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Protein

Kelch-like ECH-associated protein 1

Gene

KEAP1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Acts as a substrate adapter protein for the E3 ubiquitin ligase complex formed by CUL3 and RBX1 and targets NFE2L2/NRF2 for ubiquitination and degradation by the proteasome, thus resulting in the suppression of its transcriptional activity and the repression of antioxidant response element-mediated detoxifying enzyme gene expression. Retains NFE2L2/NRF2 and may also retain BPTF in the cytosol. Targets PGAM5 for ubiquitination and degradation by the proteasome.5 Publications

Activity regulationi

Ubiquitination and subsequent degradation of PGAM5 is inhibited by oxidative stress and sulforaphane. Sulforaphane also inhibits ubiquitination of NFE2L2/NRF2.2 Publications

Pathwayi: protein ubiquitination

This protein is involved in the pathway protein ubiquitination, which is part of Protein modification.
View all proteins of this organism that are known to be involved in the pathway protein ubiquitination and in Protein modification.

GO - Molecular functioni

GO - Biological processi

Keywordsi

Biological processTranscription, Transcription regulation, Ubl conjugation pathway

Enzyme and pathway databases

ReactomeiR-HSA-5689880 Ub-specific processing proteases
R-HSA-8951664 Neddylation
R-HSA-983168 Antigen processing: Ubiquitination & Proteasome degradation
SIGNORiQ14145
UniPathwayi
UPA00143

Names & Taxonomyi

Protein namesi
Recommended name:
Kelch-like ECH-associated protein 1
Alternative name(s):
Cytosolic inhibitor of Nrf2
Short name:
INrf2
Kelch-like protein 19
Gene namesi
Name:KEAP1
Synonyms:INRF2, KIAA0132, KLHL19
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 19

Organism-specific databases

EuPathDBiHostDB:ENSG00000079999.13
HGNCiHGNC:23177 KEAP1
MIMi606016 gene
neXtProtiNX_Q14145

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi125 – 127IEG → AAA: Increases ubiquitination and proteolytic degradation. 1 Publication3
Mutagenesisi151C → S: Constitutive repression of NFE2L2-dependent gene expression. Promotes increased degradation of NFE2L2. Resistance of ubiquitination of PGAM5 to inhibition by oxidative stress and sulforaphane. Does not prevent its ubiquitination and degradation in response to quinone-induced oxidative stress. 3 Publications1
Mutagenesisi162 – 164YQI → AAA: Increases ubiquitination and proteolytic degradation. 1 Publication3
Mutagenesisi273C → S: Abolishes repression of NFE2L2-dependent gene expression. Slows down degradation of NFE2L2. 1 Publication1
Mutagenesisi288C → S: Abolishes repression of NFE2L2-dependent gene expression. Slows down degradation of NFE2L2. 1 Publication1
Mutagenesisi308L → A: Loss of export from nucleus; when associated with A-310. 1 Publication1
Mutagenesisi310L → A: Loss of export from nucleus; when associated with A-308. 1 Publication1
Mutagenesisi334Y → A: Loss of interaction with NFE2L2. Strongly reduces repression of NFE2L2-dependent gene expression. Loss of interaction with PGAM5. 2 Publications1
Mutagenesisi380R → A: Loss of interaction with NFE2L2. Abolishes repression of NFE2L2-dependent gene expression. 1 Publication1
Mutagenesisi382N → A: Loss of interaction with NFE2L2. Strongly reduces repression of NFE2L2-dependent gene expression. 1 Publication1
Mutagenesisi415R → A: Loss of interaction with NFE2L2. Abolishes repression of NFE2L2-dependent gene expression. Loss of interaction with PGAM5. 2 Publications1
Mutagenesisi436H → A: Loss of interaction with NFE2L2. Abolishes repression of NFE2L2-dependent gene expression. 1 Publication1
Mutagenesisi478F → A: Abolishes repression of NFE2L2-dependent gene expression. 1 Publication1
Mutagenesisi483R → A: Loss of interaction with NFE2L2. Abolishes repression of NFE2L2-dependent gene expression. Loss of interaction with PGAM5. 2 Publications1
Mutagenesisi525Y → A: Loss of interaction with NFE2L2. Strongly reduces repression of NFE2L2-dependent gene expression. 1 Publication1
Mutagenesisi572Y → A: Loss of interaction with NFE2L2. Strongly reduces repression of NFE2L2-dependent gene expression. Loss of interaction with PGAM5. 2 Publications1

