ID   ICP4_HHV11              Reviewed;        1298 AA.
AC   P08392;
DT   01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
DT   01-AUG-1988, sequence version 1.
DT   24-JAN-2024, entry version 120.
DE   RecName: Full=Major viral transcription factor ICP4;
DE   AltName: Full=Alpha-4 protein;
DE   AltName: Full=Infected cell protein 4;
DE   AltName: Full=Transcriptional activator IE175;
GN   Name=ICP4; Synonyms=IE175; ORFNames=RS1;
OS   Human herpesvirus 1 (strain 17) (HHV-1) (Human herpes simplex virus 1).
OC   Viruses; Duplodnaviria; Heunggongvirae; Peploviricota; Herviviricetes;
OC   Herpesvirales; Orthoherpesviridae; Alphaherpesvirinae; Simplexvirus;
OC   Simplexvirus humanalpha1; Human herpesvirus 1.
OX   NCBI_TaxID=10299;
OH   NCBI_TaxID=9606; Homo sapiens (Human).
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=3005980; DOI=10.1093/nar/14.4.1727;
RA   McGeoch D.J., Dolan A., Donald S., Brauer D.H.K.;
RT   "Complete DNA sequence of the short repeat region in the genome of herpes
RT   simplex virus type 1.";
RL   Nucleic Acids Res. 14:1727-1745(1986).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=2839594; DOI=10.1099/0022-1317-69-7-1531;
RA   McGeoch D.J., Dalrymple M.A., Davison A.J., Dolan A., Frame M.C., McNab D.,
RA   Perry L.J., Scott J.E., Taylor P.;
RT   "The complete DNA sequence of the long unique region in the genome of
RT   herpes simplex virus type 1.";
RL   J. Gen. Virol. 69:1531-1574(1988).
RN   [3]
RP   HOMODIMERIZATION.
RX   PubMed=2991559; DOI=10.1128/jvi.55.2.329-337.1985;
RA   Metzler D.W., Wilcox K.W.;
RT   "Isolation of herpes simplex virus regulatory protein ICP4 as a homodimeric
RT   complex.";
RL   J. Virol. 55:329-337(1985).
RN   [4]
RP   DNA-BINDING DOMAIN.
RX   PubMed=2155403; DOI=10.1093/nar/18.3.531;
RA   Wu C.-L., Wilcox K.W.;
RT   "Codons 262 to 490 from the herpes simplex virus ICP4 gene are sufficient
RT   to encode a sequence-specific DNA binding protein.";
RL   Nucleic Acids Res. 18:531-538(1990).
RN   [5]
RP   FUNCTION, AND PHOSPHORYLATION.
RX   PubMed=1846804; DOI=10.1002/j.1460-2075.1991.tb07961.x;
RA   Papavassiliou A.G., Wilcox K.W., Silverstein S.J.;
RT   "The interaction of ICP4 with cell/infected-cell factors and its state of
RT   phosphorylation modulate differential recognition of leader sequences in
RT   herpes simplex virus DNA.";
RL   EMBO J. 10:397-406(1991).
RN   [6]
RP   FUNCTION, AND INTERACTION WITH HOST GTF2B.
RX   PubMed=8392607; DOI=10.1128/jvi.67.8.4676-4687.1993;
RA   Smith C.A., Bates P., Rivera-Gonzalez R., Gu B., DeLuca N.A.;
RT   "ICP4, the major transcriptional regulatory protein of herpes simplex virus
RT   type 1, forms a tripartite complex with TATA-binding protein and TFIIB.";
RL   J. Virol. 67:4676-4687(1993).
RN   [7]
RP   FUNCTION, AND INTERACTION WITH HOST TBP AND TAF1.
RX   PubMed=8649420; DOI=10.1128/mcb.16.6.3085;
RA   Carrozza M.J., DeLuca N.A.;
RT   "Interaction of the viral activator protein ICP4 with TFIID through
RT   TAF250.";
RL   Mol. Cell. Biol. 16:3085-3093(1996).
RN   [8]
RP   INTERACTION WITH ICP27.
RX   PubMed=8995681; DOI=10.1128/jvi.71.2.1547-1557.1997;
RA   Panagiotidis C.A., Lium E.K., Silverstein S.J.;
RT   "Physical and functional interactions between herpes simplex virus
RT   immediate-early proteins ICP4 and ICP27.";
RL   J. Virol. 71:1547-1557(1997).
