KEAP1: Difference between revisions

Jump to navigation Jump to search
VisualWikitext
m (Robot: Automated text replacement (-{{WikiDoc Cardiology Network Infobox}} +, -<references /> +{{reflist|2}}, -{{reflist}} +{{reflist|2}}))
 
m (Bot: HTTP→HTTPS (v470))
Line 1: Line 1:
<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox_gene}}
{{PBB_Controls
'''Kelch-like ECH-associated protein 1''' is a [[protein]] that in humans is encoded by the ''Keap1'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: KEAP1 kelch-like ECH-associated protein 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9817| accessdate = }}</ref>
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Structure ==
{{GNF_Protein_box
| image = PBB_Protein_KEAP1_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1u6d.
| PDB = {{PDB2|1u6d}}, {{PDB2|1x2j}}, {{PDB2|1x2r}}, {{PDB2|1zgk}}, {{PDB2|2flu}}
| Name = Kelch-like ECH-associated protein 1
| HGNCid = 23177
| Symbol = KEAP1
| AltSymbols =; INrf2; KIAA0132; KLHL19; MGC10630; MGC1114; MGC20887; MGC4407; MGC9454
| OMIM = 606016
| ECnumber = 
| Homologene = 8184
| MGIid = 1858732
| GeneAtlas_image1 = PBB_GE_KEAP1_202417_at_tn.png
| Function = {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0030528 |text = transcription regulator activity}}
| Component = {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0005783 |text = endoplasmic reticulum}}
| Process = {{GNF_GO|id=GO:0001701 |text = in utero embryonic development}} {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0045604 |text = regulation of epidermal cell differentiation}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 9817
    | Hs_Ensembl = ENSG00000079999
    | Hs_RefseqProtein = NP_036421
    | Hs_RefseqmRNA = NM_012289
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 19
    | Hs_GenLoc_start = 10457802
    | Hs_GenLoc_end = 10475243
    | Hs_Uniprot = Q14145
    | Mm_EntrezGene = 50868
    | Mm_Ensembl = ENSMUSG00000003308
    | Mm_RefseqmRNA = NM_016679
    | Mm_RefseqProtein = NP_057888
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 9
    | Mm_GenLoc_start = 20980133
    | Mm_GenLoc_end = 20989734
    | Mm_Uniprot = O89076
  }}
}}
'''Kelch-like ECH-associated protein 1''', also known as '''KEAP1''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: KEAP1 kelch-like ECH-associated protein 1| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9817| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
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]].
{{PBB_Summary
 
| section_title =  
== Interactions ==
| summary_text = This gene encodes a protein containing KELCH-1 like domains, as well as a BTB/POZ domain. Kelch-like ECH-associated protein 1 interacts with NF-E2-related factor 2 in a redox-sensitive manner and the dissociation of the proteins in the cytoplasm is followed by transportation of NF-E2-related factor 2 to the nucleus. This interaction results in the expression of the catalytic subunit of gamma-glutamylcysteine synthetase. Two alternatively spliced transcript variants encoding the same isoform have been found for this gene.<ref name="entrez">{{cite web | title = Entrez Gene: KEAP1 kelch-like ECH-associated protein 1| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9817| accessdate = }}</ref>
 
}}
Keap1 has been shown to [[Protein-protein interaction|interact]] with [[Nrf2]], a master regulator of the antioxidant response, which is important for the amelioration of [[oxidative stress]].<ref name = pmid14517290>{{cite journal | vauthors = Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA | title = Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival | journal = Mol. Cell. Biol. | volume = 23 | issue = 20 | pages = 7198–209 | date = Oct 2003 | pmid = 14517290 | pmc = 230321 | doi =  10.1128/mcb.23.20.7198-7209.2003}}</ref><ref name = pmid18757741>{{cite journal | vauthors = Shibata T, Ohta T, Tong KI, Kokubu A, Odogawa R, Tsuta K, Asamura H, Yamamoto M, Hirohashi S | title = Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 105 | issue = 36 | pages = 13568–73 | date = Sep 2008 | pmid = 18757741 | pmc = 2533230 | doi = 10.1073/pnas.0806268105 }}</ref><ref name = pmid18417180>{{cite journal | vauthors = Wang XJ, Sun Z, Chen W, Li Y, Villeneuve NF, Zhang DD | title = Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1-Cul3 interaction | journal = Toxicol. Appl. Pharmacol. | volume = 230 | issue = 3 | pages = 383–9 | date = Aug 2008 | pmid = 18417180 | pmc = 2610481 | doi = 10.1016/j.taap.2008.03.003 }}</ref>
 
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]].
 
