E3_VACCW
ID E3_VACCW Reviewed; 190 AA.
AC P21605; Q76ZW2;
DT 01-MAY-1991, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1991, sequence version 1.
DT 03-AUG-2022, entry version 115.
DE RecName: Full=RNA-binding protein E3 {ECO:0000305};
DE AltName: Full=p25 {ECO:0000303|PubMed:8099244};
GN OrderedLocusNames=VACWR059; ORFNames=E3L {ECO:0000303|PubMed:2398897};
OS Vaccinia virus (strain Western Reserve) (VACV) (Vaccinia virus (strain
OS WR)).
OC Viruses; Varidnaviria; Bamfordvirae; Nucleocytoviricota; Pokkesviricetes;
OC Chitovirales; Poxviridae; Chordopoxvirinae; Orthopoxvirus; Vaccinia virus.
OX NCBI_TaxID=10254;
OH NCBI_TaxID=9913; Bos taurus (Bovine).
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2398897; DOI=10.1128/mcb.10.10.5433-5441.1990;
RA Ahn B.-Y., Gershon P.D., Jones E.V., Moss B.;
RT "Identification of rpo30, a vaccinia virus RNA polymerase gene with
RT structural similarity to a eucaryotic transcription elongation factor.";
RL Mol. Cell. Biol. 10:5433-5441(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Gershon P.D., Jones E.V., Moss B., Ahn B.-Y.;
RL Submitted (JUL-1990) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Esposito J.J., Frace A.M., Sammons S.A., Olsen-Rasmussen M., Osborne J.,
RA Wohlhueter R.;
RT "Sequencing of the coding region of Vaccinia-WR to an average 9-fold
RT redundancy and an error rate of 0.16/10kb.";
RL Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP PROTEIN SEQUENCE OF 59-68, AND IDENTIFICATION.
RX PubMed=1350676; DOI=10.1073/pnas.89.11.4825;
RA Chang H.-W., Watson J.C., Jacobs B.L.;
RT "The E3L gene of vaccinia virus encodes an inhibitor of the interferon-
RT induced, double-stranded RNA-dependent protein kinase.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:4825-4829(1992).
RN [5]
RP FUNCTION, AND DEVELOPMENTAL STAGE.
RX PubMed=1681618; DOI=10.1016/0042-6822(91)90768-7;
RA Watson J.C., Chang H.-W., Jacobs B.L.;
RT "Characterization of a vaccinia virus-encoded double-stranded RNA-binding
RT protein that may be involved in inhibition of the double-stranded RNA-
RT dependent protein kinase.";
RL Virology 185:206-216(1991).
RN [6]
RP RNA-BINDING, AND ALTERNATIVE INITIATION.
RX PubMed=8099244; DOI=10.1006/viro.1993.1292;
RA Chang H.-W., Jacobs B.L.;
RT "Identification of a conserved motif that is necessary for binding of the
RT vaccinia virus E3L gene products to double-stranded RNA.";
RL Virology 194:537-547(1993).
RN [7]
RP MUTAGENESIS OF TYR-48; PRO-63 AND PRO-64.
RX PubMed=12777633; DOI=10.1073/pnas.0431131100;
RA Kim Y.G., Muralinath M., Brandt T., Pearcy M., Hauns K., Lowenhaupt K.,
RA Jacobs B.L., Rich A.;
RT "A role for Z-DNA binding in vaccinia virus pathogenesis.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:6974-6979(2003).
RN [8]
RP CAUTION.
RX PubMed=14757814; DOI=10.1073/pnas.0308260100;
RA Kim Y.G., Lowenhaupt K., Oh D.B., Kim K.K., Rich A.;
RT "Evidence that vaccinia virulence factor E3L binds to Z-DNA in vivo:
RT Implications for development of a therapy for poxvirus infection.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:1514-1518(2004).
RN [9]
RP MUTAGENESIS OF 1-MET--MET-38.