RN   [9]
RP   SUBCELLULAR LOCATION.
RX   PubMed=17959681; DOI=10.1128/jvi.01588-07;
RA   Sedlackova L., Rice S.A.;
RT   "Herpes simplex virus type 1 immediate-early protein ICP27 is required for
RT   efficient incorporation of ICP0 and ICP4 into virions.";
RL   J. Virol. 82:268-277(2008).
RN   [10]
RP   FUNCTION.
RX   PubMed=18094162; DOI=10.1128/jvi.02459-07;
RA   Sampath P., Deluca N.A.;
RT   "Binding of ICP4, TATA-binding protein, and RNA polymerase II to herpes
RT   simplex virus type 1 immediate-early, early, and late promoters in virus-
RT   infected cells.";
RL   J. Virol. 82:2339-2349(2008).
RN   [11]
RP   FUNCTION.
RX   PubMed=18216093; DOI=10.1128/jvi.02560-07;
RA   Zabierowski S.E., Deluca N.A.;
RT   "Stabilized binding of TBP to the TATA box of herpes simplex virus type 1
RT   early (tk) and late (gC) promoters by TFIIA and ICP4.";
RL   J. Virol. 82:3546-3554(2008).
RN   [12]
RP   FUNCTION, AND DOMAIN.
RX   PubMed=22496239; DOI=10.1128/jvi.00651-12;
RA   Wagner L.M., Lester J.T., Sivrich F.L., DeLuca N.A.;
RT   "The N terminus and C terminus of herpes simplex virus 1 ICP4 cooperate to
RT   activate viral gene expression.";
RL   J. Virol. 86:6862-6874(2012).
RN   [13]
RP   FUNCTION.
RX   PubMed=23135715; DOI=10.1128/jvi.02844-12;
RA   Wagner L.M., Bayer A., Deluca N.A.;
RT   "Requirement of the N-terminal activation domain of herpes simplex virus
RT   ICP4 for viral gene expression.";
RL   J. Virol. 87:1010-1018(2013).
RN   [14]
RP   FUNCTION.
RX   PubMed=24147125; DOI=10.1371/journal.pone.0078242;
RA   Wagner L.M., DeLuca N.A.;
RT   "Temporal association of herpes simplex virus ICP4 with cellular complexes
RT   functioning at multiple steps in PolII transcription.";
RL   PLoS ONE 8:E78242-E78242(2013).
RN   [15]
RP   X-RAY CRYSTALLOGRAPHY (2.12 ANGSTROMS) OF 288-487, AND HOMODIMERIZATION.
RX   PubMed=28505309; DOI=10.1093/nar/gkx419;
RA   Tunnicliffe R.B., Lockhart-Cairns M.P., Levy C., Mould A.P., Jowitt T.A.,
RA   Sito H., Baldock C., Sandri-Goldin R.M., Golovanov A.P.;
RT   "The herpes viral transcription factor ICP4 forms a novel DNA recognition
RT   complex.";
RL   Nucleic Acids Res. 45:8064-8078(2017).
CC   -!- FUNCTION: Plays an essential role in the regulation of viral gene
CC       expression by both activating and repressing host RNA polymerase II-
CC       mediated transcription. Binds with high affinity to the sequence 5'-
CC       ATCGTC-3'. Activates transcription by recruiting a form of the host
CC       TFIID to promoters and stabilizing the pre-initiation complex
CC       formation. Negatively regulates its own transcription. This immediate
CC       early (IE) protein is absolutely necessary for the transition from IE
CC       transcription to later viral gene transcription.
CC       {ECO:0000269|PubMed:18094162, ECO:0000269|PubMed:18216093,
CC       ECO:0000269|PubMed:1846804, ECO:0000269|PubMed:22496239,
CC       ECO:0000269|PubMed:23135715, ECO:0000269|PubMed:24147125,
CC       ECO:0000269|PubMed:8649420}.
CC   -!- SUBUNIT: Forms homodimers (PubMed:2991559, PubMed:28505309). Interacts
CC       with transcriptional regulator ICP27; this interaction is required for
CC       proper incorporation of ICP4 into virions (PubMed:8995681). Interacts
CC       with host TBP and host TAF1; these interactions help the stabilization
CC       of the pre-nitiation complex on specific promoters (PubMed:8649420).
