KEP1A_DANRE
ID KEP1A_DANRE Reviewed; 601 AA.
AC Q1ECZ2; Q8JIM0;
DT 16-OCT-2019, integrated into UniProtKB/Swiss-Prot.
DT 11-JUL-2006, sequence version 1.
DT 03-AUG-2022, entry version 122.
DE RecName: Full=Kelch-like ECH-associated protein 1A {ECO:0000303|PubMed:18057000};
GN Name=keap1a {ECO:0000303|PubMed:18057000,
GN ECO:0000312|ZFIN:ZDB-GENE-030131-556};
OS Danio rerio (Zebrafish) (Brachydanio rerio).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Actinopterygii; Neopterygii; Teleostei; Ostariophysi; Cypriniformes;
OC Danionidae; Danioninae; Danio.
OX NCBI_TaxID=7955;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBUNIT, DOMAIN, TISSUE SPECIFICITY,
RP AND MUTAGENESIS OF CYS-264.
RX PubMed=18057000; DOI=10.1074/jbc.m708702200;
RA Li L., Kobayashi M., Kaneko H., Nakajima-Takagi Y., Nakayama Y.,
RA Yamamoto M.;
RT "Molecular evolution of Keap1. Two Keap1 molecules with distinctive
RT intervening region structures are conserved among fish.";
RL J. Biol. Chem. 283:3248-3255(2008).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Tuebingen;
RX PubMed=23594743; DOI=10.1038/nature12111;
RA Howe K., Clark M.D., Torroja C.F., Torrance J., Berthelot C., Muffato M.,
RA Collins J.E., Humphray S., McLaren K., Matthews L., McLaren S., Sealy I.,
RA Caccamo M., Churcher C., Scott C., Barrett J.C., Koch R., Rauch G.J.,
RA White S., Chow W., Kilian B., Quintais L.T., Guerra-Assuncao J.A., Zhou Y.,
RA Gu Y., Yen J., Vogel J.H., Eyre T., Redmond S., Banerjee R., Chi J., Fu B.,
RA Langley E., Maguire S.F., Laird G.K., Lloyd D., Kenyon E., Donaldson S.,
RA Sehra H., Almeida-King J., Loveland J., Trevanion S., Jones M., Quail M.,
RA Willey D., Hunt A., Burton J., Sims S., McLay K., Plumb B., Davis J.,
RA Clee C., Oliver K., Clark R., Riddle C., Elliot D., Threadgold G.,
RA Harden G., Ware D., Begum S., Mortimore B., Kerry G., Heath P.,
RA Phillimore B., Tracey A., Corby N., Dunn M., Johnson C., Wood J., Clark S.,
RA Pelan S., Griffiths G., Smith M., Glithero R., Howden P., Barker N.,
RA Lloyd C., Stevens C., Harley J., Holt K., Panagiotidis G., Lovell J.,
RA Beasley H., Henderson C., Gordon D., Auger K., Wright D., Collins J.,
RA Raisen C., Dyer L., Leung K., Robertson L., Ambridge K., Leongamornlert D.,
RA McGuire S., Gilderthorp R., Griffiths C., Manthravadi D., Nichol S.,
RA Barker G., Whitehead S., Kay M., Brown J., Murnane C., Gray E.,
RA Humphries M., Sycamore N., Barker D., Saunders D., Wallis J., Babbage A.,
RA Hammond S., Mashreghi-Mohammadi M., Barr L., Martin S., Wray P.,
RA Ellington A., Matthews N., Ellwood M., Woodmansey R., Clark G., Cooper J.,
RA Tromans A., Grafham D., Skuce C., Pandian R., Andrews R., Harrison E.,
RA Kimberley A., Garnett J., Fosker N., Hall R., Garner P., Kelly D., Bird C.,
RA Palmer S., Gehring I., Berger A., Dooley C.M., Ersan-Urun Z., Eser C.,
RA Geiger H., Geisler M., Karotki L., Kirn A., Konantz J., Konantz M.,
RA Oberlander M., Rudolph-Geiger S., Teucke M., Lanz C., Raddatz G.,
RA Osoegawa K., Zhu B., Rapp A., Widaa S., Langford C., Yang F.,
RA Schuster S.C., Carter N.P., Harrow J., Ning Z., Herrero J., Searle S.M.,
RA Enright A., Geisler R., Plasterk R.H., Lee C., Westerfield M.,
RA de Jong P.J., Zon L.I., Postlethwait J.H., Nusslein-Volhard C.,
RA Hubbard T.J., Roest Crollius H., Rogers J., Stemple D.L.;
RT "The zebrafish reference genome sequence and its relationship to the human
RT genome.";
RL Nature 496:498-503(2013).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=AB;
RG NIH - Zebrafish Gene Collection (ZGC) project;
RL Submitted (JUN-2006) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3
CC ubiquitin ligase complex that regulates the response to oxidative
CC stress by targeting nfe2l2/nrf2 for ubiquitination (PubMed:18057000).
