Q684M4 · KEAP1_PIG
- ProteinKelch-like ECH-associated protein 1
- GeneKEAP1
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids624 (go to sequence)
- Protein existenceInferred from homology
- Annotation score5/5
Function
function
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that regulates the response to oxidative stress by targeting NFE2L2/NRF2 for ubiquitination. KEAP1 acts as a key sensor of oxidative and electrophilic stress: in normal conditions, the BCR(KEAP1) complex mediates ubiquitination and degradation of NFE2L2/NRF2, a transcription factor regulating expression of many cytoprotective genes. In response to oxidative stress, different electrophile metabolites trigger non-enzymatic covalent modifications of highly reactive cysteine residues in KEAP1, leading to inactivate the ubiquitin ligase activity of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and expression of phase II detoxifying enzymes. In response to selective autophagy, KEAP1 is sequestered in inclusion bodies following its interaction with SQSTM1/p62, leading to inactivation of the BCR(KEAP1) complex and activation of NFE2L2/NRF2. The BCR(KEAP1) complex also mediates ubiquitination of SQSTM1/p62, increasing SQSTM1/p62 sequestering activity and degradation (By similarity).
The BCR(KEAP1) complex also targets BPTF and PGAM5 for ubiquitination and degradation by the proteasome (By similarity).
The BCR(KEAP1) complex also targets BPTF and PGAM5 for ubiquitination and degradation by the proteasome (By similarity).
Activity regulation
Ubiquitin ligase activity of the BCR(KEAP1) complex is inhibited by oxidative stress and electrophile metabolites such as sulforaphane. Electrophile metabolites react with reactive cysteine residues in KEAP1 and trigger non-enzymatic covalent modifications of these cysteine residues, leading to inactivate the ubiquitin ligase activity of the BCR(KEAP1) complex. Selective autophagy also inactivates the BCR(KEAP1) complex via interaction between KEAP1 and SQSTM1/p62, which sequesters the complex in inclusion bodies and promotes its degradation.
Pathway
Protein modification; protein ubiquitination.
Features
Showing features for site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Site | 151 | Sensor for electrophilic agents | ||||
Sequence: C | ||||||
Site | 257 | Sensor for electrophilic agents | ||||
Sequence: C | ||||||
Site | 273 | Sensor for electrophilic agents | ||||
Sequence: C | ||||||
Site | 288 | Sensor for electrophilic agents | ||||
Sequence: C | ||||||
Site | 434 | Sensor for electrophilic agents | ||||
Sequence: C |
GO annotations
Keywords
- Biological process
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameKelch-like ECH-associated protein 1
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Laurasiatheria > Artiodactyla > Suina > Suidae > Sus
Accessions
- Primary accessionQ684M4
Proteomes
Organism-specific databases
PTM/Processing
Features
Showing features for chain, modified residue, cross-link.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000286392 | 1-624 | Kelch-like ECH-associated protein 1 | |||
Sequence: MQPEPRPSGAGAHTQFLPLRSQRPEGAGDTVMYASTECKAEVTPSQHGNRTFSYTLEDHTKQAFGIMNELRLSQQLCDVTLQVKYEDAPAAQFMAHKVVLASSSPVFKAMFTNGLREQGMEVVSIEGIHPKVMERLIEFAYTASISMGEKCVLHVMNGAVMYQIDSVVRACSDFLVQQLDPSNAIGIANFAEQIGCAELHQRAREYIYMHFGEVAKQEEFFNLSHCQLVTLISRDDLNVRCESEVFHACINWVKYDCEQRRFYVQALLRAVRCHSLTPHFLQMQLQKCEILQSDSRCKDYLVKIFQELTLHKPTQVMPCRAPKVGRLIYTAGGYFRQSLSYLEAYNPSDGTWLRLADLQVPRSGLAGCVVGGLLYAVGGRNNSPDGNTDSSALDCYNPMTNQWSPCAPMSVPRNRIGVGVIDGHIYAVGGSHGCIHHNSVERYEPERDEWHLVAPMLTRRIGVGVAVLNRLLYAVGGFDGTNRLNSAECYYPERNEWRMITPMNTIRSGAGVCVLHNCIYAAGGYDGQDQLNSVERYDVETETWTFVAPMKHRRSALGITVHQGRIYVLGGYDGHTFLDSVECYDPDTDTWSEVTRMTSGRSGVGVAVTMEPCRKQIDQQNCTC | ||||||
