KEAP1_MOUSE
ID KEAP1_MOUSE Reviewed; 624 AA.
AC Q9Z2X8; Q3U243; Q3U8N7; Q547S3; Q6ZQI6; Q8BQY3;
DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1999, sequence version 1.
DT 03-AUG-2022, entry version 198.
DE RecName: Full=Kelch-like ECH-associated protein 1 {ECO:0000303|PubMed:9887101};
DE AltName: Full=Cytosolic inhibitor of Nrf2 {ECO:0000303|Ref.2};
DE Short=INrf2 {ECO:0000303|Ref.2};
GN Name=Keap1 {ECO:0000303|PubMed:9887101, ECO:0000312|MGI:MGI:1858732};
GN Synonyms=Inrf2 {ECO:0000303|Ref.2}, Kiaa0132 {ECO:0000303|PubMed:14621295};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND FUNCTION.
RC TISSUE=Embryo;
RX PubMed=9887101; DOI=10.1101/gad.13.17.2328;
RA Itoh K., Wakabayashi N., Katoh Y., Ishii T., Igarashi K., Engel J.D.,
RA Yamamoto M.;
RT "Keap1 represses nuclear activation of antioxidant responsive elements by
RT Nrf2 through binding to the amino-terminal Neh2 domain.";
RL Genes Dev. 13:76-86(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=C57BL/6J;
RA Dhakshinamoorthy S., Jaiswal A.K.;
RT "Mouse INrf2 gene structure.";
RL Submitted (NOV-2001) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Fetal brain;
RX PubMed=14621295; DOI=10.1093/dnares/10.4.167;
RA Okazaki N., Kikuno R., Ohara R., Inamoto S., Koseki H., Hiraoka S.,
RA Saga Y., Nagase T., Ohara O., Koga H.;
RT "Prediction of the coding sequences of mouse homologues of KIAA gene: III.
RT The complete nucleotide sequences of 500 mouse KIAA-homologous cDNAs
RT identified by screening of terminal sequences of cDNA clones randomly
RT sampled from size-fractionated libraries.";
RL DNA Res. 10:167-180(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J, and NOD;
RC TISSUE=Bone marrow, Corpora quadrigemina, Dendritic cell, Liver, and Lung;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP FUNCTION, ACTIVITY REGULATION, AND DOMAIN.
RX PubMed=12193649; DOI=10.1073/pnas.172398899;
RA Dinkova-Kostova A.T., Holtzclaw W.D., Cole R.N., Itoh K., Wakabayashi N.,
RA Katoh Y., Yamamoto M., Talalay P.;
RT "Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating
RT induction of phase 2 enzymes that protect against carcinogens and
RT oxidants.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:11908-11913(2002).
RN [7]
RP FUNCTION.
RX PubMed=12682069; DOI=10.1074/jbc.m300931200;
RA McMahon M., Itoh K., Yamamoto M., Hayes J.D.;
RT "Keap1-dependent proteasomal degradation of transcription factor Nrf2
RT contributes to the negative regulation of antioxidant response element-
RT driven gene expression.";
RL J. Biol. Chem. 278:21592-21600(2003).
RN [8]
RP DISRUPTION PHENOTYPE.
RX PubMed=14517554; DOI=10.1038/ng1248;
RA Wakabayashi N., Itoh K., Wakabayashi J., Motohashi H., Noda S.,
RA Takahashi S., Imakado S., Kotsuji T., Otsuka F., Roop D.R., Harada T.,
RA Engel J.D., Yamamoto M.;
RT "Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2
RT activation.";
RL Nat. Genet. 35:238-245(2003).
RN [9]
RP SUBCELLULAR LOCATION.
RX PubMed=15379550; DOI=10.1021/bi0494166;
RA Strachan G.D., Morgan K.L., Otis L.L., Caltagarone J., Gittis A.,
RA Bowser R., Jordan-Sciutto K.L.;
RT "Fetal Alz-50 clone 1 interacts with the human orthologue of the Kelch-like
RT Ech-associated protein.";
RL Biochemistry 43:12113-12122(2004).
