KEAP1

Kelch-like ECH-associated protein 1 is a protein that in humans is encoded by the Keap1 gene.[5]

KEAP1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1U6D, 1ZGK, 2FLU, 3VNG, 3VNH, 3ZGC, 3ZGD, 4CXI, 4CXJ, 4CXT, 4IFJ, 4IFL, 4IFN, 4IN4, 4IQK, 4L7B, 4L7C, 4L7D, 4N1B, 4XMB
Identifiers
Aliases	KEAP1, INrf2, KLHL19, kelch like ECH associated protein 1
External IDs	OMIM: 606016 MGI: 1858732 HomoloGene: 8184 GeneCards: KEAP1
Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19p13.2 Start 10,486,125 bp[1] End 10,503,558 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9|9 A3 Start 21,229,730 bp[2] End 21,239,361 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • transcription factor binding • ubiquitin-protein transferase activity • GO:0001948 protein binding • protein homodimerization activity • disordered domain specific binding • identical protein binding Cellular component • cytoplasm • Cul3-RING ubiquitin ligase complex • nucleoplasm • microtubule organizing center • midbody • endoplasmic reticulum • actin filament • cell nucleus • cytosol • macromolecular complex Biological process • cellular response to interleukin-4 • regulation of epidermal cell differentiation • regulation of transcription, DNA-templated • in utero embryonic development • proteasomal ubiquitin-independent protein catabolic process • negative regulation of sequence-specific DNA binding transcription factor activity • transcription, DNA-templated • protein ubiquitination • positive regulation of proteasomal ubiquitin-dependent protein catabolic process • cytoplasmic sequestering of transcription factor • protein deubiquitination • post-translational modification • GO:0022415 viral process Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	9817	50868
Ensembl	ENSG00000079999	ENSMUSG00000003308
UniProt	Q14145	Q9Z2X8
RefSeq (mRNA)	NM_012289 NM_203500	NM_001110305 NM_001110306 NM_001110307 NM_016679
RefSeq (protein)	NP_036421 NP_987096	NP_001103775 NP_001103776 NP_001103777 NP_057888
Location (UCSC)	Chr 19: 10.49 – 10.5 Mb	Chr 9: 21.23 – 21.24 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Structure

Keap1 has four discrete protein domains. The N-terminal Broad complex, Tramtrack and Bric-à-Brac (BTB) domain contains the Cys151 residue, which is one of the important cysteines in stress sensing. The intervening region (IVR) domain contains two critical cysteine residues, Cys273 and Cys288, which are a second group of cysteines important for stress sensing. A double glycine repeat (DGR) and C-terminal region (CTR) domains collaborate to form a β-propeller structure, which is where Keap1 interacts with Nrf2.

Interactions

The KEAP1/NRF2 pathway modulates the body's antitumor response

Keap1 has been shown to interact with Nrf2, a master regulator of the antioxidant response, which is important for the amelioration of oxidative stress.[6][7][8]

Under quiescent conditions, Nrf2 is anchored in the cytoplasm through binding to Keap1, which, in turn, facilitates the ubiquitination and subsequent proteolysis of Nrf2. Such sequestration and further degradation of Nrf2 in the cytoplasm are mechanisms for the repressive effects of Keap1 on Nrf2. Keap1 is not only a tumor suppressor gene, but also a metastasis suppressor gene.[9]

As a drug target

Because Nrf2 activation leads to a coordinated antioxidant and anti-inflammatory response, and Keap1 represses Nrf2 activation, Keap1 has become a very attractive drug target.[10][11][12][13]

A series of synthetic oleane triterpenoid compounds, known as antioxidant inflammation modulators (AIMs), are being developed by Reata Pharmaceuticals, Inc. and are potent inducers of the Keap1-Nrf2 pathway, blocking Keap1-dependent Nrf2 ubiquitination and leading to the stabilization and nuclear translocation of Nrf2 and subsequent induction of Nrf2 target genes. The lead compound in this series, bardoxolone methyl (also known as CDDO-Me or RTA 402), was in late-stage clinical trials for the treatment of chronic kidney disease (CKD) in patients with type 2 diabetes mellitus and showed an ability to improve markers of renal function in these patients. However, the Phase 3 trial was halted due to safety concerns.