RX PubMed=15721360; DOI=10.1016/j.virol.2005.01.006;
RA Brandt T., Heck M.C., Vijaysri S., Jentarra G.M., Cameron J.M.,
RA Jacobs B.L.;
RT "The N-terminal domain of the vaccinia virus E3L-protein is required for
RT neurovirulence, but not induction of a protective immune response.";
RL Virology 333:263-270(2005).
RN [10]
RP FUNCTION.
RX PubMed=18604270; DOI=10.1371/journal.ppat.1000096;
RA Guerra S., Caceres A., Knobeloch K.P., Horak I., Esteban M.;
RT "Vaccinia virus E3 protein prevents the antiviral action of ISG15.";
RL PLoS Pathog. 4:E1000096-E1000096(2008).
RN [11]
RP FUNCTION.
RX PubMed=22419806; DOI=10.1128/jvi.06889-11;
RA White S.D., Jacobs B.L.;
RT "The amino terminus of the vaccinia virus E3 protein is necessary to
RT inhibit the interferon response.";
RL J. Virol. 86:5895-5904(2012).
RN [12]
RP FUNCTION, AND INTERACTION WITH HOST ISG15.
RX PubMed=24257616; DOI=10.1128/jvi.03293-13;
RA Eduardo-Correia B., Martinez-Romero C., Garcia-Sastre A., Guerra S.;
RT "ISG15 is counteracted by vaccinia virus E3 protein and controls the
RT proinflammatory response against viral infection.";
RL J. Virol. 88:2312-2318(2014).
RN [13]
RP FUNCTION, AND INTERACTION WITH HOST EIF2AK2.
RX PubMed=25740987; DOI=10.1128/jvi.03288-14;
RA Dueck K.J., Hu Y.S., Chen P., Deschambault Y., Lee J., Varga J., Cao J.;
RT "Mutational analysis of vaccinia virus E3 protein: the biological functions
RT do not correlate with its biochemical capacity to bind double-stranded
RT RNA.";
RL J. Virol. 89:5382-5394(2015).
RN [14]
RP INTERACTION WITH HOST ZBP1.
RX PubMed=29073079; DOI=10.1073/pnas.1700999114;
RA Koehler H., Cotsmire S., Langland J., Kibler K.V., Kalman D., Upton J.W.,
RA Mocarski E.S., Jacobs B.L.;
RT "Inhibition of DAI-dependent necroptosis by the Z-DNA binding domain of the
RT vaccinia virus innate immune evasion protein, E3.";
RL Proc. Natl. Acad. Sci. U.S.A. 114:11506-11511(2017).
RN [15]
RP FUNCTION, RNA-BINDING, AND MUTAGENESIS OF GLU-42; TYR-48 AND PRO-63.
RX PubMed=34192517; DOI=10.1016/j.chom.2021.05.009;
RA Koehler H., Cotsmire S., Zhang T., Balachandran S., Upton J.W.,
RA Langland J., Kalman D., Jacobs B.L., Mocarski E.S.;
RT "Vaccinia virus E3 prevents sensing of Z-RNA to block ZBP1-dependent
RT necroptosis.";
RL Cell Host Microbe 29:1266-1276(2021).
CC -!- FUNCTION: RNA-binding protein that plays a role in the inhibition of
CC multiple cellular antiviral responses activated by double-stranded RNA
CC (dsRNA), such as inhibition of PKR activation, necroptosis, and IFN-
CC mediated antiviral activities (PubMed:1681618, PubMed:18604270,
CC PubMed:24257616, PubMed:25740987). Recognizes and binds Z-RNA
CC structures via its Z-binding domain and dsRNA via its DRBM domain: RNA-
CC binding activity is required to escape host ZBP1-dependent necroptosis
CC (PubMed:29073079, PubMed:34192517). Mechanistically, the Z-binding
CC domain binds Z-RNAs that are produced during vaccinia virus infection,
CC thereby competing with Z-RNA detection by host ZBP1, suppressing ZBP1-
CC dependent necroptosis (PubMed:34192517). Acts as a key inhibitor of the
CC interferon response by blocking the phosphorylation and subsequent
CC activation of IRF3 and IRF7 kinases that are required for interferon-
CC alpha gene expression (PubMed:22419806). Inhibits NF-kappa-B activation
CC and the ubiquitin-like protein ISG15, which is an early antiviral
CC protein (PubMed:18604270, PubMed:24257616). The binding with host ISG15
CC subsequently blocks host ISGylation (PubMed:18604270, PubMed:24257616).