RN [10]
RP FUNCTION, IDENTIFICATION IN THE BCR(KEAP1) COMPLEX, AND INTERACTION WITH
RP NFE2L2.
RX PubMed=15282312; DOI=10.1128/mcb.24.16.7130-7139.2004;
RA Kobayashi A., Kang M.I., Okawa H., Ohtsuji M., Zenke Y., Chiba T.,
RA Igarashi K., Yamamoto M.;
RT "Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3
RT ligase to regulate proteasomal degradation of Nrf2.";
RL Mol. Cell. Biol. 24:7130-7139(2004).
RN [11]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH NFE2L2.
RX PubMed=15367669; DOI=10.1128/mcb.24.19.8477-8486.2004;
RA Cullinan S.B., Gordan J.D., Jin J., Harper J.W., Diehl J.A.;
RT "The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3
RT ligase: oxidative stress sensing by a Cul3-Keap1 ligase.";
RL Mol. Cell. Biol. 24:8477-8486(2004).
RN [12]
RP FUNCTION, ACTIVITY REGULATION, DOMAIN, AND MUTAGENESIS OF CYS-273 AND
RP CYS-288.
RX PubMed=14764894; DOI=10.1073/pnas.0307301101;
RA Wakabayashi N., Dinkova-Kostova A.T., Holtzclaw W.D., Kang M.I.,
RA Kobayashi A., Yamamoto M., Kensler T.W., Talalay P.;
RT "Protection against electrophile and oxidant stress by induction of the
RT phase 2 response: fate of cysteines of the Keap1 sensor modified by
RT inducers.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:2040-2045(2004).
RN [13]
RP FUNCTION, AND INTERACTION WITH NFE2L2.
RX PubMed=15581590; DOI=10.1016/j.abb.2004.10.012;
RA Katoh Y., Iida K., Kang M.I., Kobayashi A., Mizukami M., Tong K.I.,
RA McMahon M., Hayes J.D., Itoh K., Yamamoto M.;
RT "Evolutionary conserved N-terminal domain of Nrf2 is essential for the
RT Keap1-mediated degradation of the protein by proteasome.";
RL Arch. Biochem. Biophys. 433:342-350(2005).
RN [14]
RP IDENTIFICATION IN THE BCR(KEAP1) COMPLEX, INTERACTION WITH NFE2L2, AND
RP MUTAGENESIS OF ARG-71; ARG-380; ARG-415 AND ARG-483.
RX PubMed=16790436; DOI=10.1074/jbc.m601119200;
RA McMahon M., Thomas N., Itoh K., Yamamoto M., Hayes J.D.;
RT "Dimerization of substrate adaptors can facilitate cullin-mediated
RT ubiquitylation of proteins by a 'tethering' mechanism: a two-site
RT interaction model for the Nrf2-Keap1 complex.";
RL J. Biol. Chem. 281:24756-24768(2006).
RN [15]
RP INTERACTION WITH NFE2L2.
RX PubMed=16581765; DOI=10.1128/mcb.26.8.2887-2900.2006;
RA Tong K.I., Katoh Y., Kusunoki H., Itoh K., Tanaka T., Yamamoto M.;
RT "Keap1 recruits Neh2 through binding to ETGE and DLG motifs:
RT characterization of the two-site molecular recognition model.";
RL Mol. Cell. Biol. 26:2887-2900(2006).
RN [16]
RP SUBCELLULAR LOCATION.
RX PubMed=17903176; DOI=10.1111/j.1365-2443.2007.01118.x;
RA Watai Y., Kobayashi A., Nagase H., Mizukami M., McEvoy J., Singer J.D.,
RA Itoh K., Yamamoto M.;
RT "Subcellular localization and cytoplasmic complex status of endogenous
RT Keap1.";
RL Genes Cells 12:1163-1178(2007).
RN [17]
RP GUANYLATION.
