Kelch-like ECH-associated protein 1

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. The BCR(KEAP1) complex also targets BPTF and PGAM5 for ubiquitination and degradation by the proteasome.

Classification

Family (Pfam)

PF07707 BACK, PF00651 BTB, PF01344 Kelch_1, PF24681 Kelch_KLHDC2_KLHL20_DRC7

InterPro

BACK, BTB-kelch_protein, BTB/POZ_dom, KEAP1_BACK, KEAP1_BTB_POZ_dom, Kelch-typ_b-propeller, Kelch_1, SKP1/BTB/POZ_sf

Functional cluster

Zinc-Finger & Chromatin Regulatory Proteins

Experimental structures · PDB · 115

• 1U6D X-ray 1.85A
• 1ZGK X-ray 1.35A
• 2FLU X-ray 1.50A
• 3VNG X-ray 2.10A
• 3VNH X-ray 2.10A
• 3ZGC X-ray 2.20A
• 3ZGD X-ray 1.98A
• 4CXI X-ray 2.35A
• 4CXJ X-ray 2.80A
• 4CXT X-ray 2.66A
• 4IFJ X-ray 1.80A
• 4IFL X-ray 1.80A
• … and 103 more

A predicted model is available from AlphaFold.

Gene Ontology · 21

• GO:0005884 actin filament
• GO:0031463 Cul3-RING ubiquitin ligase complex
• GO:0005737 cytoplasm
• GO:0005829 cytosol
• GO:0005783 endoplasmic reticulum
• GO:0016234 inclusion body
• GO:0030496 midbody
• GO:0005654 nucleoplasm
• GO:0097718 disordered domain specific binding
• GO:0042802 identical protein binding
• GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding
• GO:0140416 transcription regulator inhibitor activity
• GO:1990756 ubiquitin-like ligase-substrate adaptor activity
• GO:0034599 cellular response to oxidative stress
• GO:1902883 negative regulation of response to oxidative stress
• GO:0000122 negative regulation of transcription by RNA polymerase II
• GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process
• GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process
• GO:0016567 protein ubiquitination
• GO:0010506 regulation of autophagy
• GO:0006511 ubiquitin-dependent protein catabolic process

Drugs targeting this protein · 4

• BARDOXOLONE METHYL inhibitor
• DIMETHYL FUMARATE inhibitor
• DIROXIMEL FUMARATE inhibitor
• MONOMETHYL FUMARATE inhibitor

Related proteins · sequence + function similarity

• Kelch-like ECH-associated protein 1 1.00
• Kelch-like ECH-associated protein 1 1.00
• Kelch-like ECH-associated protein 1 1.00
• Kelch-like ECH-associated protein 1 0.99
• Kelch-like ECH-associated protein 1B 0.97
• Kelch-like ECH-associated protein 1A 0.88
• Kelch-like protein 2 0.87
• Kelch-like protein 2 0.87
• Kelch-like protein 12 0.87
• Kelch-like protein 18 0.87
• Kelch-like protein 18 0.87
• Kelch-like protein 2 0.86

Co-cited proteins · studied together in the literature

• Nuclear factor erythroid 2-related factor 2 9 shared papers
• PDCD10 and GCKIII kinases-associated protein 1 1 shared papers
• Kelch-like ECH-associated protein 1 6 shared papers
• Phosphoglycerate kinase 1 1 shared papers
• Serine/threonine-protein phosphatase PGAM5, mitochondrial 2 shared papers
• Endoplasmic reticulum membrane sensor NFE2L1 1 shared papers
• Membrane-associated protein VP24 1 shared papers
• Ectoderm-neural cortex protein 1 2 shared papers
• Kelch-like protein 41 2 shared papers
• Ubiquitin carboxyl-terminal hydrolase 25 1 shared papers
• Cullin-3 3 shared papers
• Sequestosome-1 5 shared papers

Literature · 39 cited papers

• USP25 regulates KEAP1-NRF2 anti-oxidation axis and its inactivation protects acetaminophen-induced liver injury in male mice. Nat. Commun. · 2023
• C4orf19 inhibits colorectal cancer cell proliferation by competitively binding to Keap1 with TRIM25 via the USP17/Elk-1/CDK6 axis. Oncogene · 2023
• TRIM25 promotes the cell survival and growth of hepatocellular carcinoma through targeting Keap1-Nrf2 pathway. Nat. Commun. · 2020
• A metabolite-derived protein modification integrates glycolysis with KEAP1-NRF2 signalling. Nature · 2018
• Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature · 2018
• Stress-sensing mechanisms and the physiological roles of the Keap1-Nrf2 system during cellular stress. J. Biol. Chem. · 2017
• Keap1/cullin3 modulates p62/SQSTM1 activity via UBA domain ubiquitination. Cell Rep. · 2017
• Client proteins and small molecule inhibitors display distinct binding preferences for constitutive and stress-induced HSP90 isoforms and their conformationally restricted mutants. PLoS ONE · 2015
• Structure of the BTB domain of Keap1 and its interaction with the triterpenoid antagonist CDDO. PLoS ONE · 2014
• The Marburg virus VP24 protein interacts with Keap1 to activate the cytoprotective antioxidant response pathway. Cell Rep. · 2014
• Autophagy promotes primary ciliogenesis by removing OFD1 from centriolar satellites. Nature · 2013
• Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation of Keap1 and prevent oxidative liver damage. Cell Metab. · 2013
• … and 27 more in the literature graph