CC Keap1 acts as a key sensor of oxidative and electrophilic stress: in
CC normal conditions, the BCR(KEAP1) complex mediates ubiquitination and
CC degradation of nfe2l2/nrf2, a transcription factor regulating
CC expression of many cytoprotective genes (PubMed:18057000). In response
CC to oxidative stress, different electrophile metabolites trigger non-
CC enzymatic covalent modifications of highly reactive cysteine residues
CC in KEAP1, leading to inactivate the ubiquitin ligase activity of the
CC BCR(KEAP1) complex, promoting nfe2l2/nrf2 nuclear accumulation and
CC expression of phase II detoxifying enzymes (By similarity).
CC {ECO:0000250|UniProtKB:Q9Z2X8, ECO:0000269|PubMed:18057000}.
CC -!- ACTIVITY REGULATION: Ubiquitin ligase activity of the BCR(KEAP1)
CC complex is inhibited by oxidative stress and electrophile metabolites
CC such as sulforaphane. Electrophile metabolites react with reactive
CC cysteine residues in keap1 and trigger non-enzymatic covalent
CC modifications of these cysteine residues, leading to inactivate the
CC ubiquitin ligase activity of the BCR(KEAP1) complex.
CC {ECO:0000250|UniProtKB:Q9Z2X8}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000250|UniProtKB:Q9Z2X8}.
CC -!- SUBUNIT: Homodimer and heterodimer; heterodimerizes with keap1b
CC (PubMed:18057000). Component of the BCR(KEAP1) E3 ubiquitin ligase
CC complex, at least composed of 2 molecules of cul3, 2 molecules of keap1
CC (keap1a and/or keap1b), and rbx1 (By similarity). Interacts with
CC nfe2l2/nrf2; the interaction is direct (By similarity).
CC {ECO:0000250|UniProtKB:Q9Z2X8, ECO:0000269|PubMed:18057000}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9Z2X8}. Nucleus
CC {ECO:0000250|UniProtKB:Q9Z2X8}. Note=Mainly cytoplasmic.
CC {ECO:0000250|UniProtKB:Q9Z2X8}.
CC -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:18057000}.
CC -!- DOMAIN: Keap1 contains reactive cysteine residues that act as sensors
CC for endogenously produced and exogenously encountered small molecules,
CC which react with sulfhydryl groups and modify the cysteine sensors,
CC leading to impair ability of the BCR(KEAP1) complex to ubiquitinate
CC target proteins. {ECO:0000269|PubMed:18057000}.
CC -!- PTM: Non-enzymatic covalent modifications of reactive cysteines by
CC electrophile metabolites inactivate the BCR(KEAP1) complex.
CC {ECO:0000250|UniProtKB:Q9Z2X8}.
CC -!- SIMILARITY: Belongs to the KEAP1 family. {ECO:0000305}.
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DR EMBL; AB081315; BAC10574.2; -; mRNA.
DR EMBL; BX663525; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BX927124; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC117613; AAI17614.1; -; mRNA.
DR RefSeq; NP_878284.2; NM_182864.2.
DR AlphaFoldDB; Q1ECZ2; -.
DR SMR; Q1ECZ2; -.
DR STRING; 7955.ENSDARP00000045762; -.
DR PaxDb; Q1ECZ2; -.
DR Ensembl; ENSDART00000045763; ENSDARP00000045762; ENSDARG00000016132.
DR GeneID; 321837; -.
DR KEGG; dre:321837; -.
DR CTD; 321837; -.
DR ZFIN; ZDB-GENE-030131-556; keap1a.
DR eggNOG; KOG4441; Eukaryota.
DR GeneTree; ENSGT00940000165458; -.
DR HOGENOM; CLU_004253_14_2_1; -.
DR InParanoid; Q1ECZ2; -.
DR OMA; FDGENRW; -.
DR OrthoDB; 746011at2759; -.
DR PhylomeDB; Q1ECZ2; -.
DR TreeFam; TF329218; -.
DR UniPathway; UPA00143; -.
DR PRO; PR:Q1ECZ2; -.
DR Proteomes; UP000000437; Genome assembly.
DR Proteomes; UP000814640; Chromosome 2.
DR Bgee; ENSDARG00000016132; Expressed in liver and 23 other tissues.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0016234; C:inclusion body; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0034599; P:cellular response to oxidative stress; ISS:UniProtKB.