RX PubMed=17906641; DOI=10.1038/nchembio.2007.33;
RA Sawa T., Zaki M.H., Okamoto T., Akuta T., Tokutomi Y., Kim-Mitsuyama S.,
RA Ihara H., Kobayashi A., Yamamoto M., Fujii S., Arimoto H., Akaike T.;
RT "Protein S-guanylation by the biological signal 8-nitroguanosine 3',5'-
RT cyclic monophosphate.";
RL Nat. Chem. Biol. 3:727-735(2007).
RN [18]
RP MUTAGENESIS OF CYS-151; CYS-273 AND CYS-288.
RX PubMed=18268004; DOI=10.1128/mcb.01704-07;
RA Yamamoto T., Suzuki T., Kobayashi A., Wakabayashi J., Maher J.,
RA Motohashi H., Yamamoto M.;
RT "Physiological significance of reactive cysteine residues of Keap1 in
RT determining Nrf2 activity.";
RL Mol. Cell. Biol. 28:2758-2770(2008).
RN [19]
RP INTERACTION WITH SQSTM1, AND SUBCELLULAR LOCATION.
RX PubMed=20495340; DOI=10.4161/auto.6.5.12189;
RA Fan W., Tang Z., Chen D., Moughon D., Ding X., Chen S., Zhu M., Zhong Q.;
RT "Keap1 facilitates p62-mediated ubiquitin aggregate clearance via
RT autophagy.";
RL Autophagy 6:614-621(2010).
RN [20]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Lung, and Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [21]
RP GUANYLATION AT CYS-434, ACTIVITY REGULATION, FUNCTION, AND DOMAIN.
RX PubMed=20498371; DOI=10.1074/jbc.m110.145441;
RA Fujii S., Sawa T., Ihara H., Tong K.I., Ida T., Okamoto T., Ahtesham A.K.,
RA Ishima Y., Motohashi H., Yamamoto M., Akaike T.;
RT "The critical role of nitric oxide signaling, via protein S-guanylation and
RT nitrated cyclic GMP, in the antioxidant adaptive response.";
RL J. Biol. Chem. 285:23970-23984(2010).
RN [22]
RP FUNCTION, INTERACTION WITH SQSTM1, ACTIVITY REGULATION, SUBCELLULAR
RP LOCATION, AND MUTAGENESIS OF ARG-380; ARG-415 AND ARG-483.
RX PubMed=20421418; DOI=10.1128/mcb.00248-10;
RA Lau A., Wang X.J., Zhao F., Villeneuve N.F., Wu T., Jiang T., Sun Z.,
RA White E., Zhang D.D.;
RT "A noncanonical mechanism of Nrf2 activation by autophagy deficiency:
RT direct interaction between Keap1 and p62.";
RL Mol. Cell. Biol. 30:3275-3285(2010).
RN [23]
RP S-NITROSYLATION AT CYS-151.
RX PubMed=20956331; DOI=10.1073/pnas.1007387107;
RA McMahon M., Lamont D.J., Beattie K.A., Hayes J.D.;
RT "Keap1 perceives stress via three sensors for the endogenous signaling
RT molecules nitric oxide, zinc, and alkenals.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:18838-18843(2010).
RN [24]
RP SUCCINATION AT CYS-38; CYS-151; CYS-241; CYS-288; CYS-319 AND CYS-613,
RP DOMAIN, ACTIVITY REGULATION, AND FUNCTION.
RX PubMed=22014577; DOI=10.1016/j.ccr.2011.09.006;
RA Adam J., Hatipoglu E., O'Flaherty L., Ternette N., Sahgal N., Lockstone H.,
RA Baban D., Nye E., Stamp G.W., Wolhuter K., Stevens M., Fischer R.,
RA Carmeliet P., Maxwell P.H., Pugh C.W., Frizzell N., Soga T., Kessler B.M.,
RA El-Bahrawy M., Ratcliffe P.J., Pollard P.J.;
RT "Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd
RT pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling.";
RL Cancer Cell 20:524-537(2011).
RN [25]
RP DEGRADATION.
RX PubMed=22872865; DOI=10.1073/pnas.1121572109;
RA Taguchi K., Fujikawa N., Komatsu M., Ishii T., Unno M., Akaike T.,
RA Motohashi H., Yamamoto M.;
RT "Keap1 degradation by autophagy for the maintenance of redox homeostasis.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:13561-13566(2012).
