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NF2L2_BOVIN
ID   NF2L2_BOVIN             Reviewed;         607 AA.
AC   Q5NUA6; Q3T0S8;
DT   01-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-2007, sequence version 2.
DT   25-MAY-2022, entry version 106.
DE   RecName: Full=Nuclear factor erythroid 2-related factor 2 {ECO:0000303|Ref.1};
DE            Short=NF-E2-related factor 2 {ECO:0000303|Ref.1};
DE            Short=NFE2-related factor 2 {ECO:0000303|Ref.1};
DE   AltName: Full=Nuclear factor, erythroid derived 2, like 2 {ECO:0000250|UniProtKB:Q16236};
GN   Name=NFE2L2 {ECO:0000250|UniProtKB:Q16236};
GN   Synonyms=NRF2 {ECO:0000250|UniProtKB:Q16236};
OS   Bos taurus (Bovine).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC   Bovinae; Bos.
OX   NCBI_TaxID=9913;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Artery;
RA   Hara S., Nishimoto M., Kunimoto M.;
RT   "Characterization of bovine endothelial NF-E2-related factor-2.";
RL   Submitted (FEB-2004) to the EMBL/GenBank/DDBJ databases.
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-522.
RC   STRAIN=Crossbred X Angus; TISSUE=Ileum;
RG   NIH - Mammalian Gene Collection (MGC) project;
RL   Submitted (AUG-2005) to the EMBL/GenBank/DDBJ databases.
CC   -!- FUNCTION: Transcription factor that plays a key role in the response to
CC       oxidative stress: binds to antioxidant response (ARE) elements present
CC       in the promoter region of many cytoprotective genes, such as phase 2
CC       detoxifying enzymes, and promotes their expression, thereby
CC       neutralizing reactive electrophiles. In normal conditions,
CC       ubiquitinated and degraded in the cytoplasm by the BCR(KEAP1) complex.
CC       In response to oxidative stress, electrophile metabolites inhibit
CC       activity of the BCR(KEAP1) complex, promoting nuclear accumulation of
CC       NFE2L2/NRF2, heterodimerization with one of the small Maf proteins and
CC       binding to ARE elements of cytoprotective target genes. The NFE2L2/NRF2
CC       pathway is also activated in response to selective autophagy: autophagy
CC       promotes interaction between KEAP1 and SQSTM1/p62 and subsequent
CC       inactivation of the BCR(KEAP1) complex, leading to NFE2L2/NRF2 nuclear
CC       accumulation and expression of cytoprotective genes (By similarity).
CC       May also be involved in the transcriptional activation of genes of the
CC       beta-globin cluster by mediating enhancer activity of hypersensitive
CC       site 2 of the beta-globin locus control region (By similarity). Plays
CC       also an important role in the regulation of the innate immune response.
CC       It is a critical regulator of the innate immune response and survival
CC       during sepsis by maintaining redox homeostasis and restraint of the
CC       dysregulation of pro-inflammatory signaling pathways like MyD88-
CC       dependent and -independent and TNF-alpha signaling. Suppresses
CC       macrophage inflammatory response by blocking pro-inflammatory cytokine
CC       transcription and the induction of IL6. Binds to the proximity of pro-
CC       inflammatory genes in macrophages and inhibits RNA Pol II recruitment.
CC       The inhibition is independent of the Nrf2-binding motif and reactive
CC       oxygen species level (By similarity). Represses antiviral cytosolic DNA
CC       sensing by suppressing the expression of the adapter protein STING1 and
CC       decreasing responsiveness to STING1 agonists while increasing
CC       susceptibility to infection with DNA viruses (By similarity).
CC       {ECO:0000250|UniProtKB:Q16236, ECO:0000250|UniProtKB:Q60795}.
CC   -!- SUBUNIT: Heterodimer; heterodimerizes with small Maf proteins.
CC       Interacts (via the bZIP domain) with MAFG and MAFK; required for
CC       binding to antioxidant response elements (AREs) on DNA. Interacts with
CC       KEAP1; the interaction is direct and promotes ubiquitination by the
CC       BCR(KEAP1) E3 ubiquitin ligase complex (By similarity). Forms a ternary
CC       complex with PGAM5 and KEAP1. Interacts with EEF1D at heat shock
CC       promoter elements (HSE) (By similarity). Interacts via its leucine-
CC       zipper domain with the coiled-coil domain of PMF1 (By similarity).
CC       Interacts with CHD6; involved in activation of the transcription (By
CC       similarity). Interacts with ESRRB; represses NFE2L2 transcriptional
CC       activity (By similarity). Interacts with MOTS-c, a peptide produced by
CC       the mitochondrially encoded 12S rRNA MT-RNR1; the interaction occurs in
CC       the nucleus following metabolic stress (By similarity).
