P03126 (VE6_HPV16) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Protein E6

Gene names

Name:

E6

Organism

Human papillomavirus type 16 [Reference proteome]

Taxonomic identifier

333760 [NCBI]

Taxonomic lineage

Viruses › dsDNA viruses, no RNA stage › Papillomaviridae › Alphapapillomavirus › Alphapapillomavirus 9

Virus host

Homo sapiens (Human) [TaxID: 9606]

Protein attributes

Sequence length	158 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Plays a major role in the induction and maintenance of cellular transformation. Acts mainly as an oncoprotein by stimulating the destruction of many host cell key regulatory proteins. E6 associates with host E6-AP ubiquitin-protein ligase, and inactivates tumor suppressors TP53 and TP73 by targeting them to the 26S proteasome for degradation. In turn, DNA damage and chromosomal instabilities increase and lead to cell proliferation and cancer development. The complex E6/E6P targets several other substrates to degradation via the proteasome including host NFX1-91, a repressor of human telomerase reverse transcriptase (hTERT). The resulting increased expression of hTERT prevents the shortening of telomere length leading to cell immortalization. Other cellular targets including Bak, Fas-associated death domain-containing protein (FADD) and procaspase 8, are degraded by E6/E6AP causing inhibition of apoptosis. E6 also inhibits immune response by interacting with host IRF3 and TYK2. These interactions prevent IRF3 transcriptional activities and inhibit TYK2-mediated JAK-STAT activation by interferon alpha resulting in inhibition of the interferon signaling pathway. Ref.4 Ref.5 Ref.6
Subunit structure	Forms a complex E6-AP ubiquitin-protein ligase which interacts with human TP53. Binds to human FBLN1 and MPDZ By similarity. Interacts with human NFX1 and MAGI3. Interacts with human IRF3; this interaction inhibits the establishment of antiviral state. Interacts with human TYK2; this interaction inhibits JAK-STAT activation by interferon alpha. Ref.5 Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11
Subcellular location	Host nucleus matrix.
Miscellaneous	HPV16, in comparison to HPV types 6 and 11, is more often associated with malignant genital cancers in humans.
Sequence similarities	Belongs to the papillomaviridae E6 protein family.

Ontologies

Keywords
Biological process	Host-virus interaction Inhibition of host IFN-mediated response initiation by virus Inhibition of host IRF3 by virus Inhibition of host PKR by virus Inhibition of host innate immune response by virus Inhibition of host interferon signaling pathway by virus Modulation of host E3 ubiquitin ligases by virus Modulation of host ubiquitin pathway by virus Transcription Transcription regulation Viral immunoevasion
Cellular component	Host nucleus
Developmental stage	Early protein
Disease	Oncogene
Domain	Zinc-finger
Ligand	DNA-binding Metal-binding Zinc
Molecular function	Activator
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	activation of Cdc42 GTPase activity Inferred from direct assay PubMed 21139582. Source: BHF-UCL modulation by virus of host ubiquitin-protein ligase activity Inferred from electronic annotation. Source: UniProtKB-KW positive regulation of transcription from RNA polymerase II promoter Inferred from direct assay PubMed 21139582. Source: BHF-UCL suppression by virus of host IRF3 activity Inferred from electronic annotation. Source: UniProtKB-KW suppression by virus of host PKR activity Inferred from electronic annotation. Source: UniProtKB-KW suppression by virus of host type I interferon production Inferred from electronic annotation. Source: UniProtKB-KW suppression by virus of host type I interferon-mediated signaling pathway Inferred from electronic annotation. Source: UniProtKB-KW transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	host cell nuclear matrix Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	DNA binding Inferred from electronic annotation. Source: UniProtKB-KW metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
TP73	O15350-1	2	EBI-1177242,EBI-389619	From a different organism.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 158

158

Protein E6

PRO_0000133336

Regions

Zinc finger

37 – 73

37

Potential

Zinc finger

110 – 146

37

Potential

Motif

155 – 158

4

PDZ-binding By similarity

Experimental info

Sequence conflict

17

1

R → G in AAQ10712. Ref.2

Sequence conflict

90

1

L → V in AAQ10712. Ref.2

Secondary structure

1

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158

Helix Strand Turn

Details...