RN [26]
RP MUTAGENESIS OF CYS-273 AND CYS-288.
RX PubMed=26527616; DOI=10.1128/mcb.00868-15;
RA Saito R., Suzuki T., Hiramoto K., Asami S., Naganuma E., Suda H., Iso T.,
RA Yamamoto H., Morita M., Baird L., Furusawa Y., Negishi T., Ichinose M.,
RA Yamamoto M.;
RT "Characterizations of Three Major Cysteine Sensors of Keap1 in Stress
RT Response.";
RL Mol. Cell. Biol. 36:271-284(2016).
RN [27]
RP SUBCELLULAR LOCATION, IDENTIFICATION IN THE BCR(KEAP1) COMPLEX, AND
RP INTERACTION WITH NFE2L2.
RX PubMed=27697860; DOI=10.1128/mcb.00389-16;
RA Iso T., Suzuki T., Baird L., Yamamoto M.;
RT "Absolute Amounts and Status of the Nrf2-Keap1-Cul3 Complex within Cells.";
RL Mol. Cell. Biol. 36:3100-3112(2016).
RN [28]
RP FUNCTION.
RX PubMed=28380357; DOI=10.1016/j.celrep.2017.03.030;
RA Lee Y., Chou T.F., Pittman S.K., Keith A.L., Razani B., Weihl C.C.;
RT "Keap1/cullin3 modulates p62/SQSTM1 activity via UBA domain
RT ubiquitination.";
RL Cell Rep. 19:188-202(2017).
RN [29]
RP REVIEW.
RX PubMed=28842501; DOI=10.1074/jbc.r117.800169;
RA Suzuki T., Yamamoto M.;
RT "Stress-sensing mechanisms and the physiological roles of the Keap1-Nrf2
RT system during cellular stress.";
RL J. Biol. Chem. 292:16817-16824(2017).
RN [30]
RP FUNCTION, AND ALKYLATION.
RX PubMed=29590092; DOI=10.1038/nature25986;
RA Mills E.L., Ryan D.G., Prag H.A., Dikovskaya D., Menon D., Zaslona Z.,
RA Jedrychowski M.P., Costa A.S.H., Higgins M., Hams E., Szpyt J.,
RA Runtsch M.C., King M.S., McGouran J.F., Fischer R., Kessler B.M.,
RA McGettrick A.F., Hughes M.M., Carroll R.G., Booty L.M., Knatko E.V.,
RA Meakin P.J., Ashford M.L.J., Modis L.K., Brunori G., Sevin D.C.,
RA Fallon P.G., Caldwell S.T., Kunji E.R.S., Chouchani E.T., Frezza C.,
RA Dinkova-Kostova A.T., Hartley R.C., Murphy M.P., O'Neill L.A.;
RT "Itaconate is an anti-inflammatory metabolite that activates Nrf2 via
RT alkylation of KEAP1.";
RL Nature 556:113-117(2018).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) OF 309-624 IN COMPLEX WITH NFE2L2,
RP AND MUTAGENESIS OF 599-SER--ARG-601; 602-SER--VAL-604 AND 605-GLY--VAL-608.
RX PubMed=16507366; DOI=10.1016/j.molcel.2006.01.013;
RA Padmanabhan B., Tong K.I., Ohta T., Nakamura Y., Scharlock M., Ohtsuji M.,
RA Kang M., Kobayashi A., Yokoyama S., Yamamoto M.;
RT "Structural basis for defects of Keap1 activity provoked by its point
RT mutations in lung cancer.";
RL Mol. Cell 21:689-700(2006).
RN [32] {ECO:0007744|PDB:3ADE}
RP X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 309-624 IN COMPLEX WITH SQSTM1,
RP FUNCTION, INTERACTION WITH SQSTM1, ACTIVITY REGULATION, SUBCELLULAR
RP LOCATION, AND MUTAGENESIS OF TYR-334; SER-363; ARG-380; ASN-382; ARG-415;
RP ARG-483; SER-508; GLN-530; SER-555 AND SER-602.