CC       {ECO:0000250|UniProtKB:O54968, ECO:0000250|UniProtKB:Q16236,
CC       ECO:0000250|UniProtKB:Q60795}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC       {ECO:0000250|UniProtKB:Q60795}. Nucleus {ECO:0000250|UniProtKB:Q60795,
CC       ECO:0000255|PROSITE-ProRule:PRU00978}. Note=Cytosolic under unstressed
CC       conditions: ubiquitinated and degraded by the BCR(KEAP1) E3 ubiquitin
CC       ligase complex. Translocates into the nucleus upon induction by
CC       electrophilic agents that inactivate the BCR(KEAP1) E3 ubiquitin ligase
CC       complex. {ECO:0000250|UniProtKB:Q60795}.
CC   -!- DOMAIN: The ETGE motif, and to a lower extent the DLG motif, mediate
CC       interaction with KEAP1. {ECO:0000250|UniProtKB:Q60795}.
CC   -!- PTM: Ubiquitinated in the cytoplasm by the BCR(KEAP1) E3 ubiquitin
CC       ligase complex leading to its degradation. In response to oxidative
CC       stress, electrophile metabolites, such as sulforaphane, modify KEAP1,
CC       leading to inhibit activity of the BCR(KEAP1) complex, promoting
CC       NFE2L2/NRF2 nuclear accumulation and activity. In response to
CC       autophagy, the BCR(KEAP1) complex is inactivated.
CC       {ECO:0000250|UniProtKB:Q60795}.
CC   -!- PTM: Phosphorylation of Ser-40 by PKC in response to oxidative stress
CC       dissociates NFE2L2 from its cytoplasmic inhibitor KEAP1, promoting its
CC       translocation into the nucleus. {ECO:0000250|UniProtKB:O54968}.
CC   -!- PTM: Acetylation at Lys-598 and Lys-601 increases nuclear localization
CC       whereas deacetylation by SIRT1 enhances cytoplasmic presence.
CC       {ECO:0000250|UniProtKB:Q16236}.
CC   -!- PTM: Glycation impairs transcription factor activity by preventing
CC       heterodimerization with small Maf proteins. Deglycation by FN3K
CC       restores activity. {ECO:0000250|UniProtKB:Q16236}.
CC   -!- SIMILARITY: Belongs to the bZIP family. CNC subfamily. {ECO:0000305}.
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DR   EMBL; AB162435; BAD81030.1; -; mRNA.
DR   EMBL; BC102275; AAI02276.1; ALT_TERM; mRNA.
DR   AlphaFoldDB; Q5NUA6; -.
DR   SMR; Q5NUA6; -.
DR   STRING; 9913.ENSBTAP00000025637; -.
DR   PaxDb; Q5NUA6; -.
DR   PRIDE; Q5NUA6; -.
DR   eggNOG; KOG3863; Eukaryota.
DR   InParanoid; Q5NUA6; -.
DR   Proteomes; UP000009136; Unplaced.
DR   GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR   GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR   GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR   GO; GO:0003700; F:DNA-binding transcription factor activity; ISS:UniProtKB.
DR   GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IBA:GO_Central.
DR   GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR   GO; GO:0043565; F:sequence-specific DNA binding; ISS:UniProtKB.
DR   GO; GO:0000976; F:transcription cis-regulatory region binding; ISS:UniProtKB.
DR   GO; GO:0045454; P:cell redox homeostasis; ISS:UniProtKB.
DR   GO; GO:0071498; P:cellular response to fluid shear stress; ISS:UniProtKB.
DR   GO; GO:0034599; P:cellular response to oxidative stress; ISS:UniProtKB.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR   GO; GO:0010499; P:proteasomal ubiquitin-independent protein catabolic process; ISS:UniProtKB.
DR   GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR   GO; GO:0016567; P:protein ubiquitination; ISS:UniProtKB.
DR   GO; GO:0045088; P:regulation of innate immune response; ISS:UniProtKB.
DR   GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR   InterPro; IPR004827; bZIP.
DR   InterPro; IPR004826; bZIP_Maf.
DR   InterPro; IPR046347; bZIP_sf.
DR   InterPro; IPR029845; Nrf2.
DR   InterPro; IPR008917; TF_DNA-bd_sf.
DR   PANTHER; PTHR24411:SF3; PTHR24411:SF3; 1.
DR   Pfam; PF03131; bZIP_Maf; 1.
DR   SMART; SM00338; BRLZ; 1.
DR   SUPFAM; SSF47454; SSF47454; 1.
DR   SUPFAM; SSF57959; SSF57959; 1.
