Q684M4 · KEAP1_PIG

  • Protein
    Kelch-like ECH-associated protein 1
  • Gene
    KEAP1
  • Status
    UniProtKB reviewed (Swiss-Prot)
  • Amino acids
  • Protein existence
    Inferred from homology
  • Annotation score
    5/5

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).

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.

TypeIDPosition(s)Description
Site151Sensor for electrophilic agents
Site257Sensor for electrophilic agents
Site273Sensor for electrophilic agents
Site288Sensor for electrophilic agents
Site434Sensor for electrophilic agents

GO annotations

AspectTerm
Cellular Componentactin filament
Cellular Componentcentriolar satellite
Cellular ComponentCul3-RING ubiquitin ligase complex
Cellular Componentcytoplasm
Cellular Componentcytosol
Cellular Componentendoplasmic reticulum
Cellular Componentinclusion body
Cellular Componentmidbody
Cellular Componentnucleoplasm
Molecular Functiondisordered domain specific binding
Molecular Functionidentical protein binding
Molecular FunctionRNA polymerase II-specific DNA-binding transcription factor binding
Molecular Functiontranscription regulator inhibitor activity
Molecular Functionubiquitin-like ligase-substrate adaptor activity
Biological Processcellular response to interleukin-4
Biological Processcellular response to oxidative stress
Biological Processin utero embryonic development
Biological Processnegative regulation of response to oxidative stress
Biological Processnegative regulation of transcription by RNA polymerase II
Biological Processprotein ubiquitination
Biological Processregulation of autophagy
Biological Processregulation of epidermal cell differentiation
Biological Processubiquitin-dependent protein catabolic process

Keywords

Enzyme and pathway databases

Names & Taxonomy

Protein names

  • Recommended name
    Kelch-like ECH-associated protein 1

Gene names

    • Name
      KEAP1

Organism names

  • Taxonomic identifier
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Laurasiatheria > Artiodactyla > Suina > Suidae > Sus

Accessions

  • Primary accession
    Q684M4

Proteomes

Organism-specific databases

Subcellular Location

Cytoplasm
Nucleus
Note: Mainly cytoplasmic. In response to selective autophagy, relocalizes to inclusion bodies following interaction with SQSTM1/p62.

Keywords

PTM/Processing

Features

Showing features for chain, modified residue, cross-link.

TypeIDPosition(s)Description
ChainPRO_00002863921-624Kelch-like ECH-associated protein 1
Modified residue38S-(2-succinyl)cysteine
Cross-link135N5-[4-(S-L-cysteinyl)-5-methyl-1H-imidazol-2-yl]-L-ornithine (Arg-Cys) (interchain with C-151 in KEAP1)
Modified residue151S-(2,3-dicarboxypropyl)cysteine; alternate
Modified residue151S-(2-succinyl)cysteine
Modified residue151S-nitrosocysteine; alternate
Cross-link151N5-[4-(S-L-cysteinyl)-5-methyl-1H-imidazol-2-yl]-L-ornithine (Cys-Arg) (interchain with R-135 in KEAP1)
Modified residue241S-(2-succinyl)cysteine
Modified residue257S-(2,3-dicarboxypropyl)cysteine
Modified residue273S-(2,3-dicarboxypropyl)cysteine
Modified residue288S-(2,3-dicarboxypropyl)cysteine; alternate
Modified residue288S-(2-succinyl)cysteine
Modified residue319S-(2-succinyl)cysteine
Modified residue434S-cGMP-cysteine
Modified residue613S-(2-succinyl)cysteine

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).
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

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).

Protein-protein interaction databases

Family & Domains

Features

Showing features for region, domain, repeat.

TypeIDPosition(s)Description
Region1-27Disordered
Domain77-149BTB
Domain184-286BACK
Repeat327-372Kelch 1
Repeat373-423Kelch 2
Repeat424-470Kelch 3
Repeat471-517Kelch 4
Repeat519-564Kelch 5
Repeat565-611Kelch 6

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

Phylogenomic databases

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Length
    624
  • Mass (Da)
    69,816
  • Last updated
    2004-10-11 v1
  • Checksum
    F087ECC342299444
MQPEPRPSGAGAHTQFLPLRSQRPEGAGDTVMYASTECKAEVTPSQHGNRTFSYTLEDHTKQAFGIMNELRLSQQLCDVTLQVKYEDAPAAQFMAHKVVLASSSPVFKAMFTNGLREQGMEVVSIEGIHPKVMERLIEFAYTASISMGEKCVLHVMNGAVMYQIDSVVRACSDFLVQQLDPSNAIGIANFAEQIGCAELHQRAREYIYMHFGEVAKQEEFFNLSHCQLVTLISRDDLNVRCESEVFHACINWVKYDCEQRRFYVQALLRAVRCHSLTPHFLQMQLQKCEILQSDSRCKDYLVKIFQELTLHKPTQVMPCRAPKVGRLIYTAGGYFRQSLSYLEAYNPSDGTWLRLADLQVPRSGLAGCVVGGLLYAVGGRNNSPDGNTDSSALDCYNPMTNQWSPCAPMSVPRNRIGVGVIDGHIYAVGGSHGCIHHNSVERYEPERDEWHLVAPMLTRRIGVGVAVLNRLLYAVGGFDGTNRLNSAECYYPERNEWRMITPMNTIRSGAGVCVLHNCIYAAGGYDGQDQLNSVERYDVETETWTFVAPMKHRRSALGITVHQGRIYVLGGYDGHTFLDSVECYDPDTDTWSEVTRMTSGRSGVGVAVTMEPCRKQIDQQNCTC

Computationally mapped potential isoform sequences

There are 3 potential isoforms mapped to this entry

View all
EntryEntry nameGene nameLength
A0A5S6GCY8A0A5S6GCY8_PIGKEAP1610
A0A5S6GD92A0A5S6GD92_PIGKEAP1565
A0A5G2QVT9A0A5G2QVT9_PIGKEAP1615

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
AJ632303
EMBL· GenBank· DDBJ
CAG15151.1
EMBL· GenBank· DDBJ
Genomic DNA

Genome annotation databases

Similar Proteins

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