E1A_ADE12
ID E1A_ADE12 Reviewed; 266 AA.
AC P03259;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 21-JUL-1986, sequence version 1.
DT 23-FEB-2022, entry version 99.
DE RecName: Full=Early E1A protein;
DE AltName: Full=Early E1A 29.5 kDa protein;
OS Human adenovirus A serotype 12 (HAdV-12) (Human adenovirus 12).
OC Viruses; Varidnaviria; Bamfordvirae; Preplasmiviricota; Tectiliviricetes;
OC Rowavirales; Adenoviridae; Mastadenovirus; Human mastadenovirus A.
OX NCBI_TaxID=28282;
OH NCBI_TaxID=9606; Homo sapiens (Human).
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=6251973; DOI=10.1016/0092-8674(80)90324-4;
RA Sugisaki H., Sugimoto K., Takanami M., Shiroki K., Saito I., Shimojo H.,
RA Sawada Y., Uemizu Y., Uesugi S., Fujinaga K.;
RT "Structure and gene organization in the transformed Hind III-G fragment of
RT Ad12.";
RL Cell 20:777-786(1980).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=7432516; DOI=10.1038/288174a0;
RA Perricaudet M., le Moullec J.-M., Tiollais P., Pettersson U.;
RT "Structure of two adenovirus type 12 transforming polypeptides and their
RT evolutionary implications.";
RL Nature 288:174-176(1980).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=8254750; DOI=10.1128/jvi.68.1.379-389.1994;
RA Sprengel J., Schmitz B., Heuss-Neitzel D., Zock C., Doerfler W.;
RT "Nucleotide sequence of human adenovirus type 12 DNA: comparative
RT functional analysis.";
RL J. Virol. 68:379-389(1994).
RN [4]
RP INTERACTION WITH UBE2I.
RX PubMed=8824223; DOI=10.1074/jbc.271.42.25906;
RA Hateboer G., Hijmans E.M., Nooij J.B.D., Schlenker S., Jentsch S.,
RA Bernards R.;
RT "mUBC9, a novel adenovirus E1A-interacting protein that complements a yeast
RT cell cycle defect.";
RL J. Biol. Chem. 271:25906-25911(1996).
RN [5]
RP INTERACTION WITH HUMAN ZBED1.
RX PubMed=25210186; DOI=10.1128/jvi.02538-14;
RA Radko S., Koleva M., James K.M., Jung R., Mymryk J.S., Pelka P.;
RT "Adenovirus E1A targets the DREF nuclear factor to regulate virus gene
RT expression, DNA replication, and growth.";
RL J. Virol. 88:13469-13481(2014).
CC -!- FUNCTION: Plays a role in viral genome replication by driving entry of
CC quiescent cells into the cell cycle. Stimulation of progression from G1
CC to S phase allows the virus to efficiently use the cellular DNA
CC replicating machinery to achieve viral genome replication. E1A protein
CC has both transforming and trans-activating activities. Induces the
CC disassembly of the E2F1 transcription factor from RB1 by direct
CC competition for the same binding site on RB1, with subsequent
CC transcriptional activation of E2F1-regulated S-phase genes and of the
CC E2 region of the adenoviral genome. Release of E2F1 leads to the ARF-
CC mediated inhibition of MDM2 and causes TP53/p53 to accumulate because
CC it is not targeted for degradation by MDM2-mediated ubiquitination
CC anymore. This increase in TP53, in turn, would arrest the cell
CC proliferation and direct its death but this effect is counteracted by
CC the viral protein E1B-55K. Inactivation of the ability of RB1 to arrest
CC the cell cycle is critical for cellular transformation, uncontrolled
CC cellular growth and proliferation induced by viral infection.
CC Interaction with RBX1 and CUL1 inhibits ubiquitination of the proteins
CC targeted by SCF(FBXW7) ubiquitin ligase complex, and may be linked to
CC unregulated host cell proliferation. The tumorigenesis-restraining
CC activity of E1A may be related to the disruption of the host CtBP-CtIP
CC complex through the CtBP binding motif. Interaction with host
CC TMEM173/STING impairs the ability of TMEM173/STING to sense cytosolic
CC DNA and promote the production of type I interferon (IFN-alpha and IFN-
CC beta). Promotes the sumoylation of host ZBED1/hDREF with SUMO1 (By
CC similarity). {ECO:0000250|UniProtKB:P03255}.
