Keap1 has four discrete protein domains. The N-terminal Broad complex, Tramtrack and Bric-à-Brac (BTB) domain contains the Cys151 residue, which 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.
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.
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.
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.
Nagase T, Seki N, Tanaka A, Ishikawa K, Nomura N (1996). "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 Res.2 (4): 167–74, 199–210. doi:10.1093/dnares/2.4.167. PMID8590280.
Dhakshinamoorthy S, Jaiswal AK (2001). "Functional characterization and role of INrf2 in antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene". Oncogene20 (29): 3906–17. doi:10.1038/sj.onc.1204506. PMID11439354.
Sekhar KR, Spitz DR, Harris S, Nguyen TT, Meredith MJ, Holt JT et al. (2002). "Redox-sensitive interaction between KIAA0132 and Nrf2 mediates indomethacin-induced expression of gamma-glutamylcysteine synthetase". Free Radic. Biol. Med.32 (7): 650–62. doi:10.1016/S0891-5849(02)00755-4. PMID11909699.
Velichkova M, Guttman J, Warren C, Eng L, Kline K, Vogl AW et al. (2002). "A human homologue of Drosophila kelch associates with myosin-VIIa in specialized adhesion junctions". Cell Motil. Cytoskeleton51 (3): 147–64. doi:10.1002/cm.10025. PMID11921171.
Zipper LM, Mulcahy RT (2002). "The Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm". J. Biol. Chem.277 (39): 36544–52. doi:10.1074/jbc.M206530200. PMID12145307.
Sekhar KR, Yan XX, Freeman ML (2002). "Nrf2 degradation by the ubiquitin proteasome pathway is inhibited by KIAA0132, the human homolog to INrf2". Oncogene21 (44): 6829–34. doi:10.1038/sj.onc.1205905. PMID12360409.
Bloom DA, Jaiswal AK (2004). "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". J. Biol. Chem.278 (45): 44675–82. doi:10.1074/jbc.M307633200. PMID12947090.
Strachan GD, Morgan KL, Otis LL, Caltagarone J, Gittis A, Bowser R et al. (2004). "Fetal Alz-50 clone 1 interacts with the human orthologue of the Kelch-like Ech-associated protein". Biochemistry43 (38): 12113–22. doi:10.1021/bi0494166. PMID15379550.
Li X, Zhang D, Hannink M, Beamer LJ (2005). "Crystallization and initial crystallographic analysis of the Kelch domain from human Keap1". Acta Crystallogr. D Biol. Crystallogr.60 (Pt 12 Pt 2): 2346–8. doi:10.1107/S0907444904024825. PMID15583386.
Hosoya T, Maruyama A, Kang MI, Kawatani Y, Shibata T, Uchida K et al. (2005). "Differential responses of the Nrf2-Keap1 system to laminar and oscillatory shear stresses in endothelial cells". J. Biol. Chem.280 (29): 27244–50. doi:10.1074/jbc.M502551200. PMID15917255.