RX PubMed=20173742; DOI=10.1038/ncb2021;
RA Komatsu M., Kurokawa H., Waguri S., Taguchi K., Kobayashi A., Ichimura Y.,
RA Sou Y.S., Ueno I., Sakamoto A., Tong K.I., Kim M., Nishito Y., Iemura S.,
RA Natsume T., Ueno T., Kominami E., Motohashi H., Tanaka K., Yamamoto M.;
RT "The selective autophagy substrate p62 activates the stress responsive
RT transcription factor Nrf2 through inactivation of Keap1.";
RL Nat. Cell Biol. 12:213-223(2010).
RN [33] {ECO:0007744|PDB:3WDZ}
RP X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) OF 321-609 IN COMPLEX WITH SQSTM1,
RP FUNCTION, INTERACTION WITH SQSTM1, ACTIVITY REGULATION, AND DEGRADATION.
RX PubMed=24011591; DOI=10.1016/j.molcel.2013.08.003;
RA Ichimura Y., Waguri S., Sou Y.S., Kageyama S., Hasegawa J., Ishimura R.,
RA Saito T., Yang Y., Kouno T., Fukutomi T., Hoshii T., Hirao A., Takagi K.,
RA Mizushima T., Motohashi H., Lee M.S., Yoshimori T., Tanaka K., Yamamoto M.,
RA Komatsu M.;
RT "Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective
RT autophagy.";
RL Mol. Cell 51:618-631(2013).
CC -!- FUNCTION: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3
CC ubiquitin ligase complex that regulates the response to oxidative
CC stress by targeting NFE2L2/NRF2 for ubiquitination (PubMed:9887101,
CC PubMed:12682069, PubMed:15282312, PubMed:15367669, PubMed:15581590).
CC KEAP1 acts as a key sensor of oxidative and electrophilic stress: in
CC normal conditions, the BCR(KEAP1) complex mediates ubiquitination and
CC degradation of NFE2L2/NRF2, a transcription factor regulating
CC expression of many cytoprotective genes (PubMed:9887101,
CC PubMed:12193649, PubMed:14764894). In response to oxidative stress,
CC different electrophile metabolites trigger non-enzymatic covalent
CC modifications of highly reactive cysteine residues in KEAP1, leading to
CC inactivate the ubiquitin ligase activity of the BCR(KEAP1) complex,
CC promoting NFE2L2/NRF2 nuclear accumulation and expression of phase II
CC detoxifying enzymes (PubMed:12193649, PubMed:20498371, PubMed:22014577,
CC PubMed:29590092). In response to selective autophagy, KEAP1 is
CC sequestered in inclusion bodies following its interaction with
CC SQSTM1/p62, leading to inactivation of the BCR(KEAP1) complex and
CC activation of NFE2L2/NRF2 (PubMed:20421418, PubMed:20173742,
CC PubMed:24011591). The BCR(KEAP1) complex also mediates ubiquitination
CC of SQSTM1/p62, increasing SQSTM1/p62 sequestering activity and
CC degradation (PubMed:28380357). The BCR(KEAP1) complex also targets BPTF
CC and PGAM5 for ubiquitination and degradation by the proteasome (By
CC similarity). {ECO:0000250|UniProtKB:Q14145,
CC ECO:0000269|PubMed:12193649, ECO:0000269|PubMed:12682069,
CC ECO:0000269|PubMed:14764894, ECO:0000269|PubMed:15282312,
CC ECO:0000269|PubMed:15367669, ECO:0000269|PubMed:15581590,
CC ECO:0000269|PubMed:20173742, ECO:0000269|PubMed:20421418,
CC ECO:0000269|PubMed:20498371, ECO:0000269|PubMed:22014577,
CC ECO:0000269|PubMed:24011591, ECO:0000269|PubMed:28380357,
CC ECO:0000269|PubMed:29590092, ECO:0000269|PubMed:9887101}.