DR   PROSITE; PS50217; BZIP; 1.
DR   PROSITE; PS00036; BZIP_BASIC; 1.
PE   2: Evidence at transcript level;
KW   Acetylation; Activator; Cytoplasm; DNA-binding; Glycation; Glycoprotein;
KW   Nucleus; Phosphoprotein; Reference proteome; Transcription;
KW   Transcription regulation; Ubl conjugation.
FT   CHAIN           1..607
FT                   /note="Nuclear factor erythroid 2-related factor 2"
FT                   /id="PRO_0000286396"
FT   DOMAIN          499..562
FT                   /note="bZIP"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT   REGION          42..61
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          333..363
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          380..451
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          501..520
FT                   /note="Basic motif"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT   REGION          524..531
FT                   /note="Leucine-zipper"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT   REGION          577..607
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          593..598
FT                   /note="Mediates interaction with CHD6 and is necessary to
FT                   activate transcription"
FT                   /evidence="ECO:0000250"
FT   MOTIF           29..31
FT                   /note="DLG motif"
FT                   /evidence="ECO:0000250|UniProtKB:Q60795"
FT   MOTIF           79..82
FT                   /note="ETGE motif"
FT                   /evidence="ECO:0000250|UniProtKB:Q60795"
FT   COMPBIAS        405..422
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        424..451
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        579..594
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOD_RES         40
FT                   /note="Phosphoserine; by PKC"
FT                   /evidence="ECO:0000250|UniProtKB:O54968"
FT   MOD_RES         214
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q16236"
FT   MOD_RES         598
FT                   /note="N6-acetyllysine; by CREBBP"
FT                   /evidence="ECO:0000250|UniProtKB:Q16236"
FT   MOD_RES         601
FT                   /note="N6-acetyllysine; by CREBBP"
FT                   /evidence="ECO:0000250|UniProtKB:Q16236"
FT   CARBOHYD        464
FT                   /note="N-linked (Glc) (glycation) lysine"
FT                   /evidence="ECO:0000250|UniProtKB:Q16236"
FT   CARBOHYD        474
FT                   /note="N-linked (Glc) (glycation) lysine"
FT                   /evidence="ECO:0000250|UniProtKB:Q16236"
FT   CARBOHYD        489
FT                   /note="N-linked (Glc) (glycation) lysine"
FT                   /evidence="ECO:0000250|UniProtKB:Q16236"
FT   CARBOHYD        501
FT                   /note="N-linked (Glc) (glycation) arginine"
FT                   /evidence="ECO:0000250|UniProtKB:Q16236"
FT   CARBOHYD        571
FT                   /note="N-linked (Glc) (glycation) arginine"
FT                   /evidence="ECO:0000250|UniProtKB:Q16236"
FT   CARBOHYD        576
FT                   /note="N-linked (Glc) (glycation) lysine"
FT                   /evidence="ECO:0000250|UniProtKB:Q16236"
FT   CONFLICT        287
FT                   /note="A -> T (in Ref. 1; BAD81030)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        423
FT                   /note="Q -> H (in Ref. 1; BAD81030)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   607 AA;  67895 MW;  E0C576DBAF2A1A21 CRC64;
     MMDLELPPPG LPSQQDMDLI DILWRQDIDL GVSREVFDFS QRQKEHELEK QKKLEKERQE
     QLQKEQEKAF FAQLQLDEET GEFLPIQPAQ HIPSETSGSA NYSQVAPIPK ADDLYFDDCM
     QLLAETFPFV DDNEVSSATF QSLVPDIPSH IESPVFTAPP QAQSPETLIV QVATAVLDDM
     QDIEQVWEEL LSIPELQCLN IQNDKLAETS TVPSPETKLT EIDNYHFYSS MPSLDKEVGN
     CSPHFLNAFE DSFNSILSTE DSSQLTVNSL NSSATVNTDF GDEFYSAFIA EPSTSNGMPS
     SATLSQSLSE LLNGPIDLSD LSLCKAFNQN HPESTTAEFN DSDSGISLNT TSPSMASPDH
     SVESSIYGDT LLGFSDSEME EIDSTPGNVK QKGPKTPSVW PPGDPVQPLS SSQGNSAAAR
     DSQCENAPKK EVPVSPGHRK TPFTKDKHSS RLEAHLTRDE LRAKALHIPF PVEKIINLPV
     EDFNEMMSKE QFNEAQLALI RDIRRRGKNK VAAQNCRKRK LENIVELEQD LDHLKDEKEK
     LLKERGENDK SLHLLKKQLS TLYLEVFSML RDENGKPYSP SEYSLQQTSD GNVFLVPKSK
     KPDTKKN
 
 
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