ID   KEAP1_RAT               Reviewed;         624 AA.
AC   P57790; Q9ERI3;
DT   27-APR-2001, integrated into UniProtKB/Swiss-Prot.
DT   27-APR-2001, sequence version 1.
DT   27-MAR-2024, entry version 149.
DE   RecName: Full=Kelch-like ECH-associated protein 1;
DE   AltName: Full=Cytosolic inhibitor of Nrf2 {ECO:0000303|PubMed:11439354};
DE            Short=INrf2 {ECO:0000303|PubMed:11439354};
GN   Name=Keap1 {ECO:0000312|RGD:621619};
GN   Synonyms=Inrf2 {ECO:0000303|PubMed:11439354};
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   STRAIN=Sprague-Dawley;
RX   PubMed=11439354; DOI=10.1038/sj.onc.1204506;
RA   Dhakshinamoorthy S., Jaiswal A.K.;
RT   "Functional characterization and role of INrf2 in antioxidant response
RT   element-mediated expression and antioxidant induction of NAD(P)H:quinone
RT   oxidoreductase1 gene.";
RL   Oncogene 20:3906-3917(2001).
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. KEAP1 acts as a key
CC       sensor of oxidative and electrophilic stress: in normal conditions, the
CC       BCR(KEAP1) complex mediates ubiquitination and degradation of
CC       NFE2L2/NRF2, a transcription factor regulating expression of many
CC       cytoprotective genes. In response to oxidative stress, different
CC       electrophile metabolites trigger non-enzymatic covalent modifications
CC       of highly reactive cysteine residues in KEAP1, leading to inactivate
CC       the ubiquitin ligase activity of the BCR(KEAP1) complex, promoting
CC       NFE2L2/NRF2 nuclear accumulation and expression of phase II detoxifying
CC       enzymes. In response to selective autophagy, KEAP1 is sequestered in
CC       inclusion bodies following its interaction with SQSTM1/p62, leading to
CC       inactivation of the BCR(KEAP1) complex and activation of NFE2L2/NRF2.
CC       The BCR(KEAP1) complex also mediates ubiquitination of SQSTM1/p62,
CC       increasing SQSTM1/p62 sequestering activity and degradation (By
CC       similarity). The BCR(KEAP1) complex also targets BPTF and PGAM5 for
CC       ubiquitination and degradation by the proteasome (By similarity).
CC       {ECO:0000250|UniProtKB:Q14145, ECO:0000250|UniProtKB:Q9Z2X8}.
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. Selective
CC       autophagy also inactivates the BCR(KEAP1) complex via interaction
CC       between KEAP1 and SQSTM1/p62, which sequesters the complex in inclusion
CC       bodies and promotes its degradation. {ECO:0000250|UniProtKB:Q9Z2X8}.
CC   -!- PATHWAY: Protein modification; protein ubiquitination.
CC       {ECO:0000250|UniProtKB:Q9Z2X8}.
CC   -!- SUBUNIT: Component of the BCR(KEAP1) E3 ubiquitin ligase complex, at
CC       least composed of 2 molecules of CUL3, 2 molecules of KEAP1, and RBX1.
CC       Interacts with NFE2L2/NRF2; the interaction is direct (By similarity).
CC       Forms a ternary complex with NFE2L2/NRF2 and PGAM5 (By similarity).
CC       Interacts with (phosphorylated) SQSTM1/p62; the interaction is direct
CC       and inactivates the BCR(KEAP1) complex by sequestering it in inclusion
CC       bodies, promoting its degradation (By similarity). Interacts with
CC       NFE2L1. Interacts with BPTF and PTMA. Interacts with MAP1LC3B.
CC       Interacts indirectly with ENC1. Interacts with SESN1 and SESN2.
CC       Interacts with HSP90AA1 and HSP90AB1 (By similarity).
CC       {ECO:0000250|UniProtKB:Q14145, ECO:0000250|UniProtKB:Q9Z2X8}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9Z2X8}. Nucleus
CC       {ECO:0000250|UniProtKB:Q9Z2X8}. Note=Mainly cytoplasmic. In response to
CC       selective autophagy, relocalizes to inclusion bodies following
CC       interaction with SQSTM1/p62. {ECO:0000250|UniProtKB:Q9Z2X8}.