Modified residue | 38 | S-(2-succinyl)cysteine | ||||
Sequence: C | ||||||
Cross-link | 135 | N5-[4-(S-L-cysteinyl)-5-methyl-1H-imidazol-2-yl]-L-ornithine (Arg-Cys) (interchain with C-151 in KEAP1) | ||||
Sequence: R | ||||||
Modified residue | 151 | S-(2,3-dicarboxypropyl)cysteine; alternate | ||||
Sequence: C | ||||||
Modified residue | 151 | S-(2-succinyl)cysteine | ||||
Sequence: C | ||||||
Modified residue | 151 | S-nitrosocysteine; alternate | ||||
Sequence: C | ||||||
Cross-link | 151 | N5-[4-(S-L-cysteinyl)-5-methyl-1H-imidazol-2-yl]-L-ornithine (Cys-Arg) (interchain with R-135 in KEAP1) | ||||
Sequence: C | ||||||
Modified residue | 241 | S-(2-succinyl)cysteine | ||||
Sequence: C | ||||||
Modified residue | 257 | S-(2,3-dicarboxypropyl)cysteine | ||||
Sequence: C | ||||||
Modified residue | 273 | S-(2,3-dicarboxypropyl)cysteine | ||||
Sequence: C | ||||||
Modified residue | 288 | S-(2,3-dicarboxypropyl)cysteine; alternate | ||||
Sequence: C | ||||||
Modified residue | 288 | S-(2-succinyl)cysteine | ||||
Sequence: C | ||||||
Modified residue | 319 | S-(2-succinyl)cysteine | ||||
Sequence: C | ||||||
Modified residue | 434 | S-cGMP-cysteine | ||||
Sequence: C | ||||||
Modified residue | 613 | S-(2-succinyl)cysteine | ||||
Sequence: C |
Post-translational modification
Non-enzymatic covalent modifications of reactive cysteines by electrophile metabolites inactivate the BCR(KEAP1) complex. Accumulation of fumarate promotes the formation of cysteine S-succination (S-(2-succinyl)cysteine), leading to inactivate the BCR(KEAP1) complex and promote NFE2L2/NRF2 nuclear accumulation and activation. Nitric oxide-dependent 8-Nitro-cGMP formation promotes cysteine guanylation (S-cGMP-cysteine), leading to NFE2L2/NRF2 nuclear accumulation and activation. Itaconate, an anti-inflammatory metabolite generated in response to lipopolysaccharide, alkylates cysteines, activating NFE2L2/NRF2 (By similarity).
Methylglyoxal, a reactive metabolite that accumulates when the glycolytic enzyme PGK1 is inhibited, promotes formation of a methylimidazole cross-link between proximal Cys-151 and Arg-135 on another KEAP1 molecule, resulting in an inactive dimer that inactivates the BCR(KEAP1) complex (By similarity).
Methylglyoxal, a reactive metabolite that accumulates when the glycolytic enzyme PGK1 is inhibited, promotes formation of a methylimidazole cross-link between proximal Cys-151 and Arg-135 on another KEAP1 molecule, resulting in an inactive dimer that inactivates the BCR(KEAP1) complex (By similarity).
Degraded via a proteasomal-independent process during selective autophagy: interaction with phosphorylated SQSTM1/p62 sequesters KEAP1 in inclusion bodies, leading to its degradation.
Auto-ubiquitinated by the BCR(KEAP1) complex. 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. Deubiquitinated by USP25; leading to stabilization.
Keywords
- PTM
Proteomic databases
Expression
Gene expression databases
Interaction
Subunit
Component of the BCR(KEAP1) E3 ubiquitin ligase complex, at least composed of 2 molecules of CUL3, 2 molecules of KEAP1, and RBX1. Interacts with NFE2L2/NRF2; the interaction is direct (By similarity).