CC -!- ACTIVITY REGULATION: Ubiquitin ligase activity of the BCR(KEAP1)
CC complex is inhibited by oxidative stress and electrophile metabolites
CC such as sulforaphane (PubMed:12193649, PubMed:14764894,
CC PubMed:22014577). Electrophile metabolites react with reactive cysteine
CC residues in KEAP1 and trigger non-enzymatic covalent modifications of
CC these cysteine residues, leading to inactivate the ubiquitin ligase
CC activity of the BCR(KEAP1) complex (PubMed:20498371, PubMed:22014577).
CC Selective autophagy also inactivates the BCR(KEAP1) complex via
CC interaction between KEAP1 and SQSTM1/p62, which sequesters the complex
CC in inclusion bodies and promotes its degradation (PubMed:20421418,
CC PubMed:20173742, PubMed:24011591). {ECO:0000269|PubMed:12193649,
CC ECO:0000269|PubMed:14764894, ECO:0000269|PubMed:20173742,
CC ECO:0000269|PubMed:20421418, ECO:0000269|PubMed:20498371,
CC ECO:0000269|PubMed:22014577, ECO:0000269|PubMed:24011591}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000269|PubMed:12682069, ECO:0000269|PubMed:15282312,
CC ECO:0000269|PubMed:15367669, ECO:0000269|PubMed:15581590,
CC ECO:0000269|PubMed:9887101}.
CC -!- SUBUNIT: Component of the BCR(KEAP1) E3 ubiquitin ligase complex, at
CC least composed of 2 molecules of CUL3, 2 molecules of KEAP1, and RBX1
CC (PubMed:15282312, PubMed:16790436, PubMed:27697860). Interacts with
CC NFE2L2/NRF2; the interaction is direct (PubMed:15282312,
CC PubMed:15367669, PubMed:15581590, PubMed:16790436, PubMed:16581765,
CC PubMed:27697860, PubMed:16507366). Forms a ternary complex with
CC NFE2L2/NRF2 and PGAM5 (By similarity). Interacts with (phosphorylated)
CC SQSTM1/p62; the interaction is direct and inactivates the BCR(KEAP1)
CC complex by sequestering it in inclusion bodies, promoting its
CC degradation (PubMed:20495340, PubMed:20421418, PubMed:20173742,
CC PubMed:24011591). Interacts with NFE2L1 (By similarity). Interacts with
CC BPTF and PTMA (By similarity). Interacts with MAP1LC3B (By similarity).
CC Interacts indirectly with ENC1 (By similarity). Interacts with SESN1
CC and SESN2 (By similarity). Interacts with HSP90AA1 and HSP90AB1 (By
CC similarity). {ECO:0000250|UniProtKB:Q14145,
CC ECO:0000269|PubMed:15282312, ECO:0000269|PubMed:15367669,
CC ECO:0000269|PubMed:15581590, ECO:0000269|PubMed:16507366,
CC ECO:0000269|PubMed:16581765, ECO:0000269|PubMed:16790436,
CC ECO:0000269|PubMed:20173742, ECO:0000269|PubMed:20421418,
CC ECO:0000269|PubMed:20495340, ECO:0000269|PubMed:24011591,
CC ECO:0000269|PubMed:27697860}.
CC -!- INTERACTION:
CC Q9Z2X8; Q9Z2X8: Keap1; NbExp=3; IntAct=EBI-647110, EBI-647110;
CC Q9Z2X8; Q60795: Nfe2l2; NbExp=23; IntAct=EBI-647110, EBI-642563;
CC Q9Z2X8; Q64337: Sqstm1; NbExp=6; IntAct=EBI-647110, EBI-645025;
CC Q9Z2X8; Q13501: SQSTM1; Xeno; NbExp=2; IntAct=EBI-647110, EBI-307104;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15367669,
CC ECO:0000269|PubMed:15379550, ECO:0000269|PubMed:17903176,
CC ECO:0000269|PubMed:27697860}. Nucleus {ECO:0000269|PubMed:15379550}.
