KEAP1(19p13.2),KLHL19, INRF2, avainsensori ox. ja elektrofiiliselle stressille

 https://www.ncbi.nlm.nih.gov/gene/9817

Also known as INrf2; KLHL19

Summary: 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  (GSH) synthetase. Two alternatively spliced transcript variants encoding the same isoform have been found for this gene. [provided by RefSeq, Jul 2008]

Expression Ubiquitous expression in kidney (RPKM 10.4), prostate (RPKM 9.9) and 25 other tissues See more

Preferred Names

kelch-like ECH-associated protein 1

Names

KEAP1 delta C

cytosolic inhibitor of Nrf2

kelch-like family member 19

kelch-like protein 19

 https://www.ncbi.nlm.nih.gov/protein/NP_036421.2

ORIGIN      
        1 mqpdprpsga gaccrflplq sqcpegagda vmyastecka evtpsqhgnr tfsytledht
       61 kqafgimnel rlsqqlcdvt lqvkyqdapa aqfmahkvvl assspvfkam ftnglreqgm
      121 evvsiegihp kvmerliefa ytasismgek cvlhvmngav myqidsvvra csdflvqqld
      181 psnaigianf aeqigcvelh qrareyiymh fgevakqeef fnlshcqlvt lisrddlnvr
      241 cesevfhaci nwvkydceqr rfyvqallra vrchsltpnf lqmqlqkcei lqsdsrckdy
      301 lvkifeeltl hkptqvmpcr apkvgrliyt aggyfrqsls yleaynpsdg twlrladlqv
      361 prsglagcvv ggllyavggr nnspdgntds saldcynpmt nqwspcapms vprnrigvgv
      421 idghiyavgg shgcihhnsv eryeperdew hlvapmltrr igvgvavlnr llyavggfdg
      481 tnrlnsaecy ypernewrmi tamntirsga gvcvlhnciy aaggydgqdq lnsverydve
      541 tetwtfvapm khrrsalgit vhqgriyvlg gydghtflds vecydpdtdt wsevtrmtsg
      601 rsgvgvavtm epcrkqidqq nctc

ENSP00000377245.1, ENST00000393623.6

Conserved Domains (2) summary

sd00038
Location:460 → 503

Kelch; KELCH repeat [structural motif]. Kelch repeats are 44 to 56 amino acids in length and form a four-stranded beta-sheet corresponding to a single blade of five to seven bladed beta propellers. The Kelch superfamily is a large evolutionary conserved protein family whose members are present throughout the cell and extracellularly, and have diverse activities. Kelch repeats are often in combination with other domains, like BTB and BACK or F-box domains.

cl28614
Location:95 → 596

BTB; Broad-Complex, Tramtrack and Bric a brac. Domain in Broad-Complex, Tramtrack and Bric a brac. Also known as POZ (poxvirus and zinc finger) domain. Known to be a protein-protein interaction motif found at the N-termini of several C2H2-type transcription factors as well as Shaw-type potassium channels. Known structure reveals a tightly intertwined dimer formed via interactions between N-terminal strand and helix structures. However in a subset of BTB/POZ domains, these two secondary structures appear to be missing. Be aware SMART predicts BTB/POZ domains without the beta1- and alpha1-secondary structures.

https://www.uniprot.org/uniprot/Q14145

Protein Kelch-like ECH-associated protein 1

Gene KEAP1

Functionⁱ

Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that regulates the response to oxidative stress by targeting NFE2L2/NRF2 for ubiquitination (PubMed:14585973, PubMed:15379550, PubMed:15572695, PubMed:15983046, PubMed:15601839).

 KEAP1 acts as a key sensor of oxidative and electrophilic stress: in normal conditions, the BCR(KEAP1) complex mediates ubiquitination and degradation of NFE2L2/NRF2, a transcription factor regulating expression of many cytoprotective genes (PubMed:15601839, PubMed:16006525). 

In response to oxidative stress, different electrophile metabolites trigger non-enzymatic covalent modifications of highly reactive cysteine residues in KEAP1, leading to inactivate the ubiquitin ligase activity of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and expression of phase II detoxifying enzymes (PubMed:19489739, PubMed:16006525, PubMed:17127771, PubMed:18251510, PubMed:29590092).

 In response to selective autophagy, KEAP1 is sequestered in inclusion bodies following its interaction with sequestome SQSTM1/p62, leading to inactivation of the BCR(KEAP1) complex and activation of NFE2L2/NRF2 (PubMed:20452972). 

 The BCR(KEAP1) complex also mediates ubiquitination of SQSTM1/p62, increasing sequestosome1,  SQSTM1/p62, sequestering activity and degradation (PubMed:28380357). 

The BCR(KEAP1) complex also targets BPTF and PGAM5 for ubiquitination and degradation by the proteasome (PubMed:15379550, PubMed:17046835).13 Publications

Caution* The mechanism of inactivation of the BCR(KEAP1) complex by covalent modifications of reactive cysteines is unclear. Covalent modifications were initially thought to disrupt interaction between KEAP1 and NFE2L2/NRF2 (By similarity). Recent publications suggest that cysteine modifications disrupt the interaction between KEAP1 and CUL3 without affecting the interaction between KEAP1 and NFE2L2/NRF2 (PubMed:16006525, PubMed:17127771, PubMed:18251510, PubMed:24896564).By similarity4 Publications

Activity regulationⁱ.

Ubiquitin ligase activity of the BCR(KEAP1) complex is inhibited by oxidative stress and electrophile metabolites such as sulforaphane (PubMed:15983046, PubMed:17046835, PubMed:29590092, PubMed:30323285).  Electrophile metabolites react with reactive cysteine residues in KEAP1 and trigger non-enzymatic covalent modifications of these cysteine residues, leading to inactivate the ubiquitin ligase activity of the BCR(KEAP1) complex (PubMed:19489739, PubMed:17127771, PubMed:18251510, PubMed:29590092, PubMed:30323285).

 Selective autophagy also inactivates the BCR(KEAP1) complex via interaction between KEAP1 and SQSTM1/p62, which sequesters the complex in inclusion bodies and promotes its degradation (PubMed:20495340, PubMed:20452972).9 Publications

Pathwayⁱ: protein ubiquitination

This protein is involved in the pathway protein ubiquitination, which is part of Protein modification.5 Publications

View all proteins of this organism that are known to be involved in the pathway protein ubiquitination and in Protein modification.

(17.10.2019: "Herää kysymys" - Sulforafaania suositellaan ravinnossa ( ravintoeräisenä) .  Miten se sopii tähän kuvioon?) Ainakin se summavaikuttaa  tähän KEAP1:een ja tuloksena  tiedetään olevan  edullista vaikutusta, Ehkä juuri tuo  faasi II-detoksikatiosentsyymisyseemin expression aktivoituminen.