CC   -!- DOMAIN: The Kelch repeats mediate interaction with NFE2L2/NRF2, BPTF
CC       and PGAM5. {ECO:0000250|UniProtKB:Q14145}.
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:0000250|UniProtKB:Q9Z2X8}.
CC   -!- PTM: Non-enzymatic covalent modifications of reactive cysteines by
CC       electrophile metabolites inactivate the BCR(KEAP1) complex.
CC       Accumulation of fumarate promotes the formation of cysteine S-
CC       succination (S-(2-succinyl)cysteine), leading to inactivate the
CC       BCR(KEAP1) complex and promote NFE2L2/NRF2 nuclear accumulation and
CC       activation. Nitric oxide-dependent 8-Nitro-cGMP formation promotes
CC       cysteine guanylation (S-cGMP-cysteine), leading to NFE2L2/NRF2 nuclear
CC       accumulation and activation. Itaconate, an anti-inflammatory metabolite
CC       generated in response to lipopolysaccharide, alkylates cysteines,
CC       activating NFE2L2/NRF2 (By similarity). Methylglyoxal, a reactive
CC       metabolite that accumulates when the glycolytic enzyme PGK1 is
CC       inhibited, promotes formation of a methylimidazole cross-link between
CC       proximal Cys-151 and Arg-135 on another KEAP1 molecule, resulting in an
CC       inactive dimer that inactivates the BCR(KEAP1) complex (By similarity).
CC       {ECO:0000250|UniProtKB:Q14145, ECO:0000250|UniProtKB:Q9Z2X8}.
CC   -!- PTM: Degraded via a proteasomal-independent process during selective
CC       autophagy: interaction with phosphorylated SQSTM1/p62 sequesters KEAP1
CC       in inclusion bodies, leading to its degradation.
CC       {ECO:0000250|UniProtKB:Q9Z2X8}.
CC   -!- PTM: Auto-ubiquitinated by the BCR(KEAP1) complex. Quinone-induced
CC       oxidative stress, but not sulforaphane, increases its ubiquitination.
CC       Ubiquitination and subsequent degradation is most pronounced following
CC       prolonged exposure of cells to oxidative stress, particularly in
CC       glutathione-deficient cells that are highly susceptible to oxidative
CC       stress. Deubiquitinated by USP25; leading to stabilization.
CC       {ECO:0000250|UniProtKB:Q14145}.
CC   -!- SIMILARITY: Belongs to the KEAP1 family. {ECO:0000305}.
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; AF304364; AAG16275.1; -; mRNA.
DR   AlphaFoldDB; P57790; -.
DR   SMR; P57790; -.
DR   STRING; 10116.ENSRNOP00000028360; -.
DR   ChEMBL; CHEMBL4523596; -.
DR   iPTMnet; P57790; -.
DR   PhosphoSitePlus; P57790; -.
DR   PaxDb; 10116-ENSRNOP00000028360; -.
DR   UCSC; RGD:621619; rat.
DR   AGR; RGD:621619; -.
DR   RGD; 621619; Keap1.
DR   eggNOG; KOG4441; Eukaryota.
DR   InParanoid; P57790; -.
DR   PhylomeDB; P57790; -.
DR   Reactome; R-RNO-5689880; Ub-specific processing proteases.
DR   Reactome; R-RNO-8951664; Neddylation.
DR   Reactome; R-RNO-9755511; KEAP1-NFE2L2 pathway.
DR   Reactome; R-RNO-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR   UniPathway; UPA00143; -.
DR   PRO; PR:P57790; -.
DR   Proteomes; UP000002494; Unplaced.
DR   GO; GO:0005884; C:actin filament; ISO:RGD.
DR   GO; GO:0005912; C:adherens junction; IDA:RGD.
DR   GO; GO:0031463; C:Cul3-RING ubiquitin ligase complex; ISS:UniProtKB.
DR   GO; GO:0005737; C:cytoplasm; ISO:RGD.
DR   GO; GO:0005783; C:endoplasmic reticulum; ISO:RGD.