CC Note=Mainly cytoplasmic (PubMed:17903176). In response to selective
CC autophagy, relocalizes to inclusion bodies following interaction with
CC SQSTM1/p62 (PubMed:20495340, PubMed:20421418, PubMed:20173742).
CC {ECO:0000269|PubMed:17903176, ECO:0000269|PubMed:20173742,
CC ECO:0000269|PubMed:20421418, ECO:0000269|PubMed:20495340}.
CC -!- DOMAIN: The Kelch repeats mediate interaction with NFE2L2/NRF2, BPTF
CC and PGAM5. {ECO:0000250|UniProtKB:Q14145}.
CC -!- DOMAIN: KEAP1 contains reactive cysteine residues that act as sensors
CC for endogenously produced and exogenously encountered small molecules,
CC which react with sulfhydryl groups and modify the cysteine sensors,
CC leading to impair ability of the BCR(KEAP1) complex to ubiquitinate
CC target proteins. {ECO:0000269|PubMed:12193649,
CC ECO:0000269|PubMed:14764894, ECO:0000269|PubMed:20498371,
CC ECO:0000269|PubMed:22014577, ECO:0000269|PubMed:26527616}.
CC -!- PTM: Non-enzymatic covalent modifications of reactive cysteines by
CC electrophile metabolites inactivate the BCR(KEAP1) complex
CC (PubMed:12193649, PubMed:20498371, PubMed:22014577). Accumulation of
CC fumarate promotes the formation of cysteine S-succination (S-(2-
CC succinyl)cysteine), leading to inactivate the BCR(KEAP1) complex and
CC promote NFE2L2/NRF2 nuclear accumulation and activation
CC (PubMed:22014577). Nitric oxide-dependent 8-Nitro-cGMP formation
CC promotes cysteine guanylation (S-cGMP-cysteine), leading to NFE2L2/NRF2
CC nuclear accumulation and activation (PubMed:17906641, PubMed:20498371).
CC Itaconate, an anti-inflammatory metabolite generated in response to
CC lipopolysaccharide, alkylates cysteines, activating NFE2L2/NRF2
CC (PubMed:29590092). Methylglyoxal, a reactive metabolite that
CC accumulates when the glycolytic enzyme PGK1 is inhibited, promotes
CC formation of a methylimidazole cross-link between proximal Cys-151 and
CC Arg-135 on another KEAP1 molecule, resulting in an inactive dimer that
CC inactivates the BCR(KEAP1) complex (By similarity).
CC {ECO:0000250|UniProtKB:Q14145, ECO:0000269|PubMed:12193649,
CC ECO:0000269|PubMed:17906641, ECO:0000269|PubMed:20498371,
CC ECO:0000269|PubMed:22014577, ECO:0000269|PubMed:29590092}.
CC -!- PTM: Degraded via a proteasomal-independent process during selective
CC autophagy: interaction with phosphorylated SQSTM1/p62 sequesters KEAP1
CC in inclusion bodies, leading to its degradation.
CC {ECO:0000269|PubMed:22872865, ECO:0000269|PubMed:24011591}.
CC -!- PTM: Auto-ubiquitinated by the BCR(KEAP1) complex. Quinone-induced
CC oxidative stress, but not sulforaphane, increases its ubiquitination.
CC Ubiquitination and subsequent degradation is most pronounced following
CC prolonged exposure of cells to oxidative stress, particularly in
CC glutathione-deficient cells that are highly susceptible to oxidative
CC stress. {ECO:0000250|UniProtKB:Q14145}.
CC -!- DISRUPTION PHENOTYPE: Early postnatal lethality caused by abnormal
CC cornification (PubMed:14517554). Mice survive until weaning and
CC probably die from malnutrition resulting from hyperkeratosis in the
CC esophagus and forestomach that cause gastric obstruction
CC (PubMed:14517554). Defects are caused by constitutive activation
CC Nfe2l2/Nrf2, leading to constitutive expression of phase 2 detoxifying
CC enzymes (PubMed:14517554). Mice lacking both Nfe2l2/Nrf2 and Keap1
CC reverse the hyperkeratosis phenotype and are healthy and viable in
CC normal conditions (PubMed:14517554). {ECO:0000269|PubMed:14517554}.