Human health

Mutations in KEAP1 that result in loss-of-function are not linked to familial cancers, though they do predispose individuals to multinodular goiters. The proposed mechanism leading to goiter formation is that the redox stress experienced when the thyroid produces hormones selects for loss of heterozygosity of KEAP1, leading to the goiters.[14]

Gallery

• 
  (a) NRF2 and KEAP1 protein domains; (b) KEAP1 homodimerizes through the BTB domain, and through the Kelch domains KEAP1 interacts with NRF2 at the ETGE and DLG motifs[14]
• 
  The relationship of the NRF2/KEAP1 pathway with cellular metabolism[14]

References

1. GRCh38: Ensembl release 89: ENSG00000079999 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000003308 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: KEAP1 kelch-like ECH-associated protein 1".
6. Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA (October 2003). "Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival". Molecular and Cellular Biology. 23 (20): 7198–209. doi:10.1128/mcb.23.20.7198-7209.2003. PMC 230321. PMID 14517290.
7. Shibata T, Ohta T, Tong KI, Kokubu A, Odogawa R, Tsuta K, et al. (September 2008). "Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy". Proceedings of the National Academy of Sciences of the United States of America. 105 (36): 13568–73. Bibcode:2008PNAS..10513568S. doi:10.1073/pnas.0806268105. PMC 2533230. PMID 18757741.
8. Wang XJ, Sun Z, Chen W, Li Y, Villeneuve NF, Zhang DD (August 2008). "Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1-Cul3 interaction". Toxicology and Applied Pharmacology. 230 (3): 383–9. doi:10.1016/j.taap.2008.03.003. PMC 2610481. PMID 18417180.
9. Lignitto L, LeBoeuf SE, Homer H, Jiang S, Askenazi M, Karakousi TR, et al. (July 2019). "Nrf2 Activation Promotes Lung Cancer Metastasis by Inhibiting the Degradation of Bach1". Cell. 178 (2): 316–329.e18. doi:10.1016/j.cell.2019.06.003. PMC 6625921. PMID 31257023.
10. Abed DA, Goldstein M, Albanyan H, Jin H, Hu L (July 2015). "Discovery of direct inhibitors of Keap1-Nrf2 protein-protein interaction as potential therapeutic and preventive agents". Acta Pharmaceutica Sinica. B. 5 (4): 285–99. doi:10.1016/j.apsb.2015.05.008. PMC 4629420. PMID 26579458.
11. Lu MC, Ji JA, Jiang ZY, You QD (September 2016). "The Keap1-Nrf2-ARE Pathway As a Potential Preventive and Therapeutic Target: An Update". Medicinal Research Reviews. 36 (5): 924–63. doi:10.1002/med.21396. PMID 27192495. S2CID 30047975.
12. Deshmukh P, Unni S, Krishnappa G, Padmanabhan B (February 2017). "The Keap1-Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases". Biophysical Reviews. 9 (1): 41–56. doi:10.1007/s12551-016-0244-4. PMC 5425799. PMID 28510041.
13. Kerr F, Sofola-Adesakin O, Ivanov DK, Gatliff J, Gomez Perez-Nievas B, Bertrand HC, et al. (March 2017). "Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer's disease". PLOS Genetics. 13 (3): e1006593. doi:10.1371/journal.pgen.1006593. PMC 5333801. PMID 28253260.
14. Wu WL, Papagiannakopoulos T (2020-03-09). "The Pleiotropic Role of the KEAP1/NRF2 Pathway in Cancer". Annual Review of Cancer Biology. 4 (1): 413–435. doi:10.1146/annurev-cancerbio-030518-055627. ISSN 2472-3428.