DR   GO; GO:0005925; C:focal adhesion; IDA:RGD.
DR   GO; GO:0016234; C:inclusion body; ISS:UniProtKB.
DR   GO; GO:0030496; C:midbody; ISO:RGD.
DR   GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR   GO; GO:0032991; C:protein-containing complex; IDA:RGD.
DR   GO; GO:0097718; F:disordered domain specific binding; ISO:RGD.
DR   GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR   GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; ISO:RGD.
DR   GO; GO:1990756; F:ubiquitin ligase-substrate adaptor activity; ISO:RGD.
DR   GO; GO:0071322; P:cellular response to carbohydrate stimulus; IDA:RGD.
DR   GO; GO:0071353; P:cellular response to interleukin-4; ISO:RGD.
DR   GO; GO:0071407; P:cellular response to organic cyclic compound; IEP:RGD.
DR   GO; GO:0034599; P:cellular response to oxidative stress; ISS:UniProtKB.
DR   GO; GO:0001701; P:in utero embryonic development; ISO:RGD.
DR   GO; GO:0010629; P:negative regulation of gene expression; IDA:RGD.
DR   GO; GO:0016567; P:protein ubiquitination; ISS:UniProtKB.
DR   GO; GO:0010506; P:regulation of autophagy; ISS:UniProtKB.
DR   GO; GO:0006355; P:regulation of DNA-templated transcription; ISO:RGD.
DR   GO; GO:0045604; P:regulation of epidermal cell differentiation; ISO:RGD.
DR   GO; GO:0035902; P:response to immobilization stress; IEP:RGD.
DR   GO; GO:0010038; P:response to metal ion; IEP:RGD.
DR   GO; GO:0097066; P:response to thyroid hormone; IEP:RGD.
DR   GO; GO:0001887; P:selenium compound metabolic process; IEP:RGD.
DR   GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR   CDD; cd18458; BACK_KLHL19_KEAP1; 1.
DR   CDD; cd18248; BTB_POZ_KLHL19_KEAP1; 1.
DR   Gene3D; 1.25.40.420; -; 1.
DR   Gene3D; 2.120.10.80; Kelch-type beta propeller; 1.
DR   InterPro; IPR011705; BACK.
DR   InterPro; IPR017096; BTB-kelch_protein.
DR   InterPro; IPR000210; BTB/POZ_dom.
DR   InterPro; IPR047098; KEAP1_BACK.
DR   InterPro; IPR030563; KEAP1_BTB_POZ_dom.
DR   InterPro; IPR015915; Kelch-typ_b-propeller.
DR   InterPro; IPR006652; Kelch_1.
DR   InterPro; IPR011333; SKP1/BTB/POZ_sf.
DR   PANTHER; PTHR45632:SF13; KELCH-LIKE PROTEIN 26; 1.
DR   PANTHER; PTHR45632; LD33804P; 1.
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; Kelch motif; 1.
DR   SUPFAM; SSF54695; POZ domain; 1.
DR   PROSITE; PS50097; BTB; 1.
PE   2: Evidence at transcript level;
KW   Cytoplasm; Kelch repeat; Nucleus; Reference proteome; Repeat;
KW   S-nitrosylation; Thioether bond; Ubl conjugation; Ubl conjugation pathway.