== 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.<ref name="pmid26579458">{{cite journal |vauthors=Abed DA, Goldstein M, Albanyan H, Jin H, Hu L |title=Discovery of direct inhibitors of Keap1-Nrf2 protein-protein interaction as potential therapeutic and preventive agents |journal=Acta Pharm Sin B |volume=5 |issue=4 |pages=285–99 |year=2015 |pmid=26579458 |pmc=4629420 |doi=10.1016/j.apsb.2015.05.008 |url=}}</ref><ref name="pmid27192495">{{cite journal |vauthors=Lu MC, Ji JA, Jiang ZY, You QD |title=The Keap1-Nrf2-ARE Pathway As a Potential Preventive and Therapeutic Target: An Update |journal=Med Res Rev |volume=36 |issue=5 |pages=924–63 |year=2016 |pmid=27192495 |doi=10.1002/med.21396 |url=}}</ref><ref name="pmid28510041">{{cite journal |vauthors=Deshmukh P, Unni S, Krishnappa G, Padmanabhan B |title=The Keap1-Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases |journal=Biophys Rev |volume=9 |issue=1 |pages=41–56 |year=2017 |pmid=28510041 |pmc=5425799 |doi=10.1007/s12551-016-0244-4 |url=}}</ref><ref name="pmid28253260">{{cite journal |vauthors=Kerr F, Sofola-Adesakin O, Ivanov DK, Gatliff J, Gomez Perez-Nievas B, Bertrand HC, Martinez P, Callard R, Snoeren I, Cochemé HM, Adcott J, Khericha M, Castillo-Quan JI, Wells G, Noble W, Thornton J, Partridge L |title=Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer's disease |journal=PLoS Genet. |volume=13 |issue=3 |pages=e1006593 |year=2017 |pmid=28253260 |pmc=5333801 |doi=10.1371/journal.pgen.1006593 |url=}}</ref>
 
A series of synthetic oleane [[triterpenoid]] compounds, known as antioxidant inflammation modulators (AIMs), are being developed by [[Reata Pharmaceuticals|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|date=August 2011}})  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|date=August 2011}}) However, the Phase 3 trial was halted due to safety concerns.