Organism-specific databases

DisGeNETi9817
MalaCardsiKEAP1
OpenTargetsiENSG00000079999
PharmGKBiPA134887774

Chemistry databases

ChEMBLiCHEMBL2069156
DrugBankiDB08908 Dimethyl fumarate
GuidetoPHARMACOLOGYi2757

Polymorphism and mutation databases

BioMutaiKEAP1
DMDMi146345444

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001190931 – 624Kelch-like ECH-associated protein 1Add BLAST624

Post-translational modificationi

Ubiquitinated by the E3 ubiquitin ligase complex formed by CUL3 and RBX1 and is subject to proteasomal-independent degradation. Quinone-induced oxidative stress, but not sulforaphane, increases its ubiquitination. Ubiquitination and subsequent degradation is most pronounced following prolonged exposure of cells to oxidative stress, particularly in glutathione-deficient cells that are highly susceptible to oxidative stress.2 Publications

Keywords - PTMi

Ubl conjugation

Proteomic databases

EPDiQ14145
MaxQBiQ14145
PaxDbiQ14145
PeptideAtlasiQ14145
PRIDEiQ14145
ProteomicsDBi59849

PTM databases

iPTMnetiQ14145
PhosphoSitePlusiQ14145

Expressioni

Tissue specificityi

Broadly expressed, with highest levels in skeletal muscle.1 Publication

Gene expression databases

BgeeiENSG00000079999 Expressed in 229 organ(s), highest expression level in muscle of leg
CleanExiHS_KEAP1
ExpressionAtlasiQ14145 baseline and differential
GenevisibleiQ14145 HS

Organism-specific databases

HPAiCAB025337
HPA005558

Interactioni

Subunit structurei

Homodimer. Forms a ternary complex with NFE2L2 and PGAM5. Interacts with the N-terminal regulatory domain of NFE2L2/NRF2. Interacts with BPTF and PTMA. Interacts with CUL3. Part of a complex that contains KEAP1, CUL3 and RBX1. Interacts with NFE2L1 and MAP1LC3B. Interacts indirectly with ENC1. Interacts with SESN1 and SESN2 (PubMed:23274085). Interacts with HSP90AA1 and HSP90AB1 (PubMed:26517842).12 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi115156, 132 interactors
CORUMiQ14145
DIPiDIP-42134N
ELMiQ14145
IntActiQ14145, 125 interactors
MINTiQ14145
STRINGi9606.ENSP00000171111

Chemistry databases

BindingDBiQ14145

Structurei

Secondary structure

1624
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ14145
SMRiQ14145
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ14145

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini77 – 149BTBPROSITE-ProRule annotationAdd BLAST73
Domaini184 – 286BACKAdd BLAST103
Repeati327 – 372Kelch 1Add BLAST46
Repeati373 – 423Kelch 2Add BLAST51
Repeati424 – 470Kelch 3Add BLAST47
Repeati471 – 517Kelch 4Add BLAST47
Repeati518 – 564Kelch 5Add BLAST47
Repeati565 – 611Kelch 6Add BLAST47

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi301 – 310Nuclear export signal10

Domaini

The Kelch repeats mediate interaction with NF2L2/NRF2, BPTF and PGAM5.1 Publication

Keywords - Domaini

Kelch repeat, Repeat

Phylogenomic databases

eggNOGiKOG4441 Eukaryota
ENOG410XNX8 LUCA
GeneTreeiENSGT00760000118931
HOGENOMiHOG000230814
HOVERGENiHBG014286
InParanoidiQ14145
KOiK10456
OMAiEQIGCTE
OrthoDBiEOG091G02T3
PhylomeDBiQ14145
TreeFamiTF329218