CC {ECO:0000269|PubMed:1681618, ECO:0000269|PubMed:18604270,
CC ECO:0000269|PubMed:22419806, ECO:0000269|PubMed:24257616,
CC ECO:0000269|PubMed:25740987, ECO:0000269|PubMed:29073079,
CC ECO:0000269|PubMed:34192517}.
CC -!- SUBUNIT: Interacts with host G1P2/ISG15 (PubMed:24257616). Interacts
CC with host EIF2AK2/PKR (PubMed:25740987). Interacts with host ZBP1
CC (PubMed:29073079). {ECO:0000269|PubMed:24257616,
CC ECO:0000269|PubMed:25740987, ECO:0000269|PubMed:29073079}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative initiation; Named isoforms=2;
CC Name=Long {ECO:0000303|PubMed:8099244};
CC IsoId=P21605-1; Sequence=Displayed;
CC Name=Short {ECO:0000303|PubMed:8099244};
CC IsoId=P21605-2; Sequence=VSP_018957;
CC -!- DEVELOPMENTAL STAGE: Detected at early times, by 2 hours post
CC infection, peaks at 5 hours post infection, and decreases during the
CC late phase of virus replication. {ECO:0000269|PubMed:1681618}.
CC -!- DOMAIN: The Z-binding domain recognizes and binds Z-RNA structures.
CC {ECO:0000269|PubMed:34192517}.
CC -!- SIMILARITY: Belongs to the poxviridae E3 protein family. {ECO:0000305}.
CC -!- CAUTION: Was reported to bind Z-DNA structures (PubMed:12777633,
CC PubMed:14757814). However, it probably binds Z-RNA in vivo
CC (PubMed:34192517). {ECO:0000269|PubMed:12777633,
CC ECO:0000269|PubMed:14757814, ECO:0000269|PubMed:34192517}.
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DR EMBL; M36339; AAB59823.1; -; Genomic_DNA.
DR EMBL; AY243312; AAO89338.1; -; Genomic_DNA.
DR PIR; B35928; B35928.
DR RefSeq; YP_232941.1; NC_006998.1.
DR PDB; 7C0I; X-ray; 2.40 A; A/B/C=2-40, A/B/C=56-78.
DR PDBsum; 7C0I; -.
DR SMR; P21605; -.
DR DIP; DIP-2175N; -.
DR IntAct; P21605; 45.
DR MINT; P21605; -.
DR DNASU; 3707592; -.
DR GeneID; 3707592; -.
DR KEGG; vg:3707592; -.
DR Proteomes; UP000000344; Genome.
DR GO; GO:0003726; F:double-stranded RNA adenosine deaminase activity; IEA:InterPro.
DR GO; GO:0003725; F:double-stranded RNA binding; IDA:UniProtKB.
DR GO; GO:0030291; F:protein serine/threonine kinase inhibitor activity; IEA:UniProtKB-KW.
DR GO; GO:0019050; P:suppression by virus of host apoptotic process; IDA:UniProtKB.
DR GO; GO:0039579; P:suppression by virus of host ISG15-protein conjugation; IDA:UniProtKB.
DR GO; GO:0039580; P:suppression by virus of host PKR signaling; IDA:UniProtKB.
DR GO; GO:0039501; P:suppression by virus of host type I interferon production; IDA:UniProtKB.
DR GO; GO:0039502; P:suppression by virus of host type I interferon-mediated signaling pathway; IDA:UniProtKB.
DR GO; GO:0039548; P:suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity; IEA:UniProtKB-KW.
DR GO; GO:0039557; P:suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF7 activity; IEA:UniProtKB-KW.
DR Gene3D; 1.10.10.10; -; 1.
DR InterPro; IPR014720; dsRBD_dom.
