IKBL_ASFM2
ID IKBL_ASFM2 Reviewed; 239 AA.
AC O36972;
DT 05-MAY-2009, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1998, sequence version 1.
DT 03-AUG-2022, entry version 93.
DE RecName: Full=IkB-like protein;
DE AltName: Full=Ankyrin repeat domain-containing protein A238L;
DE AltName: Full=p28;
GN Name=A238L; OrderedLocusNames=Mal-047; ORFNames=5EL;
OS African swine fever virus (isolate Tick/Malawi/Lil 20-1/1983) (ASFV).
OC Viruses; Varidnaviria; Bamfordvirae; Nucleocytoviricota; Pokkesviricetes;
OC Asfuvirales; Asfarviridae; Asfivirus.
OX NCBI_TaxID=10500;
OH NCBI_TaxID=6937; Ornithodoros (relapsing fever ticks).
OH NCBI_TaxID=85517; Phacochoerus aethiopicus (Warthog).
OH NCBI_TaxID=41426; Phacochoerus africanus (Warthog).
OH NCBI_TaxID=273792; Potamochoerus larvatus (Bushpig).
OH NCBI_TaxID=9823; Sus scrofa (Pig).
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9281518; DOI=10.1006/viro.1997.8693;
RA Neilan J.G., Lu Z., Kutish G.F., Zsak L., Lewis T.L., Rock D.L.;
RT "A conserved African swine fever virus IkappaB homolog, 5EL, is
RT nonessential for growth in vitro and virulence in domestic swine.";
RL Virology 235:377-385(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Kutish G.F., Rock D.L.;
RT "African swine fever virus genomes.";
RL Submitted (MAR-2003) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP FUNCTION.
RX PubMed=8970976; DOI=10.1128/jvi.70.12.8527-8533.1996;
RA Powell P.P., Dixon L.K., Parkhouse R.M.;
RT "An IkappaB homolog encoded by African swine fever virus provides a novel
RT mechanism for downregulation of proinflammatory cytokine responses in host
RT macrophages.";
RL J. Virol. 70:8527-8533(1996).
RN [4]
RP FUNCTION, INTERACTION WITH HOST PPIA, AND INTERACTION WITH HOST PPP3CA.
RX PubMed=9677199; DOI=10.1126/science.281.5376.562;
RA Miskin J.E., Abrams C.C., Goatley L.C., Dixon L.K.;
RT "A viral mechanism for inhibition of the cellular phosphatase
RT calcineurin.";
RL Science 281:562-565(1998).
RN [5]
RP INTERACTION WITH HOST PPP3CA.
RX PubMed=11000210; DOI=10.1128/jvi.74.20.9412-9420.2000;
RA Miskin J.E., Abrams C.C., Dixon L.K.;
RT "African swine fever virus protein A238L interacts with the cellular
RT phosphatase calcineurin via a binding domain similar to that of NFAT.";
RL J. Virol. 74:9412-9420(2000).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) OF 200-239 IN COMPLEX WITH HUMAN
RP PPP3R1 AND PPP3CA, INTERACTION WITH HOST PPP3CA, INTERACTION WITH HOST
RP PPP3R1, FUNCTION, MOTIF, AND MUTAGENESIS OF 200-ARG--LYS-239;
RP 206-PRO--THR-211 AND 228-PHE--LYS-232.
RX PubMed=23468591; DOI=10.1371/journal.pbio.1001492;
RA Grigoriu S., Bond R., Cossio P., Chen J.A., Ly N., Hummer G., Page R.,
RA Cyert M.S., Peti W.;
RT "The molecular mechanism of substrate engagement and immunosuppressant
RT inhibition of calcineurin.";
RL PLoS Biol. 11:E1001492-E1001492(2013).
CC -!- FUNCTION: IkB-like protein that inhibits the binding of NF-kappa-B to
CC DNA, thereby downregulating pro-inflammatory cytokine production
CC (PubMed:8970976). Forms a heterodimer with the NF-kappa-B subunit
CC RELA/p65 and prevents the activation of the NF-kappa-B transcription
CC factor (By similarity). Inhibits calcineurin function, which is
CC required for the induction of nuclear factor of activated T cells
CC (NFAT)-dependent immune response genes (PubMed:23468591,
CC PubMed:9677199). Prevents the binding of substrates to calcineurin
CC without affecting the phosphatase activity (PubMed:23468591). Does not
CC contain the serine residues that are phosphorylated by host IkB kinase
CC and thus is not degraded following stimulation of the NFkB pathway (By
CC similarity). {ECO:0000250|UniProtKB:Q76U48,
CC ECO:0000269|PubMed:23468591, ECO:0000269|PubMed:8970976,
CC ECO:0000269|PubMed:9677199}.
CC -!- SUBUNIT: Interacts with host PPIA (PubMed:9677199). Interacts with host
CC PPP3CA/Calcineurin (PubMed:9677199, PubMed:11000210, PubMed:23468591).
CC Interacts with host RELA/p65; interaction of the 32 kDa form with host
CC RELA results in the formation of a stable complex with NF-kappa-B (By
CC similarity). Interacts with host PPP3R1 (PubMed:23468591). Interacts
CC with host EP300; this interaction inhibits the association of host
CC EP300 with host RELA, JUN and NFATC2 (By similarity).
CC {ECO:0000250|UniProtKB:Q76U48, ECO:0000269|PubMed:11000210,
CC ECO:0000269|PubMed:23468591, ECO:0000269|PubMed:9677199}.