==References==
==References==
{{reflist|2}}
{{reflist}}
 
==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
*{{cite journal | vauthors = Zhang DD | title = Mechanistic studies of the Nrf2-Keap1 signaling pathway | journal = Drug Metab. Rev. | volume = 38 | issue = 4 | pages = 769–89 | year = 2007 | pmid = 17145701 | doi = 10.1080/03602530600971974 }}
| citations =
*{{cite journal | vauthors = Nagase T, Seki N, Tanaka A, Ishikawa K, Nomura N | title = 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 | journal = DNA Res. | volume = 2 | issue = 4 | pages = 167–74, 199–210 | year = 1996 | pmid = 8590280 | doi = 10.1093/dnares/2.4.167 }}
*{{cite journal | author=Zhang DD |title=Mechanistic studies of the Nrf2-Keap1 signaling pathway. |journal=Drug Metab. Rev. |volume=38 |issue= 4 |pages= 769-89 |year= 2007 |pmid= 17145701 |doi= 10.1080/03602530600971974 }}
*{{cite journal | vauthors = Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M | title = Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain | journal = Genes Dev. | volume = 13 | issue = 1 | pages = 76–86 | year = 1999 | pmid = 9887101 | pmc = 316370 | doi = 10.1101/gad.13.1.76 }}
*{{cite journal | author=Nagase T, Seki N, Tanaka A, ''et al.'' |title=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. |journal=DNA Res. |volume=2 |issue= 4 |pages= 167-74, 199-210 |year= 1996 |pmid= 8590280 |doi= }}
*{{cite journal | vauthors = Dhakshinamoorthy S, Jaiswal AK | title = Functional characterization and role of INrf2 in antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene | journal = Oncogene | volume = 20 | issue = 29 | pages = 3906–17 | year = 2001 | pmid = 11439354 | doi = 10.1038/sj.onc.1204506 }}
*{{cite journal | author=Itoh K, Wakabayashi N, Katoh Y, ''et al.'' |title=Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. |journal=Genes Dev. |volume=13 |issue= 1 |pages= 76-86 |year= 1999 |pmid= 9887101 |doi= }}
*{{cite journal | vauthors = Sekhar KR, Spitz DR, Harris S, Nguyen TT, Meredith MJ, Holt JT, Gius D, Marnett LJ, Summar ML, Freeman ML, Guis D | title = Redox-sensitive interaction between KIAA0132 and Nrf2 mediates indomethacin-induced expression of gamma-glutamylcysteine synthetase | journal = Free Radic. Biol. Med. | volume = 32 | issue = 7 | pages = 650–62 | year = 2002 | pmid = 11909699 | doi = 10.1016/S0891-5849(02)00755-4 }}
*{{cite journal | author=Dhakshinamoorthy S, Jaiswal AK |title=Functional characterization and role of INrf2 in antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene. |journal=Oncogene |volume=20 |issue= 29 |pages= 3906-17 |year= 2001 |pmid= 11439354 |doi= 10.1038/sj.onc.1204506 }}
*{{cite journal | vauthors = Velichkova M, Guttman J, Warren C, Eng L, Kline K, Vogl AW, Hasson T | title = A human homologue of Drosophila kelch associates with myosin-VIIa in specialized adhesion junctions | journal = Cell Motil. Cytoskeleton | volume = 51 | issue = 3 | pages = 147–64 | year = 2002 | pmid = 11921171 | doi = 10.1002/cm.10025 }}
*{{cite journal | author=Sekhar KR, Spitz DR, Harris S, ''et al.'' |title=Redox-sensitive interaction between KIAA0132 and Nrf2 mediates indomethacin-induced expression of gamma-glutamylcysteine synthetase. |journal=Free Radic. Biol. Med. |volume=32 |issue= 7 |pages= 650-62 |year= 2002 |pmid= 11909699 |doi= }}
*{{cite journal | vauthors = Zipper LM, Mulcahy RT | title = The Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm | journal = J. Biol. Chem. | volume = 277 | issue = 39 | pages = 36544–52 | year = 2002 | pmid = 12145307 | doi = 10.1074/jbc.M206530200 }}
*{{cite journal | author=Velichkova M, Guttman J, Warren C, ''et al.'' |title=A human homologue of Drosophila kelch associates with myosin-VIIa in specialized adhesion junctions. |journal=Cell Motil. Cytoskeleton |volume=51 |issue= 3 |pages= 147-64 |year= 2002 |pmid= 11921171 |doi= 10.1002/cm.10025 }}
*{{cite journal | vauthors = Sekhar KR, Yan XX, Freeman ML | title = Nrf2 degradation by the ubiquitin proteasome pathway is inhibited by KIAA0132, the human homolog to INrf2 | journal = Oncogene | volume = 21 | issue = 44 | pages = 6829–34 | year = 2002 | pmid = 12360409 | doi = 10.1038/sj.onc.1205905 }}
*{{cite journal | author=Zipper LM, Mulcahy RT |title=The Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm. |journal=J. Biol. Chem. |volume=277 |issue= 39 |pages= 36544-52 |year= 2002 |pmid= 12145307 |doi= 10.1074/jbc.M206530200 }}
*{{cite journal | vauthors = Bloom DA, Jaiswal AK | title = 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 | journal = J. Biol. Chem. | volume = 278 | issue = 45 | pages = 44675–82 | year = 2004 | pmid = 12947090 | doi = 10.1074/jbc.M307633200 }}
*{{cite journal | author=Sekhar KR, Yan XX, Freeman ML |title=Nrf2 degradation by the ubiquitin proteasome pathway is inhibited by KIAA0132, the human homolog to INrf2. |journal=Oncogene |volume=21 |issue= 44 |pages= 6829-34 |year= 2002 |pmid= 12360409 |doi= 10.1038/sj.onc.1205905 }}
*{{cite journal | vauthors = Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA | title = Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival | journal = Mol. Cell. Biol. | volume = 23 | issue = 20 | pages = 7198–209 | year = 2003 | pmid = 14517290 | pmc = 230321 | doi = 10.1128/MCB.23.20.7198-7209.2003 }}
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