CC       Interacts with host GTF2B (PubMed:8392607).
CC       {ECO:0000269|PubMed:28505309, ECO:0000269|PubMed:2991559,
CC       ECO:0000269|PubMed:8392607, ECO:0000269|PubMed:8649420,
CC       ECO:0000269|PubMed:8995681}.
CC   -!- INTERACTION:
CC       P08392; P10238: UL54; NbExp=5; IntAct=EBI-7185388, EBI-6883946;
CC   -!- SUBCELLULAR LOCATION: Host nucleus {ECO:0000269|PubMed:17959681}. Host
CC       cytoplasm {ECO:0000269|PubMed:17959681}. Virion tegument
CC       {ECO:0000269|PubMed:17959681}. Note=Localizes to the cytoplasm when
CC       phosphorylated. {ECO:0000250}.
CC   -!- DOMAIN: The N-terminal and C-terminal domains are required for the
CC       transcriptional activation function of ICP4.
CC       {ECO:0000269|PubMed:22496239}.
CC   -!- PTM: ADP-ribosylated.
CC   -!- PTM: The long stretch of Ser is a major site of phosphorylation. Only
CC       the phosphorylated forms are capable of interacting with beta or gamma
CC       genes. {ECO:0000269|PubMed:1846804}.
CC   -!- SIMILARITY: Belongs to the herpesviridae ICP4 family. {ECO:0000305}.
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DR   EMBL; X14112; CAA32286.1; -; Genomic_DNA.
DR   EMBL; X14112; CAA32278.1; -; Genomic_DNA.
DR   EMBL; X06461; CAA29763.1; -; Genomic_DNA.
DR   EMBL; L00036; AAA96675.1; -; Genomic_DNA.
DR   EMBL; L00036; AAA96688.1; -; Genomic_DNA.
DR   PIR; A23510; EDBE75.
DR   PDB; 5MHJ; X-ray; 2.12 A; A/B=288-487.
DR   PDB; 5MHK; X-ray; 2.28 A; A/B/C/D=258-487, J=283-286.
DR   PDBsum; 5MHJ; -.
DR   PDBsum; 5MHK; -.
DR   BMRB; P08392; -.
DR   SASBDB; P08392; -.
DR   SMR; P08392; -.
DR   BioGRID; 971428; 1.
DR   BioGRID; 971429; 10.
DR   IntAct; P08392; 4.
DR   MINT; P08392; -.
DR   Proteomes; UP000009294; 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:0019033; C:viral tegument; IDA:CACAO.
DR   GO; GO:0003677; F:DNA binding; EXP:DisProt.
DR   GO; GO:0039695; P:DNA-templated viral transcription; ISS:UniProtKB.
DR   GO; GO:0045893; P:positive regulation of DNA-templated transcription; IEA:InterPro.
DR   GO; GO:0034340; P:response to type I interferon; IDA:BHF-UCL.
DR   DisProt; DP01305; -.
DR   InterPro; IPR005205; Herpes_ICP4_C.
DR   InterPro; IPR005206; Herpes_ICP4_N.
DR   Pfam; PF03585; Herpes_ICP4_C; 1.
DR   Pfam; PF03584; Herpes_ICP4_N; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Activator; ADP-ribosylation; DNA-binding; Early protein;
KW   Host cytoplasm; Host nucleus; Phosphoprotein; Reference proteome;
KW   Transcription; Transcription regulation; Virion; Virion tegument.