CC -!- INTERACTION:
CC O36972; Q08209-1: PPP3CA; Xeno; NbExp=2; IntAct=EBI-16039701, EBI-15637215;
CC -!- SUBCELLULAR LOCATION: Host nucleus {ECO:0000250|UniProtKB:Q76U48}. Host
CC cytoplasm {ECO:0000250|UniProtKB:Q76U48}. Note=Binding to host
CC PPP3CA/Calcineurin may mask the second nuclear localization signal
CC thereby contributing to the cytoplasmic retention of A238L.
CC {ECO:0000250|UniProtKB:Q76U48}.
CC -!- INDUCTION: Expressed in the early phase of the viral replicative cycle.
CC {ECO:0000305}.
CC -!- DOMAIN: The C-terminal region contains the docking motifs PxIxITxC and
CC FLCV, which are required and sufficient for binding to host
CC calcineurin. {ECO:0000269|PubMed:23468591}.
CC -!- PTM: The protein exists in a 28 kDa and a 32 kDa form, probably due to
CC post-translational modifications which are neither phosphorylation, nor
CC sumoylation. {ECO:0000250|UniProtKB:Q76U48}.
CC -!- SIMILARITY: Belongs to the asfivirus A238L family. {ECO:0000305}.
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DR EMBL; AF014479; AAB71361.1; -; Genomic_DNA.
DR EMBL; AY261361; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR PDB; 4F0Z; X-ray; 1.70 A; C=200-239.
DR PDBsum; 4F0Z; -.
DR SMR; O36972; -.
DR DIP; DIP-60108N; -.
DR ELM; O36972; -.
DR IntAct; O36972; 2.
DR Proteomes; UP000000860; 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:0039517; P:modulation by virus of host protein serine/threonine phosphatase activity; IMP:UniProtKB.
DR GO; GO:0039513; P:suppression by virus of host catalytic activity; IMP:UniProtKB.
DR GO; GO:0039644; P:suppression by virus of host NF-kappaB cascade; IEA:UniProtKB-KW.
DR Gene3D; 1.25.40.20; -; 1.
DR IDEAL; IID90028; -.
DR InterPro; IPR002110; Ankyrin_rpt.
DR InterPro; IPR036770; Ankyrin_rpt-contain_sf.
DR Pfam; PF00023; Ank; 1.
DR SMART; SM00248; ANK; 4.
DR SUPFAM; SSF48403; SSF48403; 1.
DR PROSITE; PS50297; ANK_REP_REGION; 1.
DR PROSITE; PS50088; ANK_REPEAT; 1.
PE 1: Evidence at protein level;
KW 3D-structure; ANK repeat; Early protein; Host cytoplasm; Host nucleus;
KW Host-virus interaction; Inhibition of host NF-kappa-B by virus; Repeat;
KW Ubl conjugation.
FT CHAIN 1..239
FT /note="IkB-like protein"
FT /id="PRO_0000372838"
FT REPEAT 48..77
FT /note="ANK 1"
FT REPEAT 87..116
FT /note="ANK 2"
FT REPEAT 124..153
FT /note="ANK 3"
FT REPEAT 158..187
FT /note="ANK 4"
FT MOTIF 81..87
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250|UniProtKB:Q76U48"
FT MOTIF 203..214
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250|UniProtKB:Q76U48"
FT MOTIF 206..213
FT /note="PxIxITxC motif; Interaction with host PPP3CA"
FT /evidence="ECO:0000269|PubMed:11000210,
FT ECO:0000269|PubMed:23468591"
FT MOTIF 228..231
FT /note="FLCV motif"
FT /evidence="ECO:0000269|PubMed:23468591"
FT MUTAGEN 1..199
FT /note="Missing: No defect in the competitive inhibition of
FT PPP3CA-mediated dephosphorylation of a peptide substrate.
FT Reduced interaction with PPP3CA while maintaining the
FT competitive inhibition of PPP3CA-mediated dephosphorylation
FT of a peptide substrate; when associated with 206-A--A-211.
FT Reduced interaction with PPP3CA and severe loss of
FT competitive inhibition of PPP3CA-mediated dephosphorylation
FT of a peptide substrate; when associated with 228-A--A-232."
FT /evidence="ECO:0000269|PubMed:23468591"
FT MUTAGEN 206..211
FT /note="PKIIIT->AKAIAA: Partial loss of NFAT-mediated
FT transcription inhibition. Reduced interaction with PPP3CA
FT while maintaining the competitive inhibition of PPP3CA-
FT mediated dephosphorylation of a peptide substrate; when
FT associated with 1-M--H-199 DEL."
FT /evidence="ECO:0000269|PubMed:23468591"
FT MUTAGEN 228..232
FT /note="FLCVK->AACAA: Partial loss of NFAT-mediated
FT transcription inhibition. Reduced interaction with PPP3CA
FT and severe loss of competitive inhibition of PPP3CA-
FT mediated dephosphorylation of a peptide substrate; when
FT associated with 1-M--H-199 DEL."
FT /evidence="ECO:0000269|PubMed:23468591"
FT STRAND 207..211
FT /evidence="ECO:0007829|PDB:4F0Z"
SQ SEQUENCE 239 AA; 28080 MW; C6FA085308BF2CBD CRC64;
MDTIGLFSVE AEHLFVEWVK KCIKKGDLTL FETLFNADPW IVNRCNKNKI TVFMLICIYG
RLDFLRFLFK QESYPGEIVN HYRRDKDGNS AWHYLAEKNN HLLLEEVLDY FGKNGIRVCF
PNFNGVTPIM KAAMRGRTLS VLSLLKYGAN PNRKDYLKGF TTWDWAVFTG HADLVKTLNK
GYQKPLFMHF PLYKLDVFHR RFKKKPKIII TGCEDNVYEK LPEQNSNFLC VKKLNKYGK
