KEP1B_DANRE
ID KEP1B_DANRE Reviewed; 587 AA.
AC A0A2R8Q1W5; A9CP01; A9JSU4;
DT 16-OCT-2019, integrated into UniProtKB/Swiss-Prot.
DT 20-JUN-2018, sequence version 1.
DT 03-AUG-2022, entry version 18.
DE RecName: Full=Kelch-like ECH-associated protein 1B {ECO:0000303|PubMed:18057000};
GN Name=keap1b {ECO:0000303|PubMed:18057000,
GN ECO:0000312|ZFIN:ZDB-GENE-080508-1};
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] (ISOFORM 2), FUNCTION, SUBUNIT, DOMAIN, TISSUE
RP SPECIFICITY, AND MUTAGENESIS OF CYS-241.
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 TISSUE=Embryo;
RG NIH - Zebrafish Gene Collection (ZGC) project;
RL Submitted (NOV-2007) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP DOMAIN, AND MUTAGENESIS OF LYS-118 AND CYS-119.
RX PubMed=19001094; DOI=10.1128/mcb.01080-08;
RA Kobayashi M., Li L., Iwamoto N., Nakajima-Takagi Y., Kaneko H.,
RA Nakayama Y., Eguchi M., Wada Y., Kumagai Y., Yamamoto M.;
RT "The antioxidant defense system Keap1-Nrf2 comprises a multiple sensing
RT mechanism for responding to a wide range of chemical compounds.";
RL Mol. Cell. Biol. 29:493-502(2009).
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 keap1a
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 -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=A0A2R8Q1W5-1; Sequence=Displayed;
CC Name=2;
CC IsoId=A0A2R8Q1W5-3; Sequence=VSP_060371;
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 ECO:0000269|PubMed:19001094}.
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; AB271119; BAF95684.1; -; mRNA.
DR EMBL; CU693486; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC155079; AAI55080.1; -; mRNA.
DR RefSeq; NP_001106948.1; NM_001113477.1. [A0A2R8Q1W5-3]
DR RefSeq; XP_005168742.1; XM_005168685.2. [A0A2R8Q1W5-3]
DR AlphaFoldDB; A0A2R8Q1W5; -.
DR SMR; A0A2R8Q1W5; -.
DR STRING; 7955.ENSDARP00000124228; -.
DR Ensembl; ENSDART00000148911; ENSDARP00000124136; ENSDARG00000074634. [A0A2R8Q1W5-3]
DR Ensembl; ENSDART00000148974; ENSDARP00000124228; ENSDARG00000074634. [A0A2R8Q1W5-3]
DR Ensembl; ENSDART00000186561; ENSDARP00000147759; ENSDARG00000074634. [A0A2R8Q1W5-1]
DR GeneID; 100003679; -.
DR KEGG; dre:100003679; -.
DR CTD; 100003679; -.
DR ZFIN; ZDB-GENE-080508-1; keap1b.
DR eggNOG; KOG4441; Eukaryota.
DR GeneTree; ENSGT00940000159543; -.
DR HOGENOM; CLU_004253_14_3_1; -.
DR OMA; CYHPEND; -.
DR OrthoDB; 746011at2759; -.
DR TreeFam; TF329218; -.
DR Reactome; R-DRE-5689880; Ub-specific processing proteases.
DR Reactome; R-DRE-8951664; Neddylation.
DR Reactome; R-DRE-9755511; KEAP1-NFE2L2 pathway.
DR Reactome; R-DRE-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR UniPathway; UPA00143; -.
DR PRO; PR:A0A2R8Q1W5; -.
DR Proteomes; UP000000437; Genome assembly.
DR Proteomes; UP000814640; Chromosome 6.
DR Bgee; ENSDARG00000074634; Expressed in muscle tissue and 21 other tissues.
DR ExpressionAtlas; A0A2R8Q1W5; baseline.
DR GO; GO:0031463; C:Cul3-RING ubiquitin ligase complex; IEA:InterPro.
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; IPR030563; KEAP1.