Family and domain databases

Gene3Di2.120.10.80, 1 hit
InterProiView protein in InterPro
IPR011705 BACK
IPR017096 BTB-kelch_protein
IPR000210 BTB/POZ_dom
IPR030563 KEAP1
IPR015915 Kelch-typ_b-propeller
IPR006652 Kelch_1
IPR011333 SKP1/BTB/POZ_sf
PANTHERiPTHR24412:SF162 PTHR24412:SF162, 1 hit
PfamiView protein in Pfam
PF07707 BACK, 1 hit
PF00651 BTB, 1 hit
PF01344 Kelch_1, 6 hits
PIRSFiPIRSF037037 Kelch-like_protein_gigaxonin, 1 hit
SMARTiView protein in SMART
SM00875 BACK, 1 hit
SM00225 BTB, 1 hit
SM00612 Kelch, 6 hits
SUPFAMiSSF117281 SSF117281, 1 hit
SSF54695 SSF54695, 1 hit
PROSITEiView protein in PROSITE
PS50097 BTB, 1 hit

Sequence (1+)i

Sequence statusi: Complete.

This entry has 1 described isoform and 6 potential isoforms that are computationally mapped.Show allAlign All

Q14145-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MQPDPRPSGA GACCRFLPLQ SQCPEGAGDA VMYASTECKA EVTPSQHGNR
60 70 80 90 100
TFSYTLEDHT KQAFGIMNEL RLSQQLCDVT LQVKYQDAPA AQFMAHKVVL
110 120 130 140 150
ASSSPVFKAM FTNGLREQGM EVVSIEGIHP KVMERLIEFA YTASISMGEK
160 170 180 190 200
CVLHVMNGAV MYQIDSVVRA CSDFLVQQLD PSNAIGIANF AEQIGCVELH
210 220 230 240 250
QRAREYIYMH FGEVAKQEEF FNLSHCQLVT LISRDDLNVR CESEVFHACI
260 270 280 290 300
NWVKYDCEQR RFYVQALLRA VRCHSLTPNF LQMQLQKCEI LQSDSRCKDY
310 320 330 340 350
LVKIFEELTL HKPTQVMPCR APKVGRLIYT AGGYFRQSLS YLEAYNPSDG
360 370 380 390 400
TWLRLADLQV PRSGLAGCVV GGLLYAVGGR NNSPDGNTDS SALDCYNPMT
410 420 430 440 450
NQWSPCAPMS VPRNRIGVGV IDGHIYAVGG SHGCIHHNSV ERYEPERDEW
460 470 480 490 500
HLVAPMLTRR IGVGVAVLNR LLYAVGGFDG TNRLNSAECY YPERNEWRMI
510 520 530 540 550
TAMNTIRSGA GVCVLHNCIY AAGGYDGQDQ LNSVERYDVE TETWTFVAPM
560 570 580 590 600
KHRRSALGIT VHQGRIYVLG GYDGHTFLDS VECYDPDTDT WSEVTRMTSG
610 620
RSGVGVAVTM EPCRKQIDQQ NCTC
Length:624
Mass (Da):69,666
Last modified:May 1, 2007 - v2
Checksum:iCE180F3897BB8C97
GO

Computationally mapped potential isoform sequencesi

There are 6 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
K7EJ49K7EJ49_HUMAN
Kelch-like ECH-associated protein 1
KEAP1
212Annotation score:
K7EJD8K7EJD8_HUMAN
Kelch-like ECH-associated protein 1
KEAP1
213Annotation score:
K7ESE0K7ESE0_HUMAN
Kelch-like ECH-associated protein 1
KEAP1
279Annotation score:
K7EQX2K7EQX2_HUMAN
Kelch-like ECH-associated protein 1
KEAP1
172Annotation score:
K7EPZ3K7EPZ3_HUMAN
Kelch-like ECH-associated protein 1
KEAP1
116Annotation score:
K7EMY1K7EMY1_HUMAN
Kelch-like ECH-associated protein 1
KEAP1
129Annotation score:

Sequence cautioni

The sequence BAA09481 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti504N → S in BAG51647 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_03608423C → Y in a breast cancer sample; somatic mutation. 1 Publication1
Natural variantiVAR_032102167V → F in a lung adenocarcinoma patient. 1 Publication1
Natural variantiVAR_032103236D → H in a NSCLC cell line. 1 Publication1
Natural variantiVAR_032104284Q → L in a lung adenocarcinoma patient. 1 Publication1
Natural variantiVAR_032105333G → C in a NSCLC cell line; strongly reduces interaction with NFE2L2 and reduces repression of NFE2L2-dependent gene expression. 1 Publication1
Natural variantiVAR_032106349D → N1 PublicationCorresponds to variant dbSNP:rs1048289Ensembl.1
Natural variantiVAR_032107350G → S in a NSCLC cell line. 1 PublicationCorresponds to variant dbSNP:rs777308626Ensembl.1
Natural variantiVAR_032108364G → C in a lung adenocarcinoma cell line; also in NSCLC cell lines; may be a polymorphism; strongly reduces interaction with NFE2L2 and reduces repression of NFE2L2-dependent gene expression. 1 PublicationCorresponds to variant dbSNP:rs1397945617Ensembl.1
Natural variantiVAR_032109430G → C in a lung adenocarcinoma patient; somatic mutation; strongly reduces interaction with NFE2L2 and reduces repression of NFE2L2-dependent gene expression. 1 Publication1
Natural variantiVAR_036085522A → V in a breast cancer sample; somatic mutation. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF361892
, AF361888, AF361889, AF361890, AF361891 Genomic DNA Translation: AAK43722.1
AF361886 mRNA Translation: AAK51082.1
D50922 mRNA Translation: BAA09481.3 Different initiation.
AK056204 mRNA Translation: BAG51647.1
AC011461 Genomic DNA No translation available.
BC002417 mRNA Translation: AAH02417.1
BC002930 mRNA Translation: AAH02930.1
BC015945 mRNA Translation: AAH15945.1
BC021957 mRNA Translation: AAH21957.2
CCDSiCCDS12239.1
RefSeqiNP_036421.2, NM_012289.3
NP_987096.1, NM_203500.1
XP_005260230.1, XM_005260173.1
XP_005260231.1, XM_005260174.1
XP_011526754.1, XM_011528452.1
UniGeneiHs.465870

Genome annotation databases

EnsembliENST00000171111; ENSP00000171111; ENSG00000079999
ENST00000393623; ENSP00000377245; ENSG00000079999
GeneIDi9817
KEGGihsa:9817
UCSCiuc002moq.2 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF361892
, AF361888, AF361889, AF361890, AF361891 Genomic DNA Translation: AAK43722.1
AF361886 mRNA Translation: AAK51082.1
D50922 mRNA Translation: BAA09481.3 Different initiation.
AK056204 mRNA Translation: BAG51647.1
AC011461 Genomic DNA No translation available.
BC002417 mRNA Translation: AAH02417.1
BC002930 mRNA Translation: AAH02930.1
BC015945 mRNA Translation: AAH15945.1
BC021957 mRNA Translation: AAH21957.2
CCDSiCCDS12239.1
RefSeqiNP_036421.2, NM_012289.3
NP_987096.1, NM_203500.1
XP_005260230.1, XM_005260173.1
XP_005260231.1, XM_005260174.1
XP_011526754.1, XM_011528452.1
UniGeneiHs.465870

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1U6DX-ray1.85X321-609[»]
1ZGKX-ray1.35A321-609[»]
2FLUX-ray1.50X321-609[»]
3VNGX-ray2.10A321-609[»]
3VNHX-ray2.10A321-609[»]
3ZGCX-ray2.20A/B321-609[»]
3ZGDX-ray1.98A/B321-609[»]
4CXIX-ray2.35A48-180[»]
4CXJX-ray2.80A48-180[»]
4CXTX-ray2.66A48-180[»]
4IFJX-ray1.80A321-609[»]
4IFLX-ray1.80X321-609[»]
4IFNX-ray2.40X321-609[»]
4IN4X-ray2.59A/B/C321-609[»]
4IQKX-ray1.97A321-609[»]
4L7BX-ray2.41A/B321-609[»]
4L7CX-ray2.40A/B/C321-609[»]
4L7DX-ray2.25A/B/C321-609[»]
4N1BX-ray2.55A/B/C321-609[»]
4XMBX-ray2.43A321-609[»]
5DADX-ray2.61A49-182[»]
5DAFX-ray2.37A49-182[»]
5F72X-ray1.85C/K321-611[»]
5GITX-ray2.19A48-180[»]
5NLBX-ray3.45A51-204[»]
5X54X-ray2.30A/B321-609[»]
6FMPX-ray2.92A/B321-609[»]
6FMQX-ray2.10A/B321-609[»]
ProteinModelPortaliQ14145
SMRiQ14145
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi115156, 132 interactors
CORUMiQ14145
DIPiDIP-42134N
ELMiQ14145
IntActiQ14145, 125 interactors
MINTiQ14145
STRINGi9606.ENSP00000171111

