P57790
uniprot
P57790
canonical
activity_regulation
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. {ECO:0000250|UniProtKB:Q9Z2X8}.
uniprot
proteins
amino_acid_sequence
MQPEPKPSGAPRSSQFLPLWSKCPEGAGDAVMYASTECKAEVTPSQDGNRTFSYTLEDHTKQAFGIMNELRLSQQLCDVTLQVKYEDIPAAQFMAHKVVLASSSPVFKAMFTNGLREQGMEVVSIEGIHPKVMERLIEFAYTASISVGEKCVLHVMNGAVMYQIDSVVRACSDFLVQQLDPSNAIGIANFAEQIGCTELHQRAREYIYMHFGEVAKQEEFFNLSHCQLATLISRDDLNVRCESEVFHACIDWVKYDCPQRRFYVQALLRAVRCHALTPRFLQTQLQKCEILQADARCKDYLVQIFQELTLHKPTQAVPCRAPKVGRLIYTAGGYFRQSLSYLEAYNPSNGSWLRLADLQVPRSGLAGCVVGGLLYAVGGRNNSPDGNTDSSALDCYNPMTNQWSPCASLSVPRNRSGGGVIDGHIYAVGGSHGCIHHSSVERYEPDRDEWHLVAPMLTRRIGVGVAVLNRLLYAVGGFDGTNRLNSAECYYPERNEWRMITPMNTIRSGAGVCVLHSCIYAAGGYDGQDQLNSVERYDVETETWTFVASMKHRRSALGIAVHQGRIYVLGGYDGHTFLDSVECYDPDTDTWSEVTRLTSGRSGVGVAVTMEPCRKQIDQQNCTC
uniprot
proteins
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). {ECO:0000250|UniProtKB:Q14145, ECO:0000250|UniProtKB:Q9Z2X8}.
uniprot
proteins
mass_dalton
69399
uniprot
proteins
pathway_participation
PATHWAY: Protein modification; protein ubiquitination. {ECO:0000250|UniProtKB:Q9Z2X8}.
uniprot
proteins
post_translational_modification
PTM: 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). {ECO:0000250|UniProtKB:Q14145, ECO:0000250|UniProtKB:Q9Z2X8}.; PTM: Degraded via a proteasomal-independent process during selective autophagy: interaction with phosphorylated SQSTM1/p62 sequesters KEAP1 in inclusion bodies, leading to its degradation. {ECO:0000250|UniProtKB:Q9Z2X8}.; PTM: 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. Ubiquitinated by TRIM25; leading to degradation upon ER stress (By similarity). {ECO:0000250|UniProtKB:Q14145}.
uniprot
proteins
protein_family
KEAP1 family
uniprot
proteins
pubmed
11439354
uniprot
proteins
sequence_length
624
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9Z2X8}. Nucleus {ECO:0000250|UniProtKB:Q9Z2X8}. Note=Mainly cytoplasmic. In response to selective autophagy, relocalizes to inclusion bodies following interaction with SQSTM1/p62. {ECO:0000250|UniProtKB:Q9Z2X8}.
uniprot
proteins