ID   VE4_HPV16               Reviewed;          92 AA.
AC   P06922;
DT   01-JAN-1988, integrated into UniProtKB/Swiss-Prot.
DT   18-JAN-2017, sequence version 2.
DT   02-JUN-2021, entry version 63.
DE   RecName: Full=Protein E4;
DE   AltName: Full=E1^E4;
GN   Name=E4;
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 3-92.
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   MOTIF.
RX   PubMed=7521917; DOI=10.1128/jvi.68.10.6432-6445.1994;
RA   Roberts S., Ashmole I., Gibson L.J., Rookes S.M., Barton G.J.,
RA   Gallimore P.H.;
RT   "Mutational analysis of human papillomavirus E4 proteins: identification of
RT   structural features important in the formation of cytoplasmic
RT   E4/cytokeratin networks in epithelial cells.";
RL   J. Virol. 68:6432-6445(1994).
RN   [5]
RP   FUNCTION, DOMAIN, AND MUTAGENESIS OF THR-23.
RX   PubMed=12208959; DOI=10.1128/jvi.76.19.9806-9818.2002;
RA   Davy C.E., Jackson D.J., Wang Q., Raj K., Masterson P.J., Fenner N.F.,
RA   Southern S., Cuthill S., Millar J.B., Doorbar J.;
RT   "Identification of a G(2) arrest domain in the E1 wedge E4 protein of human
RT   papillomavirus type 16.";
RL   J. Virol. 76:9806-9818(2002).
RN   [6]
RP   FUNCTION.
RX   PubMed=14694114; DOI=10.1128/jvi.78.2.821-833.2004;
RA   Wang Q., Griffin H., Southern S., Jackson D., Martin A., McIntosh P.,
RA   Davy C., Masterson P.J., Walker P.A., Laskey P., Omary M.B., Doorbar J.;
RT   "Functional analysis of the human papillomavirus type 16 E1=E4 protein
RT   provides a mechanism for in vivo and in vitro keratin filament
RT   reorganization.";
RL   J. Virol. 78:821-833(2004).
RN   [7]
RP   INTERACTION WITH HOST CDK1, AND FUNCTION.
RX   PubMed=15767402; DOI=10.1128/jvi.79.7.3998-4011.2005;
RA   Davy C.E., Jackson D.J., Raj K., Peh W.L., Southern S.A., Das P.,
RA   Sorathia R., Laskey P., Middleton K., Nakahara T., Wang Q., Masterson P.J.,
RA   Lambert P.F., Cuthill S., Millar J.B., Doorbar J.;
RT   "Human papillomavirus type 16 E1 E4-induced G2 arrest is associated with
RT   cytoplasmic retention of active Cdk1/cyclin B1 complexes.";
RL   J. Virol. 79:3998-4011(2005).
RN   [8]
RP   FUNCTION, PHOSPHORYLATION AT SER-32, AND SUBCELLULAR LOCATION.
RX   PubMed=16540140; DOI=10.1016/j.virol.2006.02.024;
RA   Davy C.E., Ayub M., Jackson D.J., Das P., McIntosh P., Doorbar J.;
RT   "HPV16 E1--E4 protein is phosphorylated by Cdk2/cyclin A and relocalizes
RT   this complex to the cytoplasm.";
RL   Virology 349:230-244(2006).
RN   [9]
RP   FUNCTION, INTERACTION WITH HOST SRPK1, AND SUBCELLULAR LOCATION.
RX   PubMed=17360743; DOI=10.1128/jvi.02609-06;
RA   Bell I., Martin A., Roberts S.;
RT   "The E1circumflexE4 protein of human papillomavirus interacts with the
RT   serine-arginine-specific protein kinase SRPK1.";
RL   J. Virol. 81:5437-5448(2007).
RN   [10]
RP   PHOSPHORYLATION AT THR-57, AND INTERACTION WITH HOST CYTOKERATIN.
RX   PubMed=19211765; DOI=10.1128/jvi.02063-08;
RA   Wang Q., Kennedy A., Das P., McIntosh P.B., Howell S.A., Isaacson E.R.,
RA   Hinz S.A., Davy C., Doorbar J.;
RT   "Phosphorylation of the human papillomavirus type 16 E1--E4 protein at T57
RT   by ERK triggers a structural change that enhances keratin binding and
RT   protein stability.";
RL   J. Virol. 83:3668-3683(2009).
RN   [11]
RP   FUNCTION, AND INTERACTION WITH HOST SRPK1.
RX   PubMed=25142587; DOI=10.1128/jvi.02029-14;
RA   Prescott E.L., Brimacombe C.L., Hartley M., Bell I., Graham S., Roberts S.;
RT   "Human papillomavirus type 1 E1^E4 protein is a potent inhibitor of the
RT   serine-arginine (SR) protein kinase SRPK1 and inhibits phosphorylation of
RT   host SR proteins and of the viral transcription and replication regulator
RT   E2.";
RL   J. Virol. 88:12599-12611(2014).