FT   CHAIN           1..1298
FT                   /note="Major viral transcription factor ICP4"
FT                   /id="PRO_0000115815"
FT   DNA_BIND        262..490
FT   REGION          1..82
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          94..291
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          534..554
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          594..620
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          718..826
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          877..904
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        45..67
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        127..148
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        175..197
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        230..248
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        597..620
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        762..783
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   HELIX           295..298
FT                   /evidence="ECO:0007829|PDB:5MHJ"
FT   HELIX           301..304
FT                   /evidence="ECO:0007829|PDB:5MHJ"
FT   STRAND          307..309
FT                   /evidence="ECO:0007829|PDB:5MHK"
FT   STRAND          326..328
FT                   /evidence="ECO:0007829|PDB:5MHJ"
FT   STRAND          335..337
FT                   /evidence="ECO:0007829|PDB:5MHJ"
FT   HELIX           343..355
FT                   /evidence="ECO:0007829|PDB:5MHJ"
FT   HELIX           364..366
FT                   /evidence="ECO:0007829|PDB:5MHJ"
FT   HELIX           369..379
FT                   /evidence="ECO:0007829|PDB:5MHJ"
FT   HELIX           387..392
FT                   /evidence="ECO:0007829|PDB:5MHJ"
FT   HELIX           398..411
FT                   /evidence="ECO:0007829|PDB:5MHJ"
FT   HELIX           432..438
FT                   /evidence="ECO:0007829|PDB:5MHJ"
FT   HELIX           441..443
FT                   /evidence="ECO:0007829|PDB:5MHJ"
FT   HELIX           444..454
FT                   /evidence="ECO:0007829|PDB:5MHJ"
FT   STRAND          456..458
FT                   /evidence="ECO:0007829|PDB:5MHJ"
FT   HELIX           460..484
FT                   /evidence="ECO:0007829|PDB:5MHJ"
SQ   SEQUENCE   1298 AA;  132844 MW;  4F32E04C95CA9344 CRC64;
     MASENKQRPG SPGPTDGPPP TPSPDRDERG ALGWGAETEE GGDDPDHDPD HPHDLDDARR
     DGRAPAAGTD AGEDAGDAVS PRQLALLASM VEEAVRTIPT PDPAASPPRT PAFRADDDDG
     DEYDDAADAA GDRAPARGRE REAPLRGAYP DPTDRLSPRP PAQPPRRRRH GRWRPSASST
     SSDSGSSSSS SASSSSSSSD EDEDDDGNDA ADHAREARAV GRGPSSAAPA APGRTPPPPG
     PPPLSEAAPK PRAAARTPAA SAGRIERRRA RAAVAGRDAT GRFTAGQPRR VELDADATSG
     AFYARYRDGY VSGEPWPGAG PPPPGRVLYG GLGDSRPGLW GAPEAEEARR RFEASGAPAA
     VWAPELGDAA QQYALITRLL YTPDAEAMGW LQNPRVVPGD VALDQACFRI SGAARNSSSF
     ITGSVARAVP HLGYAMAAGR FGWGLAHAAA AVAMSRRYDR AQKGFLLTSL RRAYAPLLAR
     ENAALTGAAG SPGAGADDEG VAAVAAAAPG ERAVPAGYGA AGILAALGRL SAAPASPAGG
     DDPDAARHAD ADDDAGRRAQ AGRVAVECLA ACRGILEALA EGFDGDLAAV PGLAGARPAS
     PPRPEGPAGP ASPPPPHADA PRLRAWLREL RFVRDALVLM RLRGDLRVAG GSEAAVAAVR
     AVSLVAGALG PALPRDPRLP SSAAAAAADL LFDNQSLRPL LAAAASAPDA ADALAAAAAS
     AAPREGRKRK SPGPARPPGG GGPRPPKTKK SGADAPGSDA RAPLPAPAPP STPPGPEPAP
     AQPAAPRAAA AQARPRPVAV SRRPAEGPDP LGGWRRQPPG PSHTAAPAAA ALEAYCSPRA
     VAELTDHPLF PVPWRPALMF DPRALASIAA RCAGPAPAAQ AACGGGDDDD NPHPHGAAGG
     RLFGPLRASG PLRRMAAWMR QIPDPEDVRV VVLYSPLPGE DLAGGGASGG PPEWSAERGG
     LSCLLAALAN RLCGPDTAAW AGNWTGAPDV SALGAQGVLL LSTRDLAFAG AVEFLGLLAS
     AGDRRLIVVN TVRACDWPAD GPAVSRQHAY LACELLPAVQ CAVRWPAARD LRRTVLASGR
     VFGPGVFARV EAAHARLYPD APPLRLCRGG NVRYRVRTRF GPDTPVPMSP REYRRAVLPA
     LDGRAAASGT TDAMAPGAPD FCEEEAHSHA ACARWGLGAP LRPVYVALGR EAVRAGPARW
     RGPRRDFCAR ALLEPDDDAP PLVLRGDDDG PGALPPAPPG IRWASATGRS GTVLAAAGAV
     EVLGAEAGLA TPPRREVVDW EGAWDEDDGG AFEGDGVL
//