View source for Kelch-like ECH-associated protein 1 (Homo sapiens)

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{{#invoke:InfoboxforTarget|run|Keap1, INrf2|[https://www.uniprot.org/uniprot/P57790 P57790]|Homo sapiens|Cys38, Cys151, Cys257,<br/>Cys273, Cys288|[http://pfam.xfam.org/family/PF00651 BTB/POZ domain],<br/>[http://pfam.xfam.org/family/PF01344 Kelch motif]|[[:Category:Kelch-like ECH-associated protein 1 (Homo sapiens)|Ligand list]]|Redox protein}}

==Summary==

===Protein Function ===
Keap1 (Kelch-like ECH-associated protein 1) is a multi-domain protein which plays a key role in the regulation of Nrf2, a transcription factor that mediates the expression of a large array of cytoprotective enzymes in response to electrophilic and oxidative assault. It acts in concert with members of the CRL3 class of Cullin-RING-Ligase E3 ligases to provide substrate-specific recruitment for ubiquitination, and consists of a three domain architecture composed of an N-terminal BTB (Broad complex, Tramtrack, and Bric-a-Brac) domain, an intervening region (IVR) or BACK domain, and a C-terminal Kelch repeat domain. (PMID: 24896564)<br/>
Acts as a substrate adapter protein for the E3 ubiquitin ligase complex formed by CUL3 and RBX1 and targets NFE2L2/NRF2 for ubiquitination and degradation by the proteasome, thus resulting in the suppression of its tran-scriptional activity and the repression of antioxidant response element-mediated detoxifying enzyme gene expression. Retains NFE2L2/NRF2 and may also retain BPTF in the cytosol. Targets PGAM5 for ubiquitination and degradation by the proteasome. (From Uniprot)<br/> 

===Cys Function & Property===
There are 25 cystiene residues in Keap1, and could form multiple disulfide bonds or free thiol groups under different situations (see below).<br/>
[[File:543_545-disulfide.png|center|600px]]
<div align="center">Cysteine residues in Keap1 sequence (PMID: 12193649)</div><br/>
[[File:543_545-function.png|center|600px]]
<div align="center">Cysteine residues in Keap1 sequence</div><br/>

* Hydrophobic property:
:[[File:545-hydro.png||600px]]
* SASA：
:Cys38: Unknown<br/>
:Cys151: 38.299 A^2 <br/>
:Cys257: Unknown<br/>
:Cys273: Unknown<br/>
:Cys288: Unknown<br/>

==Protein Sequence==
<font face="Courier">
MQPDPRPSGA GACCRFLPLQ SQCPEGAGDA VMYASTE<span style="background:#ffff00">'''C'''</span>KA EVTPSQHGNR <br/>
TFSYTLEDHT KQAFGIMNEL RLSQQLCDVT LQVKYQDAPA AQFMAHKVVL <br/>
ASSSPVFKAM FTNGLREQGM EVVSIEGIHP KVMERLIEFA YTASISMGEK <br/>
<span style="background:#ffff00">'''C'''</span>VLHVMNGAV MYQIDSVVRA CSDFLVQQLD PSNAIGIANF AEQIGCVELH <br/>
QRAREYIYMH FGEVAKQEEF FNLSHCQLVT LISRDDLNVR CESEVFHACI <br/>
NWVKYD<span style="background:#ffff00">'''C'''</span>EQR RFYVQALLRA VR<span style="background:#ffff00">'''C'''</span>HSLTPNF LQMQLQK<span style="background:#ffff00">'''C'''</span>EI LQSDSRCKDY <br/>
LVKIFEELTL HKPTQVMPCR APKVGRLIYT AGGYFRQSLS YLEAYNPSDG <br/>
TWLRLADLQV PRSGLAGCVV GGLLYAVGGR NNSPDGNTDS SALDCYNPMT <br/>
NQWSPCAPMS VPRNRIGVGV IDGHIYAVGG SHGCIHHNSV ERYEPERDEW <br/>
HLVAPMLTRR IGVGVAVLNR LLYAVGGFDG TNRLNSAECY YPERNEWRMI <br/>
TAMNTIRSGA GVCVLHNCIY AAGGYDGQDQ LNSVERYDVE TETWTFVAPM <br/>
KHRRSALGIT VHQGRIYVLG GYDGHTFLDS VECYDPDTDT WSEVTRMTSG <br/>
RSGVGVAVTM EPCRKQIDQQ NCTC   <br/> 
</font>

==Structural Information==
*Known structures with covalent ligands: <br/>
:[https://www.rcsb.org/structure/4CXT 4CXT]<br/>

*Protein structure:
[[File:545.png|center|800px]]

==Related Pathway==
*[https://www.genome.jp/kegg-bin/show_pathway?ko04120 Ubiquitin mediated proteolysis] <br/>
*[https://www.genome.jp/kegg-bin/show_pathway?ko05200 Pathways in cancer] <br/>
*[https://www.genome.jp/kegg-bin/show_pathway?ko05225 Hepatocellular carcinoma] <br/>
*[https://www.genome.jp/kegg-bin/show_pathway?ko05418 Fluid shear stress and atherosclerosis] <br/>

==Experimental Evidence==
:Crystallography, LC-ESI-MS/MS, Tryptic Digest 

==Reference==
# Copple I M, Goldring C E, Jenkins R E, et al. '''The hepatotoxic metabolite of acetaminophen directly activates the Keap1‐Nrf2 cell defense system[J].''' Hepatology, 2008, 48(4): 1292-1301. [https://www.ncbi.nlm.nih.gov/pubmed/?term=18785192 18785192]<br/> 
# Satoh T, Kosaka K, Itoh K, et al. '''Carnosic acid, a catechol‐type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap1/Nrf2 pathway via S‐alkylation of targeted cysteines on Keap1[J].''' Journal of neurochemistry, 2008, 104(4): 1116-1131. [https://www.ncbi.nlm.nih.gov/pubmed/?term=17995931 17995931]<br/>

[[Category:Targets]]
[[Category:Homo sapiens]]
[[Category:Redox protein]]
[[Category:Kelch motif]]
[[Category:BTB/POZ domain]]
[[Category:Ubiquitin mediated proteolysis]]
[[Category:Pathways in cancer]]
[[Category:Hepatocellular carcinoma]]
[[Category:Fluid shear stress and atherosclerosis]]