*{{cite journal | vauthors = Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM | title = Functional proteomics mapping of a human signaling pathway | journal = Genome Res. | volume = 14 | issue = 7 | pages = 1324–32 | year = 2004 | pmid = 15231748 | pmc = 442148 | doi = 10.1101/gr.2334104 }}
*{{cite journal  | author=Bloom DA, Jaiswal AK |title=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. |journal=J. Biol. Chem. |volume=278 |issue= 45 |pages= 44675-82 |year= 2004 |pmid= 12947090 |doi= 10.1074/jbc.M307633200 }}
*{{cite journal | vauthors = Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K, Yamamoto M | title = Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2 | journal = Mol. Cell. Biol. | volume = 24 | issue = 16 | pages = 7130–9 | year = 2004 | pmid = 15282312 | pmc = 479737 | doi = 10.1128/MCB.24.16.7130-7139.2004 }}
*{{cite journal | author=Cullinan SB, Zhang D, Hannink M, ''et al.'' |title=Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. |journal=Mol. Cell. Biol. |volume=23 |issue= 20 |pages= 7198-209 |year= 2003 |pmid= 14517290 |doi= }}
*{{cite journal | vauthors = Strachan GD, Morgan KL, Otis LL, Caltagarone J, Gittis A, Bowser R, Jordan-Sciutto KL | title = Fetal Alz-50 clone 1 interacts with the human orthologue of the Kelch-like Ech-associated protein | journal = Biochemistry | volume = 43 | issue = 38 | pages = 12113–22 | year = 2004 | pmid = 15379550 | doi = 10.1021/bi0494166 }}
*{{cite journal | author=Ota T, Suzuki Y, Nishikawa T, ''et al.'' |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40-5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 }}
*{{cite journal | vauthors = Li X, Zhang D, Hannink M, Beamer LJ | title = Crystal structure of the Kelch domain of human Keap1 | journal = J. Biol. Chem. | volume = 279 | issue = 52 | pages = 54750–8 | year = 2005 | pmid = 15475350 | doi = 10.1074/jbc.M410073200 }}
*{{cite journal | author=Colland F, Jacq X, Trouplin V, ''et al.'' |title=Functional proteomics mapping of a human signaling pathway. |journal=Genome Res. |volume=14 |issue= 7 |pages= 1324-32 |year= 2004 |pmid= 15231748 |doi= 10.1101/gr.2334104 }}
*{{cite journal | vauthors = Zhang DD, Lo SC, Cross JV, Templeton DJ, Hannink M | title = Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex | journal = Mol. Cell. Biol. | volume = 24 | issue = 24 | pages = 10941–53 | year = 2004 | pmid = 15572695 | pmc = 533977 | doi = 10.1128/MCB.24.24.10941-10953.2004 }}
*{{cite journal | author=Kobayashi A, Kang MI, Okawa H, ''et al.'' |title=Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. |journal=Mol. Cell. Biol. |volume=24 |issue= 16 |pages= 7130-9 |year= 2004 |pmid= 15282312 |doi= 10.1128/MCB.24.16.7130-7139.2004 }}
*{{cite journal | vauthors = Li X, Zhang D, Hannink M, Beamer LJ | title = Crystallization and initial crystallographic analysis of the Kelch domain from human Keap1 | journal = Acta Crystallogr. D | volume = 60 | issue = Pt 12 Pt 2 | pages = 2346–8 | year = 2005 | pmid = 15583386 | doi = 10.1107/S0907444904024825 }}
*{{cite journal | author=Strachan GD, Morgan KL, Otis LL, ''et al.'' |title=Fetal Alz-50 clone 1 interacts with the human orthologue of the Kelch-like Ech-associated protein. |journal=Biochemistry |volume=43 |issue= 38 |pages= 12113-22 |year= 2004 |pmid= 15379550 |doi= 10.1021/bi0494166 }}
*{{cite journal | vauthors = Furukawa M, Xiong Y | title = BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase | journal = Mol. Cell. Biol. | volume = 25 | issue = 1 | pages = 162–71 | year = 2005 | pmid = 15601839 | pmc = 538799 | doi = 10.1128/MCB.25.1.162-171.2005 }}
*{{cite journal | author=Li X, Zhang D, Hannink M, Beamer LJ |title=Crystal structure of the Kelch domain of human Keap1. |journal=J. Biol. Chem. |volume=279 |issue= 52 |pages= 54750-8 |year= 2005 |pmid= 15475350 |doi= 10.1074/jbc.M410073200 }}
*{{cite journal | vauthors = Hosoya T, Maruyama A, Kang MI, Kawatani Y, Shibata T, Uchida K, Warabi E, Noguchi N, Itoh K, Yamamoto M | title = Differential responses of the Nrf2-Keap1 system to laminar and oscillatory shear stresses in endothelial cells | journal = J. Biol. Chem. | volume = 280 | issue = 29 | pages = 27244–50 | year = 2005 | pmid = 15917255 | doi = 10.1074/jbc.M502551200 }}
*{{cite journal | author=Zhang DD, Lo SC, Cross JV, ''et al.'' |title=Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. |journal=Mol. Cell. Biol. |volume=24 |issue= 24 |pages= 10941-53 |year= 2004 |pmid= 15572695 |doi= 10.1128/MCB.24.24.10941-10953.2004 }}
*{{cite journal | author=Li X, Zhang D, Hannink M, Beamer LJ |title=Crystallization and initial crystallographic analysis of the Kelch domain from human Keap1. |journal=Acta Crystallogr. D Biol. Crystallogr. |volume=60 |issue= Pt 12 Pt 2 |pages= 2346-8 |year= 2005 |pmid= 15583386 |doi= 10.1107/S0907444904024825 }}
*{{cite journal  | author=Furukawa M, Xiong Y |title=BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. |journal=Mol. Cell. Biol. |volume=25 |issue= 1 |pages= 162-71 |year= 2005 |pmid= 15601839 |doi= 10.1128/MCB.25.1.162-171.2005 }}
*{{cite journal  | author=Hosoya T, Maruyama A, Kang MI, ''et al.'' |title=Differential responses of the Nrf2-Keap1 system to laminar and oscillatory shear stresses in endothelial cells. |journal=J. Biol. Chem. |volume=280 |issue= 29 |pages= 27244-50 |year= 2005 |pmid= 15917255 |doi= 10.1074/jbc.M502551200 }}
}}
{{refend}}
{{refend}}


