ID   VE4_HPV65               Reviewed;         127 AA.
AC   Q07873;
DT   01-OCT-1994, integrated into UniProtKB/Swiss-Prot.
DT   18-JAN-2017, sequence version 2.
DT   25-MAY-2022, entry version 42.
DE   RecName: Full=Protein E4;
GN   Name=E4;
OS   Human papillomavirus 65.
OC   Viruses; Monodnaviria; Shotokuvirae; Cossaviricota; Papovaviricetes;
OC   Zurhausenvirales; Papillomaviridae; Firstpapillomavirinae;
OC   Gammapapillomavirus.
OX   NCBI_TaxID=28312;
OH   NCBI_TaxID=9606; Homo sapiens (Human).
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=8389082; DOI=10.1006/viro.1993.1320;
RA   Egawa K., Delius H., Matsukura T., Kawashima M., de Villiers E.M.;
RT   "Two novel types of human papillomavirus, HPV 63 and HPV 65: comparisons of
RT   their clinical and histological features and DNA sequences to other HPV
RT   types.";
RL   Virology 194:789-799(1993).
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:0000250|UniProtKB:P06922}.
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:0000250|UniProtKB:P06922}.
CC   -!- SUBCELLULAR LOCATION: Host cytoplasm {ECO:0000250|UniProtKB:P06922}.
CC       Host nucleus {ECO:0000250|UniProtKB:P06922}.
CC   -!- PTM: Phosphorylated by host ERK. The phosphorylation triggers a
CC       structural change that enhances keratin binding and protein stability.
CC       {ECO:0000250|UniProtKB:P06922}.
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       {ECO:0000250|UniProtKB:P06922}.
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; X70829; CAA50175.1; ALT_SEQ; Genomic_DNA.
DR   SMR; Q07873; -.
DR   Proteomes; UP000007672; 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:0039592; P:suppression by virus of G2/M transition of host mitotic cell cycle; IEA:UniProtKB-KW.
PE   3: Inferred from homology;
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..127
FT                   /note="Protein E4"
FT                   /id="PRO_0000133281"
FT   REGION          1..93
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        1..20
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        53..78
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
SQ   SEQUENCE   127 AA;  14578 MW;  715664A7D4316CDF CRC64;
     MADKAQQTPP PSTLRNNNYP GPQHPPTPSL PRRALVVGGN RGNLNRPPQR PPKPRGYEYD
     EDDDKENQGP GQERPPAKEE EEEGEEEERP DWSLRHLLGK WESDIEQLKD KVCRDLDNYK
     LKLGIHP