DR InterPro; IPR015915; Kelch-typ_b-propeller.
DR InterPro; IPR006652; Kelch_1.
DR InterPro; IPR011333; SKP1/BTB/POZ_sf.
DR PANTHER; PTHR24412:SF162; PTHR24412:SF162; 1.
DR Pfam; PF07707; BACK; 1.
DR Pfam; PF00651; BTB; 1.
DR Pfam; PF01344; Kelch_1; 5.
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 Alternative splicing; Cytoplasm; Kelch repeat; Nucleus; Reference proteome;
KW Repeat; Ubl conjugation pathway.
FT CHAIN 1..587
FT /note="Kelch-like ECH-associated protein 1B"
FT /id="PRO_0000448290"
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 119
FT /note="Sensor for electrophilic agents"
FT /evidence="ECO:0000269|PubMed:19001094"
FT SITE 241
FT /note="Sensor for electrophilic agents"
FT /evidence="ECO:0000269|PubMed:18057000"
FT SITE 399
FT /note="Sensor for electrophilic agents"
FT /evidence="ECO:0000250|UniProtKB:Q9Z2X8"
FT VAR_SEQ 1
FT /note="M -> MLAAAGM (in isoform 2)"
FT /id="VSP_060371"
FT MUTAGEN 118
FT /note="K->T: Decreased response to oxidative stress."
FT /evidence="ECO:0000269|PubMed:19001094"
FT MUTAGEN 119
FT /note="C->S: Substitution with a small side chain that
FT prevents covalent modification by an electrophile; promotes
FT constitutive ubiquitination of nfe2l2/nrf2 and subsequent
FT repression of phase 2 detoxifying enzymes."
FT /evidence="ECO:0000269|PubMed:19001094"
FT MUTAGEN 119
FT /note="C->W: Substitution with a bulky side chain that
FT mimicks covalent modification by an electrophile; prevents
FT ubiquitination and degradation of nfe2l2/nrf2, leading to
FT constitutive activation of nfe2l2/nrf2."
FT /evidence="ECO:0000269|PubMed:19001094"
FT MUTAGEN 241
FT /note="C->S: Abolishes repression of nfe2l2/nrf2-dependent
FT gene expression."
FT /evidence="ECO:0000269|PubMed:18057000"
FT CONFLICT 333
FT /note="C -> R (in Ref. 3; AAI55080)"
FT /evidence="ECO:0000305"
FT CONFLICT 400
FT /note="T -> S (in Ref. 3; AAI55080)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 587 AA; 65690 MW; 1EF9B8305180C9E2 CRC64;
MTECKAEVTP SASNGHRVFS YTLESHTAAA FAIMNELRRE RQLCDVTLRV RYCPLDTHVD
FVAHKVVLAS SSPVFRAMFT NGLKECGMEV VPIEGIHPKV MGRLIEFAYT ASISVGEKCV
IHVMNGAVMY QIDSVVQACC DFLVEQLDPS NAIGIASFAE QIGCTELHQK AREYIYMNFS
QVATQEEFFT LSHCQLVTLI SRDELNVRCE SEVFHACVAW VQYDREERRP YVQALLQAVR
CHSLTPHFLQ RQLEHFEWDA QSKDYLSQIF RDLTLHKPTK VIPLRTPKVP QLIYTVGGYF
RQSLSFLEAF NPCSGAWLRL ADLQVPRSGL AACVISGLLY AVGGRNNGPD GNMDSHTLDC
YNPMNNCWRP CAHMSVPRNR IGVGVIDGMI YAVGGSHGCT HHNSVERYDP ERDSWQLVSP
MLTRRIGVGV AVINRLLYAV GGFDGTHRLS SAECYNPERD EWRSIAAMNT VRSGAGVCAL
GNYIYVMGGY DGTNQLNTVE RYDVEKDSWS FSASMRHRRS ALGVTTHHGR IYVLGGYDGN
TFLDSVECFD PETDSWTEVT HMKSGRSGVG VAVTMEPCHK ELIPCQC
