KEAP1

Kelču sličan ECH-asocirani protein 1
	; PDB prikaz baziran na 1u6d.
Dostupne strukture
	1U6D, 1ZGK, 2FLU, 3VNG, 3VNH, 3ZGC, 3ZGD, 4IN4, 4IQK
Identifikatori
Simboli	KEAP1; INrf2; KLHL19
Vanjski ID	OMIM: 606016 MGI: 1858732 HomoloGene: 8184 GeneCards: KEAP1 Gene
Ontologija gena
Molekularna funkcija	• proteinsko vezivanje;
Celularna komponenta	• jedro; • jedarce; • citoplazma;
Biološki proces	• in utero embrionsko razviće; • transkripcija, DNK zavisna; • regulacija transkripcije, DNK zavisna;
Pregled RNK izražavanja
	podaci
Ortolozi

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KEAP1 (engl. Kelch-like ECH-associated protein 1) protein je koji je kod ljudi kodiran Keap1 genom.^[1]

Struktura

Keap1 sadrži četiri odvojena proteinska domena. N-terminalni Brodov kompleks, Tramtrak i Bric-à-Brac (BTB) domen u kome je Cys151 ostatak, koji je jedan od važnih cisteina u detekciji stresa. IVR domen sadrži dva kritična cisteinska ostatka, Cys273 i Cys288, koji su druga grupa važnih cisteina za detekciju stresa. Domeni dvostrukog glicinskog ponavljanja (DGR) i C-terminalni region (CTR) zajedno formiraju strukturu β-propelera, putem koje Keap1 formira interakcije sa Nrf2.

Interactions

Keap1 formira interakcije sa Nrf2, glavnim regulatorom antioksidansnog responsa, koji je važan za amelioraciju oksidativnog stresa.^[2]^[3]^[4]

Reference

↑ „Entrez Gene: KEAP1 kelch-like ECH-associated protein 1”.
↑ Cullinan, Sara B; Zhang Donna, Hannink Mark, Arvisais Edward, Kaufman Randal J, Diehl J Alan (October 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.
↑ Shibata, Tatsuhiro; Ohta Tsutomu, Tong Kit I, Kokubu Akiko, Odogawa Reiko, Tsuta Koji, Asamura Hisao, Yamamoto Masayuki, Hirohashi Setsuo (September 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.
↑ Wang, Xiao-Jun; Sun Zheng, Chen Weimin, Li Yanjie, Villeneuve Nicole F, Zhang Donna D (August 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.

Literatura

Zhang DD (2007). „Mechanistic studies of the Nrf2-Keap1 signaling pathway”. Drug Metab. Rev. 38 (4): 769–89. DOI:10.1080/03602530600971974. PMID 17145701.
Nagase T, Seki N, Tanaka A i dr.. (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. PMID 8590280.
Itoh K, Wakabayashi N, Katoh Y i dr.. (1999). „Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain”. Genes Dev. 13 (1): 76–86. DOI:10.1101/gad.13.1.76. PMC 316370. PMID 9887101.
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”. Oncogene 20 (29): 3906–17. DOI:10.1038/sj.onc.1204506. PMID 11439354.
Sekhar KR, Spitz DR, Harris S i dr.. (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. PMID 11909699.
Velichkova M, Guttman J, Warren C i dr.. (2002). „A human homologue of Drosophila kelch associates with myosin-VIIa in specialized adhesion junctions”. Cell Motil. Cytoskeleton 51 (3): 147–64. DOI:10.1002/cm.10025. PMID 11921171.
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. PMID 12145307.
Sekhar KR, Yan XX, Freeman ML (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.
Strausberg RL, Feingold EA, Grouse LH i dr.. (2003). „Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences”. Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. DOI:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
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. PMID 12947090.
Cullinan SB, Zhang D, Hannink M i dr.. (2003). „Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival”. Mol. Cell. Biol. 23 (20): 7198–209. DOI:10.1128/MCB.23.20.7198-7209.2003. PMC 230321. PMID 14517290.
Ota T, Suzuki Y, Nishikawa T i dr.. (2004). „Complete sequencing and characterization of 21,243 full-length human cDNAs”. Nat. Genet. 36 (1): 40–5. DOI:10.1038/ng1285. PMID 14702039.
Colland F, Jacq X, Trouplin V i dr.. (2004). „Functional proteomics mapping of a human signaling pathway”. Genome Res. 14 (7): 1324–32. DOI:10.1101/gr.2334104. PMC 442148. PMID 15231748.
Kobayashi A, Kang MI, Okawa H i dr.. (2004). „Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2”. Mol. Cell. Biol. 24 (16): 7130–9. DOI:10.1128/MCB.24.16.7130-7139.2004. PMC 479737. PMID 15282312.
Strachan GD, Morgan KL, Otis LL i dr.. (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. PMID 15379550.
Li X, Zhang D, Hannink M, Beamer Lj (2005). „Crystal structure of the Kelch domain of human Keap1”. J. Biol. Chem. 279 (52): 54750–8. DOI:10.1074/jbc.M410073200. PMID 15475350.
Zhang DD, Lo SC, Cross JV i dr.. (2004). „Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex”. Mol. Cell. Biol. 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 (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. PMID 15583386.
Furukawa M, Xiong Y (2005). „BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase”. Mol. Cell. Biol. 25 (1): 162–71. DOI:10.1128/MCB.25.1.162-171.2005. PMC 538799. PMID 15601839.
Hosoya T, Maruyama A, Kang MI i dr.. (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. PMID 15917255.

[entrez-1] „Entrez Gene: KEAP1 kelch-like ECH-associated protein 1”.

[pmid14517290-2] Cullinan, Sara B; Zhang Donna, Hannink Mark, Arvisais Edward, Kaufman Randal J, Diehl J Alan (October 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.

[pmid18757741-3] Shibata, Tatsuhiro; Ohta Tsutomu, Tong Kit I, Kokubu Akiko, Odogawa Reiko, Tsuta Koji, Asamura Hisao, Yamamoto Masayuki, Hirohashi Setsuo (September 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.

[pmid18417180-4] Wang, Xiao-Jun; Sun Zheng, Chen Weimin, Li Yanjie, Villeneuve Nicole F, Zhang Donna D (August 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.

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