Forms a ternary complex with NFE2L2/NRF2 and PGAM5 (By similarity).
Interacts with (phosphorylated) SQSTM1/p62; the interaction is direct and inactivates the BCR(KEAP1) complex by sequestering it in inclusion bodies, promoting its degradation (By similarity).
Interacts with NFE2L1. Interacts with BPTF and PTMA. Interacts with MAP1LC3B. Interacts indirectly with ENC1. Interacts with SESN1 and SESN2. Interacts with HSP90AA1 and HSP90AB1 (By similarity).
Forms a ternary complex with NFE2L2/NRF2 and PGAM5 (By similarity).
Interacts with (phosphorylated) SQSTM1/p62; the interaction is direct and inactivates the BCR(KEAP1) complex by sequestering it in inclusion bodies, promoting its degradation (By similarity).
Interacts with NFE2L1. Interacts with BPTF and PTMA. Interacts with MAP1LC3B. Interacts indirectly with ENC1. Interacts with SESN1 and SESN2. Interacts with HSP90AA1 and HSP90AB1 (By similarity).
Protein-protein interaction databases
Structure
Family & Domains
Features
Showing features for region, domain, repeat.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 1-27 | Disordered | ||||
Sequence: MQPEPRPSGAGAHTQFLPLRSQRPEGA | ||||||
Domain | 77-149 | BTB | ||||
Sequence: CDVTLQVKYEDAPAAQFMAHKVVLASSSPVFKAMFTNGLREQGMEVVSIEGIHPKVMERLIEFAYTASISMGE | ||||||
Domain | 184-286 | BACK | ||||
Sequence: AIGIANFAEQIGCAELHQRAREYIYMHFGEVAKQEEFFNLSHCQLVTLISRDDLNVRCESEVFHACINWVKYDCEQRRFYVQALLRAVRCHSLTPHFLQMQLQ | ||||||
Repeat | 327-372 | Kelch 1 | ||||
Sequence: LIYTAGGYFRQSLSYLEAYNPSDGTWLRLADLQVPRSGLAGCVVGG | ||||||
Repeat | 373-423 | Kelch 2 | ||||
Sequence: LLYAVGGRNNSPDGNTDSSALDCYNPMTNQWSPCAPMSVPRNRIGVGVIDG | ||||||
Repeat | 424-470 | Kelch 3 | ||||
Sequence: HIYAVGGSHGCIHHNSVERYEPERDEWHLVAPMLTRRIGVGVAVLNR | ||||||
Repeat | 471-517 | Kelch 4 | ||||
Sequence: LLYAVGGFDGTNRLNSAECYYPERNEWRMITPMNTIRSGAGVCVLHN | ||||||
Repeat | 519-564 | Kelch 5 | ||||
Sequence: IYAAGGYDGQDQLNSVERYDVETETWTFVAPMKHRRSALGITVHQG | ||||||
Repeat | 565-611 | Kelch 6 | ||||
Sequence: RIYVLGGYDGHTFLDSVECYDPDTDTWSEVTRMTSGRSGVGVAVTME |
Domain
The Kelch repeats mediate interaction with NFE2L2/NRF2, BPTF and PGAM5.
KEAP1 contains reactive cysteine residues that act as sensors for endogenously produced and exogenously encountered small molecules, which react with sulfhydryl groups and modify the cysteine sensors, leading to impair ability of the BCR(KEAP1) complex to ubiquitinate target proteins.
Sequence similarities
Belongs to the KEAP1 family.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length624
- Mass (Da)69,816
- Last updated2004-10-11 v1
- ChecksumF087ECC342299444
Computationally mapped potential isoform sequences
There are 3 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
A0A5S6GCY8 | A0A5S6GCY8_PIG | KEAP1 | 610 | ||
A0A5S6GD92 | A0A5S6GD92_PIG | KEAP1 | 565 | ||
A0A5G2QVT9 | A0A5G2QVT9_PIG | KEAP1 | 615 |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AJ632303 EMBL· GenBank· DDBJ | CAG15151.1 EMBL· GenBank· DDBJ | Genomic DNA |