DR GO; GO:0071379; P:cellular response to prostaglandin stimulus; IGI:ZFIN.
DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IGI:ZFIN.
DR GO; GO:0016567; P:protein ubiquitination; IMP:UniProtKB.
DR GO; GO:0010506; P:regulation of autophagy; ISS:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
DR Gene3D; 2.120.10.80; -; 1.
DR Gene3D; 3.30.710.10; -; 1.
DR InterPro; IPR011705; BACK.
DR InterPro; IPR017096; BTB-kelch_protein.
DR InterPro; IPR000210; BTB/POZ_dom.
DR InterPro; IPR015915; Kelch-typ_b-propeller.
DR InterPro; IPR006652; Kelch_1.
DR InterPro; IPR011333; SKP1/BTB/POZ_sf.
DR Pfam; PF07707; BACK; 1.
DR Pfam; PF00651; BTB; 1.
DR Pfam; PF01344; Kelch_1; 6.
DR PIRSF; PIRSF037037; Kelch-like_protein_gigaxonin; 1.
DR SMART; SM00875; BACK; 1.
DR SMART; SM00225; BTB; 1.
DR SMART; SM00612; Kelch; 6.
DR SUPFAM; SSF117281; SSF117281; 1.
DR SUPFAM; SSF54695; SSF54695; 1.
DR PROSITE; PS50097; BTB; 1.
PE 1: Evidence at protein level;
KW Cytoplasm; Kelch repeat; Nucleus; Reference proteome; Repeat;
KW Ubl conjugation pathway.
FT CHAIN 1..601
FT /note="Kelch-like ECH-associated protein 1A"
FT /id="PRO_0000448289"
FT DOMAIN 44..117
FT /note="BTB"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00037"
FT DOMAIN 153..253
FT /note="BACK"
FT /evidence="ECO:0000255"
FT REPEAT 292..337
FT /note="Kelch 1"
FT /evidence="ECO:0000255"
FT REPEAT 338..388
FT /note="Kelch 2"
FT /evidence="ECO:0000255"
FT REPEAT 389..435
FT /note="Kelch 3"
FT /evidence="ECO:0000255"
FT REPEAT 436..482
FT /note="Kelch 4"
FT /evidence="ECO:0000255"
FT REPEAT 484..529
FT /note="Kelch 5"
FT /evidence="ECO:0000255"
FT REPEAT 530..576
FT /note="Kelch 6"
FT /evidence="ECO:0000255"
FT SITE 127
FT /note="Sensor for electrophilic agents"
FT /evidence="ECO:0000250|UniProtKB:Q9Z2X8"
FT SITE 264
FT /note="Sensor for electrophilic agents"
FT /evidence="ECO:0000269|PubMed:18057000"
FT MUTAGEN 264
FT /note="C->S: Abolishes repression of nfe2l2/nrf2-dependent
FT gene expression."
FT /evidence="ECO:0000269|PubMed:18057000"
FT CONFLICT 47
FT /note="L -> M (in Ref. 1; BAC10574)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 601 AA; 67405 MW; 0097E6ADB48136AD CRC64;
MICPRKKRPI KDEDFSAIVV PSMRGHGYLD YTVESHPSKA LQNMDELRHH EMLCDLVLHV
TYKDKIVDFK VHKLVLAASS PYFKAMFTSN FKECHASEVT LRDVCPQVIS RLIDFAYTSR
ITVGETCVLH VLLTAMRYQM EEVAKACCDF LMKNLEPSNV IGISRFAEEI GCTDLHLRTR
EYINTHFNEV TKEEEFFSLS HCQLLELISQ DSLKVLCESE VYKACIDWVR WDAESRAQYF
HALLNAVHIY ALPPTFLKRQ LQSCPILSKA NSCKDFLSKI FHEMALRKPL PPTPHRGTQL
IYIAGGYKQH SLDTLEAFDP HKNVWLKLGS MMSPCSGLGA CVLFGLLYTV GGRNLSLQNN
TESGSLSCYN PMTNQWTQLA PLNTPRNRVG VGVIDGSIYA VGGSHASTHH NSVERYDPET
NRWTFVAPMS VARLGAGVAA CGGCLYVVGG FDGDNRWNTV ERYQPDTNTW QHVAPMNTVR
SGLGVVCMDN YLYAVGGYDG QTQLKTMERY NITRDVWEPM ASMNHCRSAH GVSVYQCKIF
VLGGFNQGGF LSSVECYCPA SNVWTLVTDM PVGRSGMGVA VTMEPCPGIL PEEEEEVDEE
M
