KEAP1

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Kelch-like ECH-associated protein 1
Protein KEAP1 PDB 1u6d.png
PDB rendering based on 1u6d.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols KEAP1 ; INrf2; KLHL19
External IDs OMIM606016 MGI1858732 HomoloGene8184 GeneCards: KEAP1 Gene
RNA expression pattern
PBB GE KEAP1 202417 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 9817 50868
Ensembl ENSG00000079999 ENSMUSG00000003308
UniProt Q14145 Q9Z2X8
RefSeq (mRNA) NM_012289 NM_001110305
RefSeq (protein) NP_036421 NP_001103775
Location (UCSC) Chr 19:
10.6 – 10.61 Mb
Chr 9:
21.23 – 21.24 Mb
PubMed search [1] [2]

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

Structure[edit]

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.

Interactions[edit]

Keap1 has been shown to interact with Nrf2, a master regulator of the antioxidant response, which is important for the amelioration of oxidative stress.[2][3][4]

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 as a Drug Target[edit]

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.[citation needed]) 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.[citation needed]) However, the Phase 3 trial was halted due to safety concerns.

References[edit]

  1. ^ "Entrez Gene: KEAP1 kelch-like ECH-associated protein 1". 
  2. ^ Cullinan, Sara B; Zhang Donna; Hannink Mark; Arvisais Edward; Kaufman Randal J; Diehl J Alan (Oct 2003). "Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival". Mol. Cell. Biol. (United States) 23 (20): 7198–209. doi:10.1128/MCB.23.20.7198-7209.2003. ISSN 0270-7306. PMC 230321. PMID 14517290. 
  3. ^ Shibata, Tatsuhiro; Ohta Tsutomu; Tong Kit I; Kokubu Akiko; Odogawa Reiko; Tsuta Koji; Asamura Hisao; Yamamoto Masayuki; Hirohashi Setsuo (Sep 2008). "Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy". Proc. Natl. Acad. Sci. U.S.A. (United States) 105 (36): 13568–73. doi:10.1073/pnas.0806268105. PMC 2533230. PMID 18757741. 
  4. ^ Wang, Xiao-Jun; Sun Zheng; Chen Weimin; Li Yanjie; Villeneuve Nicole F; Zhang Donna D (Aug 2008). "Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1-Cul3 interaction". Toxicol. Appl. Pharmacol. (United States) 230 (3): 383–9. doi:10.1016/j.taap.2008.03.003. ISSN 0041-008X. PMC 2610481. PMID 18417180. 

Further reading[edit]