Turn

12 – 14

3

Helix

19 – 26

8

Turn

30 – 32

3

Turn

38 – 40

3

Helix

46 – 54

9

Beta strand

60 – 62

3

Beta strand

65 – 68

4

Helix

71 – 85

15

Beta strand

86 – 90

5

Helix

92 – 99

8

Helix

103 – 105

3

Beta strand

106 – 110

5

Turn

111 – 113

3

Helix

119 – 127

9

Beta strand

132 – 135

4

Beta strand

138 – 141

4

Helix

144 – 148

5

Beta strand

154 – 157

4

Sequences

	Sequence		Length	Mass (Da)
	P03126 [UniParc]. Last modified July 21, 1986. Version 1. Checksum: 01FEF5ADCFDB37EB	FASTA	158	19,187
	10 20 30 40 50 60 MHQKRTAMFQ DPQERPRKLP QLCTELQTTI HDIILECVYC KQQLLRREVY DFAFRDLCIV 70 80 90 100 110 120 YRDGNPYAVC DKCLKFYSKI SEYRHYCYSL YGTTLEQQYN KPLCDLLIRC INCQKPLCPE 130 140 150 EKQRHLDKKQ RFHNIRGRWT GRCMSCCRSS RTRRETQL

References

[1]	"Human papillomavirus type 16 DNA sequence." Seedorf K., Krammer G., Durst M., Suhai S., Rowekamp W.G. Virology 145:181-185(1985) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[2]	"Cloning and sequencing of non-European human papillomavirus (HPV) variant complete genomes from cervicovaginal cells by an overlapping PCR method." Terai M., Fu L., Ma Z., Burk R.D. Submitted (AUG-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Strain: Isolate European German 131.
[3]	"Expression of the human papillomavirus type 16 genome in SK-v cells, a line derived from a vulvar intraepithelial neoplasia." Schneider-Maunoury S., Pehau-Arnaudet G., Breitburd F., Orth G. J. Gen. Virol. 71:809-817(1990) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 31-50.
[4]	"Telomerase activation by the E6 gene product of human papillomavirus type 16." Klingelhutz A.J., Foster S.A., McDougall J.K. Nature 380:79-82(1996) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[5]	"Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity." Ronco L.V., Karpova A.Y., Vidal M., Howley P.M. Genes Dev. 12:2061-2072(1998) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH HOST IRF3.
[6]	"The human papilloma virus (HPV)-18 E6 oncoprotein physically associates with Tyk2 and impairs Jak-STAT activation by interferon-alpha." Li S., Labrecque S., Gauzzi M.C., Cuddihy A.R., Wong A.H., Pellegrini S., Matlashewski G.J., Koromilas A.E. Oncogene 18:5727-5737(1999) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH HOST TYK2.
[7]	"Interaction of oncogenic papillomavirus E6 proteins with fibulin-1." Du M., Fan X., Hong E., Chen J.J. Biochem. Biophys. Res. Commun. 296:962-969(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HUMAN FBLN1, INHIBITION OF E6-MEDIATED TRANSFORMATION.
[8]	"Identification of a novel telomerase repressor that interacts with the human papillomavirus type-16 E6/E6-AP complex." Gewin L., Myers H., Kiyono T., Galloway D.A. Genes Dev. 18:2269-2282(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HUMAN NFX1.
[9]	"Oncogenic human papillomavirus E6 proteins target the MAGI-2 and MAGI-3 proteins for degradation." Thomas M., Laura R., Hepner K., Guccione E., Sawyers C., Lasky L., Banks L. Oncogene 21:5088-5096(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HUMAN MAGI3.
[10]	"Role of the PDZ domain-binding motif of the oncoprotein E6 in the pathogenesis of human papillomavirus type 31." Lee C., Laimins L.A. J. Virol. 78:12366-12377(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HUMAN MAGI3.
[11]	"HPV E6 specifically targets different cellular pools of its PDZ domain-containing tumour suppressor substrates for proteasome-mediated degradation." Massimi P., Gammoh N., Thomas M., Banks L. Oncogene 23:8033-8039(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HUMAN MAGI3.
[12]	"Cellular and molecular biological aspects of cervical intraepithelial neoplasia." Kisseljov F., Sakharova O., Kondratjeva T. Int. Rev. Cytol. 271:35-95(2008) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

K02718 Genomic DNA. Translation: AAA46939.1.
AF536179 Genomic DNA. Translation: AAQ10712.1.
D00735 Genomic DNA. Translation: BAA00632.1.

PIR

W6WLHS. A03682.

RefSeq

NP_041325.1. NC_001526.2.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1VZN	model	-	A	1-158	[»]
2FK4	NMR	-	A	88-158	[»]
2KPL	NMR	-	B	148-157	[»]
2LJX	NMR	-	A	7-89	[»]
2LJY	NMR	-	A/B	7-89	[»]
2LJZ	NMR	-	A	88-158	[»]
4GIZ	X-ray	2.55	C/D	9-150	[»]

ProteinModelPortal

P03126.

SMR

P03126. Positions 88-151.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-44706N.

IntAct

P03126. 3 interactions.

MINT

MINT-96563.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

GeneID

1489078.

Family and domain databases

InterPro

IPR001334. E6.
[Graphical view]

Pfam

PF00518. E6. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

P03126.

Entry information

Entry name

VE6_HPV16

Accession

Primary (citable) accession number: P03126
Secondary accession number(s): Q71BI7

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 21, 1986
Last sequence update:	July 21, 1986
Last modified:	May 1, 2013
This is version 96 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Viral Protein Annotation Program