CC -!- SUBUNIT: Interacts with host UBE2I; this interaction interferes with
CC polySUMOylation (PubMed:8824223). Interacts with host RB1; this
CC interaction induces the aberrant dissociation of RB1-E2F1 complex
CC thereby disrupting the activity of RB1 and activating E2F1-regulated
CC genes. Interacts with host ATF7; the interaction enhances ATF7-mediated
CC viral transactivation activity which requires the zinc binding domains
CC of both proteins. Isoform early E1A 32 kDa protein and isoform early
CC E1A 26 kDa protein interact (via N-terminus) with CUL1 and E3 ubiquitin
CC ligase RBX1; these interactions inhibit RBX1-CUL1-dependent elongation
CC reaction of ubiquitin chains and attenuate ubiquitination of SCF(FBXW7)
CC target proteins. Interacts (via PXLXP motif) with host ZMYND11/BS69
CC (via MYND-type zinc finger); this interaction inhibits E1A mediated
CC transactivation. Interacts with host EP300; this interaction stimulates
CC the acetylation of RB1 by recruiting EP300 and RB1 into a multimeric-
CC protein complex. Interacts with host CTBP1 and CTBP2; this interaction
CC seems to potentiate viral replication. Interacts with host DCAF7.
CC Interacts with host DYRK1A. Interacts with host KPNA4; this interaction
CC allows E1A import into the host nucleus. Interacts with host EP400;
CC this interaction stabilizes MYC. Interacts with host TBP protein; this
CC interaction probably disrupts the TBP-TATA complex. Interacts (via
CC LXCXE motif) with host TMEM173/STING; this interaction impairs the
CC ability of TMEM173/STING to sense cytosolic DNA and promote the
CC production of type I interferon (IFN-alpha and IFN-beta). Interacts
CC (via C-terminus) with host ZBED1/hDREF (via C-terminus); the
CC interaction is direct (PubMed:25210186). {ECO:0000250|UniProtKB:P03254,
CC ECO:0000250|UniProtKB:P03255, ECO:0000269|PubMed:25210186,
CC ECO:0000269|PubMed:8824223}.
CC -!- INTERACTION:
CC P03259; O08769: Cdkn1b; Xeno; NbExp=2; IntAct=EBI-6947456, EBI-7796656;
CC P03259; Q92793: CREBBP; Xeno; NbExp=5; IntAct=EBI-6947456, EBI-81215;
CC P03259; Q09472: EP300; Xeno; NbExp=3; IntAct=EBI-6947456, EBI-447295;
CC P03259; Q01860: POU5F1; Xeno; NbExp=2; IntAct=EBI-6947456, EBI-475687;
CC P03259; P25490: YY1; Xeno; NbExp=3; IntAct=EBI-6947456, EBI-765538;
CC P03259-2; P18846: ATF1; Xeno; NbExp=2; IntAct=EBI-7225021, EBI-852794;
CC P03259-2; P16220: CREB1; Xeno; NbExp=2; IntAct=EBI-7225021, EBI-711855;
CC P03259-2; Q92793: CREBBP; Xeno; NbExp=3; IntAct=EBI-7225021, EBI-81215;
CC P03259-2; P10644: PRKAR1A; Xeno; NbExp=5; IntAct=EBI-7225021, EBI-476431;
CC P03259-2; P13861: PRKAR2A; Xeno; NbExp=5; IntAct=EBI-7225021, EBI-2556122;
CC -!- SUBCELLULAR LOCATION: Host nucleus {ECO:0000250|UniProtKB:P03255}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=Early E1A 29.5 kDa protein;
CC IsoId=P03259-1; Sequence=Displayed;
CC Name=Early E1A 26 kDa protein;
CC IsoId=P03259-2; Sequence=VSP_000201;
CC Name=Early E1A 22 kDa protein;
CC IsoId=P03259-3; Sequence=VSP_000202, VSP_000204;
CC Name=Early E1A 6 kDa protein;
CC IsoId=P03259-4; Sequence=VSP_000200, VSP_000203;
CC -!- SIMILARITY: Belongs to the adenoviridae E1A protein family.
CC {ECO:0000305}.
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DR EMBL; V00004; CAA23400.1; -; Genomic_DNA.
DR EMBL; V00004; CAA23401.1; -; Genomic_DNA.
DR EMBL; V00004; CAA23402.1; -; Genomic_DNA.
DR EMBL; X73487; CAA51877.1; -; Genomic_DNA.
DR PIR; A03828; AQADG2.
DR RefSeq; NP_040910.2; NC_001460.1.
DR IntAct; P03259; 13.
DR MINT; P03259; -.
DR GeneID; 1460853; -.
DR KEGG; vg:1460853; -.