Further reading

• Zhang DD (2007). "Mechanistic studies of the Nrf2-Keap1 signaling pathway". Drug Metabolism Reviews. 38 (4): 769–89. CiteSeerX 10.1.1.600.2452. doi:10.1080/03602530600971974. PMID 17145701. S2CID 7627379.
• Nagase T, Seki N, Tanaka A, Ishikawa K, Nomura N (August 1995). "Prediction of the coding sequences of unidentified human genes. IV. The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis of cDNA clones from human cell line KG-1". DNA Research. 2 (4): 167–74, 199–210. doi:10.1093/dnares/2.4.167. PMID 8590280.
• Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M (January 1999). "Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain". Genes & Development. 13 (1): 76–86. doi:10.1101/gad.13.1.76. PMC 316370. PMID 9887101.
• Dhakshinamoorthy S, Jaiswal AK (June 2001). "Functional characterization and role of INrf2 in antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene". Oncogene. 20 (29): 3906–17. doi:10.1038/sj.onc.1204506. PMID 11439354.
• Sekhar KR, Spitz DR, Harris S, Nguyen TT, Meredith MJ, Holt JT, et al. (April 2002). "Redox-sensitive interaction between KIAA0132 and Nrf2 mediates indomethacin-induced expression of gamma-glutamylcysteine synthetase". Free Radical Biology & Medicine. 32 (7): 650–62. doi:10.1016/S0891-5849(02)00755-4. PMID 11909699.
• Velichkova M, Guttman J, Warren C, Eng L, Kline K, Vogl AW, Hasson T (March 2002). "A human homologue of Drosophila kelch associates with myosin-VIIa in specialized adhesion junctions". Cell Motility and the Cytoskeleton. 51 (3): 147–64. doi:10.1002/cm.10025. PMID 11921171.
• Zipper LM, Mulcahy RT (September 2002). "The Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm". The Journal of Biological Chemistry. 277 (39): 36544–52. doi:10.1074/jbc.M206530200. PMID 12145307.
• Sekhar KR, Yan XX, Freeman ML (October 2002). "Nrf2 degradation by the ubiquitin proteasome pathway is inhibited by KIAA0132, the human homolog to INrf2". Oncogene. 21 (44): 6829–34. doi:10.1038/sj.onc.1205905. PMID 12360409.
• Bloom DA, Jaiswal AK (November 2003). "Phosphorylation of Nrf2 at Ser40 by protein kinase C in response to antioxidants leads to the release of Nrf2 from INrf2, but is not required for Nrf2 stabilization/accumulation in the nucleus and transcriptional activation of antioxidant response element-mediated NAD(P)H:quinone oxidoreductase-1 gene expression". The Journal of Biological Chemistry. 278 (45): 44675–82. doi:10.1074/jbc.M307633200. PMID 12947090.
• Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA (October 2003). "Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival". Molecular and Cellular Biology. 23 (20): 7198–209. doi:10.1128/MCB.23.20.7198-7209.2003. PMC 230321. PMID 14517290.
• Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, et al. (July 2004). "Functional proteomics mapping of a human signaling pathway". Genome Research. 14 (7): 1324–32. doi:10.1101/gr.2334104. PMC 442148. PMID 15231748.
• Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, et al. (August 2004). "Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2". Molecular and Cellular Biology. 24 (16): 7130–9. doi:10.1128/MCB.24.16.7130-7139.2004. PMC 479737. PMID 15282312.
• Strachan GD, Morgan KL, Otis LL, Caltagarone J, Gittis A, Bowser R, Jordan-Sciutto KL (September 2004). "Fetal Alz-50 clone 1 interacts with the human orthologue of the Kelch-like Ech-associated protein". Biochemistry. 43 (38): 12113–22. doi:10.1021/bi0494166. PMC 3670950. PMID 15379550.
• Li X, Zhang D, Hannink M, Beamer LJ (December 2004). "Crystal structure of the Kelch domain of human Keap1". The Journal of Biological Chemistry. 279 (52): 54750–8. doi:10.1074/jbc.M410073200. PMID 15475350.
• Zhang DD, Lo SC, Cross JV, Templeton DJ, Hannink M (December 2004). "Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex". Molecular and Cellular Biology. 24 (24): 10941–53. doi:10.1128/MCB.24.24.10941-10953.2004. PMC 533977. PMID 15572695.
• Li X, Zhang D, Hannink M, Beamer LJ (December 2004). "Crystallization and initial crystallographic analysis of the Kelch domain from human Keap1". Acta Crystallographica. Section D, Biological Crystallography. 60 (Pt 12 Pt 2): 2346–8. CiteSeerX 10.1.1.631.1273. doi:10.1107/S0907444904024825. PMID 15583386.
• Furukawa M, Xiong Y (January 2005). "BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase". Molecular and Cellular Biology. 25 (1): 162–71. doi:10.1128/MCB.25.1.162-171.2005. PMC 538799. PMID 15601839.
• Hosoya T, Maruyama A, Kang MI, Kawatani Y, Shibata T, Uchida K, et al. (July 2005). "Differential responses of the Nrf2-Keap1 system to laminar and oscillatory shear stresses in endothelial cells". The Journal of Biological Chemistry. 280 (29): 27244–50. doi:10.1074/jbc.M502551200. PMID 15917255.