{{protein-stub}}
{{PDB Gallery|geneid=9817}}
{{WikiDoc Sources}}
 
 
{{gene-19-stub}}
 
[[Category:Kelch proteins]]

Revision as of 01:51, 27 October 2017

VALUE_ERROR (nil)
Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

n/a

n/a

Ensembl

n/a

n/a

UniProt

n/a

n/a

RefSeq (mRNA)

n/a

n/a

RefSeq (protein)

n/a

n/a

Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

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

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

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.

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.[5][6][7][8]

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

  1. ↑ "Entrez Gene: KEAP1 kelch-like ECH-associated protein 1".
  2. ↑ Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA (Oct 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.
  3. ↑ Shibata T, Ohta T, Tong KI, Kokubu A, Odogawa R, Tsuta K, Asamura H, Yamamoto M, Hirohashi S (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. 105 (36): 13568–73. doi:10.1073/pnas.0806268105. PMC 2533230. PMID 18757741.
  4. ↑ Wang XJ, Sun Z, Chen W, Li Y, Villeneuve NF, Zhang DD (Aug 2008). "Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1-Cul3 interaction". Toxicol. Appl. Pharmacol. 230 (3): 383–9. doi:10.1016/j.taap.2008.03.003. PMC 2610481. PMID 18417180.
  5. ↑ Abed DA, Goldstein M, Albanyan H, Jin H, Hu L (2015). "Discovery of direct inhibitors of Keap1-Nrf2 protein-protein interaction as potential therapeutic and preventive agents". Acta Pharm Sin B. 5 (4): 285–99. doi:10.1016/j.apsb.2015.05.008. PMC 4629420. PMID 26579458.
  6. ↑ Lu MC, Ji JA, Jiang ZY, You QD (2016). "The Keap1-Nrf2-ARE Pathway As a Potential Preventive and Therapeutic Target: An Update". Med Res Rev. 36 (5): 924–63. doi:10.1002/med.21396. PMID 27192495.
  7. ↑ Deshmukh P, Unni S, Krishnappa G, Padmanabhan B (2017). "The Keap1-Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases". Biophys Rev. 9 (1): 41–56. doi:10.1007/s12551-016-0244-4. PMC 5425799. PMID 28510041.
  8. ↑ Kerr F, Sofola-Adesakin O, Ivanov DK, Gatliff J, Gomez Perez-Nievas B, Bertrand HC, Martinez P, Callard R, Snoeren I, Cochemé HM, Adcott J, Khericha M, Castillo-Quan JI, Wells G, Noble W, Thornton J, Partridge L (2017). "Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer's disease". PLoS Genet. 13 (3): e1006593. doi:10.1371/journal.pgen.1006593. PMC 5333801. PMID 28253260.

Further reading


Retrieved from "https://www.wikidoc.org/index.php?title=KEAP1&oldid=1418770"