WITH HOST
RP UBE3A/E6-AP.
RX PubMed=23393263; DOI=10.1126/science.1229934;
RA Zanier K., Charbonnier S., Sidi A.O., McEwen A.G., Ferrario M.G.,
RA Poussin-Courmontagne P., Cura V., Brimer N., Babah K.O., Ansari T.,
RA Muller I., Stote R.H., Cavarelli J., Vande Pol S., Trave G.;
RT "Structural basis for hijacking of cellular LxxLL motifs by papillomavirus
RT E6 oncoproteins.";
RL Science 339:694-698(2013).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 152-158.
RX PubMed=24210758; DOI=10.1016/j.str.2013.09.019;
RA Amacher J.F., Cushing P.R., Brooks L. III, Boisguerin P., Madden D.R.;
RT "Stereochemical preferences modulate affinity and selectivity among five
RT PDZ domains that bind CFTR: comparative structural and sequence analyses.";
RL Structure 22:82-93(2014).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 8-158, AND INTERACTION WITH HOST
RP TP53 AND UBE3A/E6-AP.
RX PubMed=26789255; DOI=10.1038/nature16481;
RA Martinez-Zapien D., Ruiz F.X., Poirson J., Mitschler A., Ramirez J.,
RA Forster A., Cousido-Siah A., Masson M., Vande Pol S., Podjarny A.,
RA Trave G., Zanier K.;
RT "Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation
RT of p53.";
RL Nature 529:541-545(2016).
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, ECO:0000269|PubMed:10523825,
CC ECO:0000269|PubMed:10523853, ECO:0000269|PubMed:8598912,
CC ECO:0000269|PubMed:9326658, ECO:0000269|PubMed:9649509}.
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:10523853, ECO:0000269|PubMed:12140759,
CC ECO:0000269|PubMed:12200142, ECO:0000269|PubMed:15371341,
CC ECO:0000269|PubMed:15378012, ECO:0000269|PubMed:15507623,
CC ECO:0000269|PubMed:16507364, ECO:0000269|PubMed:22483108,
CC ECO:0000269|PubMed:23393263, ECO:0000269|PubMed:26789255,
CC ECO:0000269|PubMed:9326658, ECO:0000269|PubMed:9649509}.
CC -!- INTERACTION:
CC P03126; P03126: E6; NbExp=2; IntAct=EBI-1177242, EBI-1177242;
CC P03126; Q12959: DLG1; Xeno; NbExp=3; IntAct=EBI-1177242, EBI-357481;
CC P03126; P52292: KPNA2; Xeno; NbExp=2; IntAct=EBI-1177242, EBI-349938;
CC P03126; Q96QZ7: MAGI1; Xeno; NbExp=2; IntAct=EBI-1177242, EBI-924464;
CC P03126; P33993: MCM7; Xeno; NbExp=2; IntAct=EBI-1177242, EBI-355924;
CC P03126; P49024: PXN; Xeno; NbExp=2; IntAct=EBI-1177242, EBI-2896280;
CC P03126; Q14257: RCN2; Xeno; NbExp=2; IntAct=EBI-1177242, EBI-356710;
CC P03126; Q14160: SCRIB; Xeno; NbExp=8; IntAct=EBI-1177242, EBI-357345;
CC P03126; O14907: TAX1BP3; Xeno; NbExp=2; IntAct=EBI-1177242, EBI-723259;
CC P03126; O14746: TERT; Xeno; NbExp=7; IntAct=EBI-1177242, EBI-1772203;
CC P03126; P04637: TP53; Xeno; NbExp=5; IntAct=EBI-1177242, EBI-366083;
CC P03126; O15350-1: TP73; Xeno; NbExp=2; IntAct=EBI-1177242, EBI-389619;
CC P03126; Q05086: UBE3A; Xeno; NbExp=10; IntAct=EBI-1177242, EBI-954357;
CC -!- SUBCELLULAR LOCATION: Host cytoplasm {ECO:0000255|HAMAP-Rule:MF_04006,
CC ECO:0000269|PubMed:16507364, ECO:0000269|PubMed:22483108}. Host nucleus
CC {ECO:0000255|HAMAP-Rule:MF_04006, ECO:0000269|PubMed:16507364,
CC ECO:0000269|PubMed:22483108}.
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 -!- MISCELLANEOUS: Part of the antigens expressed and presented within HPV-
CC positive head and neck tumors. {ECO:0000269|PubMed:33208941,
CC ECO:0000269|PubMed:34471285}.
CC -!- SIMILARITY: Belongs to the papillomaviridae E6 protein family.
CC {ECO:0000305}.
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DR EMBL; K02718; AAA46939.1; -; Genomic_DNA.
DR EMBL; AF536179; AAQ10712.1; -; Genomic_DNA.
DR EMBL; D00735; BAA00632.1; -; Genomic_DNA.
DR PIR; A03682; W6WLHS.
DR RefSeq; NP_041325.1; NC_001526.4.
DR PDB; 2FK4; NMR; -; A=87-158.
DR PDB; 2KPL; NMR; -; B=148-157.
DR PDB; 2LJX; NMR; -; A=7-89.
DR PDB; 2LJY; NMR; -; A/B=7-89.