CC   -!- FUNCTION: Contributes to multiple aspects of the viral life cycle
CC       including viral genome amplification, suppression of suprabasal cell
CC       differentiation and egress of newly formed virions. Induces host cell
CC       cycle arrest at the G2 phase by associating with and preventing the
CC       nuclear entry of host CDK1/cyclin B1 complexes. Inhibits cellular DNA
CC       replication by preventing loading of host replication licensing
CC       proteins MCM2 and MCM7 onto chromatin. Within the cytoplasm, associates
CC       with host kinase SRPK1, a splicing factor regulator, and inhibits its
CC       activity. Therefore, E4 favors expression of late viral transcripts by
CC       inhibiting SRPK1-mediated phosphorylation of host serine-arginine (SR)
CC       proteins that have critical roles in mRNA metabolism. Late in the
CC       infectious cycle, E4 also acts to diminish the integrity of the
CC       keratinocyte by disrupting the keratin cytoskeleton and inducing
CC       apoptosis through alteration of mitochondrial function to facilitate
CC       egress of the newly formed virions. {ECO:0000269|PubMed:12208959,
CC       ECO:0000269|PubMed:14694114, ECO:0000269|PubMed:15767402,
CC       ECO:0000269|PubMed:17360743, ECO:0000269|PubMed:25142587}.
CC   -!- SUBUNIT: Assembles into oligomeric complexes. Interacts with host CDK1.
CC       Interacts with host SRPK1; this interaction may favor expression of
CC       late viral transcripts. Interacts with host cytokeratin components KRT8
CC       and KRT18. {ECO:0000269|PubMed:15767402, ECO:0000269|PubMed:17360743,
CC       ECO:0000269|PubMed:19211765, ECO:0000269|PubMed:25142587}.
CC   -!- SUBCELLULAR LOCATION: Host cytoplasm {ECO:0000269|PubMed:17360743}.
CC       Host nucleus {ECO:0000269|PubMed:17360743}.
CC   -!- INDUCTION: Expressed in the middle to upper layers of host infected
CC       epithelium.
CC   -!- DOMAIN: The LLXLL motif located in the N-terminal of the protein is
CC       responsible for the association with host cytokeratins.
CC       {ECO:0000269|PubMed:12208959}.
CC   -!- PTM: Phosphorylated by host ERK. The phosphorylation triggers a
CC       structural change that enhances keratin binding and protein stability.
CC       {ECO:0000269|PubMed:19211765}.
CC   -!- MISCELLANEOUS: The major E4 form is first synthesized as an E1^E4
CC       fusion protein from spliced E1^E4 transcripts, such that the first few
CC       amino acids of the E4 protein are derived from the N terminus of E1.
CC   -!- SIMILARITY: Belongs to the papillomaviridae E4 protein family.
CC       {ECO:0000305}.
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; K02718; AAA46937.1; ALT_SEQ; Genomic_DNA.
DR   EMBL; AF536179; AAQ10716.1; ALT_SEQ; Genomic_DNA.
DR   EMBL; D00735; BAA00634.1; ALT_SEQ; Genomic_DNA.
DR   PIR; A22355; W4WLHS.
DR   RefSeq; YP_009268708.1; NC_001526.4.
DR   iPTMnet; P06922; -.
DR   PRIDE; P06922; -.
DR   GeneID; 1489076; -.
DR   KEGG; vg:1489076; -.
DR   Proteomes; UP000009251; Genome.
DR   Proteomes; UP000106302; Genome.
DR   GO; GO:0030430; C:host cell cytoplasm; IDA:CACAO.
DR   GO; GO:0042025; C:host cell nucleus; IEA:UniProtKB-SubCell.
DR   GO; GO:0039592; P:suppression by virus of G2/M transition of host mitotic cell cycle; IEA:UniProtKB-KW.
DR   InterPro; IPR003861; Papilloma_E4.
DR   Pfam; PF02711; Pap_E4; 1.
PE   1: Evidence at protein level;
KW   Early protein; Host cytoplasm; Host G2/M cell cycle arrest by virus;
KW   Host nucleus; Host-virus interaction;
KW   Modulation of host cell cycle by virus; Phosphoprotein; Reference proteome.
FT   CHAIN           1..92
FT                   /note="Protein E4"
FT                   /id="PRO_0000133265"
FT   REGION          14..42
FT                   /note="Involved in cell cycle arrest"
FT   REGION          16..59
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           9..12
FT                   /note="Association with host cytokeratins"
FT   MOD_RES         32
FT                   /note="Phosphoserine; by host"
FT                   /evidence="ECO:0000269|PubMed:16540140"
FT   MOD_RES         57
FT                   /note="Phosphothreonine; by host"
FT                   /evidence="ECO:0000269|PubMed:19211765"
FT   MUTAGEN         23
FT                   /note="T->A: Loss of E4-mediated G(2) arrest."
FT                   /evidence="ECO:0000269|PubMed:12208959"
SQ   SEQUENCE   92 AA;  10075 MW;  BFF1A9F53AFF63A6 CRC64;
     MADPAAATKY PLLKLLGSTW PTTPPRPIPK PSPWAPKKHR RLSSDQDQSQ TPETPATPLS
     CCTETQWTVL QSSLHLTAHT KDGLTVIVTL HP