DR Proteomes; UP000004993; Genome.
DR GO; GO:0042025; C:host cell nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0039645; P:modulation by virus of host G1/S transition checkpoint; IEA:UniProtKB-KW.
DR GO; GO:0039648; P:modulation by virus of host protein ubiquitination; IEA:UniProtKB-KW.
DR GO; GO:0039649; P:modulation by virus of host ubiquitin-protein ligase activity; IEA:UniProtKB-KW.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; IEA:InterPro.
DR GO; GO:0039563; P:suppression by virus of host JAK-STAT cascade via inhibition of STAT1 activity; IEA:UniProtKB-KW.
DR GO; GO:0039644; P:suppression by virus of host NF-kappaB cascade; IEA:UniProtKB-KW.
DR GO; GO:0039502; P:suppression by virus of host type I interferon-mediated signaling pathway; IEA:UniProtKB-KW.
DR DisProt; DP01151; -.
DR InterPro; IPR014410; Aden_E1A.
DR Pfam; PF02703; Adeno_E1A; 2.
DR PIRSF; PIRSF003669; Aden_E1A; 1.
PE 1: Evidence at protein level;
KW Activator; Alternative splicing; Early protein;
KW G1/S host cell cycle checkpoint dysregulation by virus; Host nucleus;
KW Host-virus interaction; Inhibition of host innate immune response by virus;
KW Inhibition of host interferon signaling pathway by virus;
KW Inhibition of host NF-kappa-B by virus; Inhibition of host STAT1 by virus;
KW Metal-binding; Modulation of host cell cycle by virus;
KW Modulation of host E3 ubiquitin ligases by virus;
KW Modulation of host ubiquitin pathway by virus; Oncogene; Transcription;
KW Transcription regulation; Viral immunoevasion; Zinc; Zinc-finger.
FT CHAIN 1..266
FT /note="Early E1A protein"
FT /id="PRO_0000221696"
FT ZN_FING 159..179
FT /evidence="ECO:0000250|UniProtKB:P03254"
FT REGION 39..47
FT /note="Interaction with RB1 in competition with E2F1"
FT /evidence="ECO:0000250"
FT REGION 75..145
FT /note="Interaction with UBE2I"
FT /evidence="ECO:0000269|PubMed:8824223"
FT REGION 195..226
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 98..102
FT /note="PXLXP motif, interaction with host ZMYND11"
FT /evidence="ECO:0000250"
FT MOTIF 107..111
FT /note="LXCXE motif, interaction with host RB1 and
FT TMEM173/STING"
FT /evidence="ECO:0000255"
FT MOTIF 255..259
FT /note="PXDLS motif, CTBP-binding"
FT /evidence="ECO:0000250"
FT MOTIF 261..265
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000255"
FT VAR_SEQ 31..244
FT /note="Missing (in isoform Early E1A 6 kDa protein)"
FT /evidence="ECO:0000305"
FT /id="VSP_000200"
FT VAR_SEQ 160..190
FT /note="Missing (in isoform Early E1A 26 kDa protein)"
FT /evidence="ECO:0000305"
FT /id="VSP_000201"
FT VAR_SEQ 191..234
FT /note="Missing (in isoform Early E1A 22 kDa protein)"
FT /evidence="ECO:0000305"
FT /id="VSP_000202"
FT VAR_SEQ 245..266
FT /note="IQEEEREQTVPVDLSVKRPRCN -> FPIMSLNLIALWMAMSDPHPRN (in
FT isoform Early E1A 6 kDa protein)"
FT /evidence="ECO:0000305"
FT /id="VSP_000203"
FT VAR_SEQ 259..266
FT /note="SVKRPRCN -> KCAMGGGR (in isoform Early E1A 22 kDa
FT protein)"
FT /evidence="ECO:0000305"
FT /id="VSP_000204"
SQ SEQUENCE 266 AA; 29691 MW; A93A93A62D4541BE CRC64;
MRTEMTPLVL SYQEADDILE HLVDNFFNEV PSDDDLYVPS LYELYDLDVE SAGEDNNEQA
VNEFFPESLI LAASEGLFLP EPPVLSPVCE PIGGECMPQL HPEDMDLLCY EMGFPCSDSE
DEQDENGMAH VSASAAAAAA DREREEFQLD HPELPGHNCK SCEHHRNSTG NTDLMCSLCY
LRAYNMFIYS PVSDNEPEPN STLDGDERPS PPKLGSAVPE GVIKPVPQRV TGRRRCAVES
ILDLIQEEER EQTVPVDLSV KRPRCN