DR PDB; 2LJZ; NMR; -; A=87-158.
DR PDB; 4GIZ; X-ray; 2.55 A; C/D=9-150.
DR PDB; 4JOP; X-ray; 1.80 A; C/D=152-158.
DR PDB; 4XR8; X-ray; 2.25 A; F/H=8-158.
DR PDB; 6HKS; X-ray; 2.19 A; G/H/I/J/K/L=148-158.
DR PDB; 6SIV; X-ray; 1.75 A; B=6-158.
DR PDB; 6SJA; X-ray; 1.50 A; B=7-158.
DR PDB; 6TWQ; X-ray; 2.65 A; C/D=149-158.
DR PDB; 6TWU; X-ray; 2.40 A; C=149-158.
DR PDB; 6TWX; X-ray; 2.30 A; C/D=149-158.
DR PDBsum; 2FK4; -.
DR PDBsum; 2KPL; -.
DR PDBsum; 2LJX; -.
DR PDBsum; 2LJY; -.
DR PDBsum; 2LJZ; -.
DR PDBsum; 4GIZ; -.
DR PDBsum; 4JOP; -.
DR PDBsum; 4XR8; -.
DR PDBsum; 6HKS; -.
DR PDBsum; 6SIV; -.
DR PDBsum; 6SJA; -.
DR PDBsum; 6TWQ; -.
DR PDBsum; 6TWU; -.
DR PDBsum; 6TWX; -.
DR BMRB; P03126; -.
DR SMR; P03126; -.
DR BioGRID; 4263557; 160.
DR DIP; DIP-44706N; -.
DR ELM; P03126; -.
DR IntAct; P03126; 42.
DR MINT; P03126; -.
DR BindingDB; P03126; -.
DR ChEMBL; CHEMBL2010633; -.
DR PRIDE; P03126; -.
DR ABCD; P03126; 1 sequenced antibody.
DR DNASU; 1489078; -.
DR GeneID; 1489078; -.
DR KEGG; vg:1489078; -.
DR EvolutionaryTrace; P03126; -.
DR PRO; PR:P03126; -.
DR Proteomes; UP000009251; Genome.
DR Proteomes; UP000106302; 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:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-UniRule.
DR GO; GO:0030165; F:PDZ domain binding; IPI:BHF-UCL.
DR GO; GO:0090630; P:activation of GTPase activity; 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:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:BHF-UCL.
DR GO; GO:0039653; P:suppression by virus of host transcription; IMP: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 DisProt; DP01615; -.
DR Gene3D; 3.30.240.40; -; 2.
DR HAMAP; MF_04006; HPV_E6; 1.
DR IDEAL; IID90005; -.
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_0000133336"
FT ZN_FING 37..73
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04006"
FT ZN_FING 110..146
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 CONFLICT 17
FT /note="R -> G (in Ref. 2; AAQ10712)"
FT /evidence="ECO:0000305"
FT CONFLICT 90
FT /note="L -> V (in Ref. 2; AAQ10712)"
FT /evidence="ECO:0000305"
FT TURN 12..14
FT /evidence="ECO:0007829|PDB:4GIZ"
FT HELIX 19..25
FT /evidence="ECO:0007829|PDB:6SJA"
FT TURN 30..32
FT /evidence="ECO:0007829|PDB:6SJA"
FT TURN 38..40
FT /evidence="ECO:0007829|PDB:6SJA"
FT HELIX 46..54
FT /evidence="ECO:0007829|PDB:6SJA"
FT STRAND 60..62
FT /evidence="ECO:0007829|PDB:6SJA"
FT STRAND 65..68
FT /evidence="ECO:0007829|PDB:6SJA"
FT HELIX 71..84
FT /evidence="ECO:0007829|PDB:6SJA"
FT STRAND 86..90
FT /evidence="ECO:0007829|PDB:6SJA"
FT HELIX 92..99
FT /evidence="ECO:0007829|PDB:6SJA"
FT HELIX 103..105
FT /evidence="ECO:0007829|PDB:6SJA"
FT STRAND 108..110
FT /evidence="ECO:0007829|PDB:4XR8"
FT TURN 111..113
FT /evidence="ECO:0007829|PDB:6SJA"
FT HELIX 119..127
FT /evidence="ECO:0007829|PDB:6SJA"
FT STRAND 132..135
FT /evidence="ECO:0007829|PDB:6SJA"
FT STRAND 138..141
FT /evidence="ECO:0007829|PDB:6SJA"
FT HELIX 145..147
FT /evidence="ECO:0007829|PDB:6SIV"
FT STRAND 155..158
FT /evidence="ECO:0007829|PDB:4JOP"
SQ SEQUENCE 158 AA; 19187 MW; 01FEF5ADCFDB37EB CRC64;
MHQKRTAMFQ DPQERPRKLP QLCTELQTTI HDIILECVYC KQQLLRREVY DFAFRDLCIV
YRDGNPYAVC DKCLKFYSKI SEYRHYCYSL YGTTLEQQYN KPLCDLLIRC INCQKPLCPE
EKQRHLDKKQ RFHNIRGRWT GRCMSCCRSS RTRRETQL