Chemistry databases

BindingDBiQ14145
ChEMBLiCHEMBL2069156
DrugBankiDB08908 Dimethyl fumarate
GuidetoPHARMACOLOGYi2757

PTM databases

iPTMnetiQ14145
PhosphoSitePlusiQ14145

Polymorphism and mutation databases

BioMutaiKEAP1
DMDMi146345444

Proteomic databases

EPDiQ14145
MaxQBiQ14145
PaxDbiQ14145
PeptideAtlasiQ14145
PRIDEiQ14145
ProteomicsDBi59849

Protocols and materials databases

DNASUi9817
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000171111; ENSP00000171111; ENSG00000079999
ENST00000393623; ENSP00000377245; ENSG00000079999
GeneIDi9817
KEGGihsa:9817
UCSCiuc002moq.2 human

Organism-specific databases

CTDi9817
DisGeNETi9817
EuPathDBiHostDB:ENSG00000079999.13
GeneCardsiKEAP1
HGNCiHGNC:23177 KEAP1
HPAiCAB025337
HPA005558
MalaCardsiKEAP1
MIMi606016 gene
neXtProtiNX_Q14145
OpenTargetsiENSG00000079999
PharmGKBiPA134887774
HUGEiSearch...
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG4441 Eukaryota
ENOG410XNX8 LUCA
GeneTreeiENSGT00760000118931
HOGENOMiHOG000230814
HOVERGENiHBG014286
InParanoidiQ14145
KOiK10456
OMAiEQIGCTE
OrthoDBiEOG091G02T3
PhylomeDBiQ14145
TreeFamiTF329218

Enzyme and pathway databases

UniPathwayi
UPA00143

ReactomeiR-HSA-5689880 Ub-specific processing proteases
R-HSA-8951664 Neddylation
R-HSA-983168 Antigen processing: Ubiquitination & Proteasome degradation
SIGNORiQ14145

Miscellaneous databases

ChiTaRSiKEAP1 human
EvolutionaryTraceiQ14145
GeneWikiiKEAP1
GenomeRNAii9817
PROiPR:Q14145
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000079999 Expressed in 229 organ(s), highest expression level in muscle of leg
CleanExiHS_KEAP1
ExpressionAtlasiQ14145 baseline and differential
GenevisibleiQ14145 HS

Family and domain databases

Gene3Di2.120.10.80, 1 hit
InterProiView protein in InterPro
IPR011705 BACK
IPR017096 BTB-kelch_protein
IPR000210 BTB/POZ_dom
IPR030563 KEAP1
IPR015915 Kelch-typ_b-propeller
IPR006652 Kelch_1
IPR011333 SKP1/BTB/POZ_sf
PANTHERiPTHR24412:SF162 PTHR24412:SF162, 1 hit
PfamiView protein in Pfam
PF07707 BACK, 1 hit
PF00651 BTB, 1 hit
PF01344 Kelch_1, 6 hits
PIRSFiPIRSF037037 Kelch-like_protein_gigaxonin, 1 hit
SMARTiView protein in SMART
SM00875 BACK, 1 hit
SM00225 BTB, 1 hit
SM00612 Kelch, 6 hits
SUPFAMiSSF117281 SSF117281, 1 hit
SSF54695 SSF54695, 1 hit
PROSITEiView protein in PROSITE
PS50097 BTB, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiKEAP1_HUMAN
AccessioniPrimary (citable) accession number: Q14145
Secondary accession number(s): B3KPD5
, Q6LEP0, Q8WTX1, Q9BPY9
Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 27, 2001
Last sequence update: May 1, 2007
Last modified: October 10, 2018
This is version 194 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  2. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. Human chromosome 19
    Human chromosome 19: entries, gene names and cross-references to MIM
  5. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  6. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
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