FT   CHAIN           1..624
FT                   /note="Kelch-like ECH-associated protein 1"
FT                   /id="PRO_0000119095"
FT   DOMAIN          77..149
FT                   /note="BTB"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00037"
FT   DOMAIN          184..286
FT                   /note="BACK"
FT   REPEAT          327..372
FT                   /note="Kelch 1"
FT   REPEAT          373..423
FT                   /note="Kelch 2"
FT   REPEAT          424..470
FT                   /note="Kelch 3"
FT   REPEAT          471..517
FT                   /note="Kelch 4"
FT   REPEAT          519..564
FT                   /note="Kelch 5"
FT   REPEAT          565..611
FT                   /note="Kelch 6"
FT   SITE            151
FT                   /note="Sensor for electrophilic agents"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Z2X8"
FT   SITE            257
FT                   /note="Sensor for electrophilic agents"
FT                   /evidence="ECO:0000250|UniProtKB:Q14145"
FT   SITE            273
FT                   /note="Sensor for electrophilic agents"
FT                   /evidence="ECO:0000250|UniProtKB:Q14145"
FT   SITE            288
FT                   /note="Sensor for electrophilic agents"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Z2X8"
FT   SITE            434
FT                   /note="Sensor for electrophilic agents"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Z2X8"
FT   MOD_RES         38
FT                   /note="S-(2-succinyl)cysteine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Z2X8"
FT   MOD_RES         151
FT                   /note="S-(2,3-dicarboxypropyl)cysteine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:Q14145"
FT   MOD_RES         151
FT                   /note="S-(2-succinyl)cysteine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Z2X8"
FT   MOD_RES         151
FT                   /note="S-nitrosocysteine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Z2X8"
FT   MOD_RES         241
FT                   /note="S-(2-succinyl)cysteine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Z2X8"
FT   MOD_RES         257
FT                   /note="S-(2,3-dicarboxypropyl)cysteine"
FT                   /evidence="ECO:0000250|UniProtKB:Q14145"
FT   MOD_RES         273
FT                   /note="S-(2,3-dicarboxypropyl)cysteine"
FT                   /evidence="ECO:0000250|UniProtKB:Q14145"
FT   MOD_RES         288
FT                   /note="S-(2,3-dicarboxypropyl)cysteine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:Q14145"
FT   MOD_RES         288
FT                   /note="S-(2-succinyl)cysteine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Z2X8"
FT   MOD_RES         319
FT                   /note="S-(2-succinyl)cysteine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Z2X8"
FT   MOD_RES         434
FT                   /note="S-cGMP-cysteine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Z2X8"
FT   MOD_RES         613
FT                   /note="S-(2-succinyl)cysteine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Z2X8"
FT   CROSSLNK        135
FT                   /note="N5-[4-(S-L-cysteinyl)-5-methyl-1H-imidazol-2-yl]-L-
FT                   ornithine (Arg-Cys) (interchain with C-151 in KEAP1)"
FT                   /evidence="ECO:0000250|UniProtKB:Q14145"
FT   CROSSLNK        151
FT                   /note="N5-[4-(S-L-cysteinyl)-5-methyl-1H-imidazol-2-yl]-L-
FT                   ornithine (Cys-Arg) (interchain with R-135 in KEAP1)"
FT                   /evidence="ECO:0000250|UniProtKB:Q14145"
SQ   SEQUENCE   624 AA;  69399 MW;  B5E77B5A72546A79 CRC64;
     MQPEPKPSGA PRSSQFLPLW SKCPEGAGDA VMYASTECKA EVTPSQDGNR TFSYTLEDHT
     KQAFGIMNEL RLSQQLCDVT LQVKYEDIPA AQFMAHKVVL ASSSPVFKAM FTNGLREQGM
     EVVSIEGIHP KVMERLIEFA YTASISVGEK CVLHVMNGAV MYQIDSVVRA CSDFLVQQLD
     PSNAIGIANF AEQIGCTELH QRAREYIYMH FGEVAKQEEF FNLSHCQLAT LISRDDLNVR
     CESEVFHACI DWVKYDCPQR RFYVQALLRA VRCHALTPRF LQTQLQKCEI LQADARCKDY
     LVQIFQELTL HKPTQAVPCR APKVGRLIYT AGGYFRQSLS YLEAYNPSNG SWLRLADLQV
     PRSGLAGCVV GGLLYAVGGR NNSPDGNTDS SALDCYNPMT NQWSPCASLS VPRNRSGGGV
     IDGHIYAVGG SHGCIHHSSV ERYEPDRDEW HLVAPMLTRR IGVGVAVLNR LLYAVGGFDG
     TNRLNSAECY YPERNEWRMI TPMNTIRSGA GVCVLHSCIY AAGGYDGQDQ LNSVERYDVE
     TETWTFVASM KHRRSALGIA VHQGRIYVLG GYDGHTFLDS VECYDPDTDT WSEVTRLTSG
     RSGVGVAVTM EPCRKQIDQQ NCTC
//