KEAP1_RAT
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 03-AUG-2022, entry version 142.
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. {ECO:0000250|UniProtKB:Q14145}.
CC -!- SIMILARITY: Belongs to the KEAP1 family. {ECO:0000305}.
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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; P57790; -.
DR PRIDE; P57790; -.
DR UCSC; RGD:621619; rat.
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; IDA: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; IDA:RGD.
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: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:0042994; P:cytoplasmic sequestering of transcription factor; IMP:RGD.
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:0045604; P:regulation of epidermal cell differentiation; ISO:RGD.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; 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 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; 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 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