DR InterPro; IPR009179; E3L.
DR InterPro; IPR036388; WH-like_DNA-bd_sf.
DR InterPro; IPR036390; WH_DNA-bd_sf.
DR InterPro; IPR042371; Z_dom.
DR Pfam; PF00035; dsrm; 1.
DR Pfam; PF02295; z-alpha; 1.
DR PIRSF; PIRSF004008; VAC_E3L; 1.
DR SMART; SM00358; DSRM; 1.
DR SMART; SM00550; Zalpha; 1.
DR SUPFAM; SSF46785; SSF46785; 1.
DR PROSITE; PS50137; DS_RBD; 1.
DR PROSITE; PS50139; Z_BINDING; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative initiation; Direct protein sequencing;
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 IRF3 by virus; Inhibition of host IRF7 by virus;
KW Inhibition of host ISG15 by virus; Inhibition of host PKR by virus;
KW Inhibition of host RLR pathway by virus;
KW Modulation of host cell apoptosis by virus; Reference proteome;
KW RNA-binding; Viral immunoevasion.
FT CHAIN 1..190
FT /note="RNA-binding protein E3"
FT /id="PRO_0000099448"
FT DOMAIN 5..70
FT /note="Z-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00073"
FT DOMAIN 117..184
FT /note="DRBM"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00266"
FT VAR_SEQ 1..37
FT /note="Missing (in isoform Short)"
FT /evidence="ECO:0000305"
FT /id="VSP_018957"
FT MUTAGEN 1..38
FT /note="Missing: Strongly attenuated virulence. Defects are
FT caused by impaired Z-RNA-binding."
FT /evidence="ECO:0000269|PubMed:15721360"
FT MUTAGEN 42
FT /note="E->A: Does not affect virulence or ability to
FT inhibit host ZBP1-dependent necroptosis."
FT /evidence="ECO:0000269|PubMed:34192517"
FT MUTAGEN 48
FT /note="Y->A: Strongly attenuated virulence caused by
FT reduced replication of the virus in mice. Defects are
FT caused by impaired Z-RNA-binding that prevents host ZBP1-
FT dependent necroptosis."
FT /evidence="ECO:0000269|PubMed:12777633,
FT ECO:0000269|PubMed:34192517"
FT MUTAGEN 63
FT /note="P->A: Strongly attenuated virulence caused by
FT reduced replication of the virus in mice. Defects are
FT caused by impaired Z-RNA-binding that prevents host ZBP1-
FT dependent necroptosis."
FT /evidence="ECO:0000269|PubMed:12777633,
FT ECO:0000269|PubMed:34192517"
FT MUTAGEN 64
FT /note="P->A: Strongly attenuated virulence caused by
FT reduced replication of the virus in mice."
FT /evidence="ECO:0000269|PubMed:12777633"
FT CONFLICT 64
FT /note="P -> T (in Ref. 4; AA sequence)"
FT /evidence="ECO:0000305"
FT HELIX 5..8
FT /evidence="ECO:0007829|PDB:7C0I"
FT HELIX 11..22
FT /evidence="ECO:0007829|PDB:7C0I"
FT HELIX 29..35
FT /evidence="ECO:0007829|PDB:7C0I"
FT STRAND 56..58
FT /evidence="ECO:0007829|PDB:7C0I"
FT STRAND 60..63
FT /evidence="ECO:0007829|PDB:7C0I"
FT STRAND 66..68
FT /evidence="ECO:0007829|PDB:7C0I"
SQ SEQUENCE 190 AA; 21504 MW; C76888864BE662AC CRC64;
MSKIYIDERS NAEIVCEAIK TIGIEGATAA QLTRQLNMEK REVNKALYDL QRSAMVYSSD
DIPPRWFMTT EADKPDADAM ADVIIDDVSR EKSMREDHKS FDDVIPAKKI IDWKGANPVT
VINEYCQITR RDWSFRIESV GPSNSPTFYA CVDIDGRVFD KADGKSKRDA KNNAAKLAVD
KLLGYVIIRF