CC -!- SIMILARITY: Belongs to the KEAP1 family. {ECO:0000305}.
CC -!- CAUTION: According to a report, not degraded in response to autophagy
CC (PubMed:20495340). However, publications have shown that KEAP1 is
CC degraded via a proteasomal-independent process during selective
CC autophagy (PubMed:22872865, PubMed:24011591).
CC {ECO:0000269|PubMed:20495340, ECO:0000269|PubMed:22872865,
CC ECO:0000269|PubMed:24011591}.
CC -!- CAUTION: The mechanism of inactivation of the BCR(KEAP1) complex by
CC covalent modifications of reactive cysteines is unclear. Covalent
CC modifications were initially thought to disrupt interaction between
CC KEAP1 and NFE2L2/NRF2 (PubMed:12193649). Recent publications suggest
CC that cysteine modifications disrupt the interaction between KEAP1 and
CC CUL3 without affecting the interaction between KEAP1 and NFE2L2/NRF2
CC (By similarity). {ECO:0000250|UniProtKB:Q14145,
CC ECO:0000269|PubMed:12193649}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAC97871.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC ---------------------------------------------------------------------------
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DR EMBL; AB020063; BAA34639.1; -; mRNA.
DR EMBL; AF454353; AAL84711.1; -; Genomic_DNA.
DR EMBL; AK129061; BAC97871.1; ALT_INIT; mRNA.
DR EMBL; AK046178; BAC32621.1; -; mRNA.
DR EMBL; AK076234; BAC36267.1; -; mRNA.
DR EMBL; AK150437; BAE29559.1; -; mRNA.
DR EMBL; AK150485; BAE29601.1; -; mRNA.
DR EMBL; AK152142; BAE30980.1; -; mRNA.
DR EMBL; AK154430; BAE32581.1; -; mRNA.
DR EMBL; AK155507; BAE33299.1; -; mRNA.
DR EMBL; AK159858; BAE35433.1; -; mRNA.
DR EMBL; BC055732; AAH55732.1; -; mRNA.
DR CCDS; CCDS22897.1; -.
DR RefSeq; NP_001103775.1; NM_001110305.1.
DR RefSeq; NP_001103776.1; NM_001110306.1.
DR RefSeq; NP_001103777.1; NM_001110307.1.
DR RefSeq; NP_057888.1; NM_016679.4.
DR PDB; 1X2J; X-ray; 1.60 A; A=309-624.
DR PDB; 1X2R; X-ray; 1.70 A; A=309-624.
DR PDB; 2DYH; X-ray; 1.90 A; A=309-624.
DR PDB; 2Z32; X-ray; 2.00 A; A=309-624.
DR PDB; 3ADE; X-ray; 2.80 A; A=309-624.
DR PDB; 3WDZ; X-ray; 2.60 A; A=321-609.
DR PDB; 3WN7; X-ray; 1.57 A; A/L=321-609.
DR PDB; 4ZY3; X-ray; 1.80 A; A/B=321-609.
DR PDB; 5CGJ; X-ray; 3.36 A; A=309-624.
DR PDB; 5FNQ; X-ray; 1.91 A; A=322-624.
DR PDB; 5FNR; X-ray; 1.89 A; A=322-624.
DR PDB; 5FNS; X-ray; 1.79 A; A=322-624.
DR PDB; 5FNT; X-ray; 1.79 A; A=322-624.
DR PDB; 5FNU; X-ray; 1.78 A; A=322-624.
DR PDB; 5FZJ; X-ray; 2.01 A; A=322-624.
DR PDB; 5FZN; X-ray; 1.97 A; A=322-624.
DR PDB; 6QMC; X-ray; 1.77 A; A=322-624.
DR PDB; 6QMD; X-ray; 1.94 A; A=322-624.
DR PDB; 6QME; X-ray; 1.81 A; A=322-624.
DR PDB; 6QMJ; X-ray; 1.86 A; A=322-624.
DR PDB; 6QMK; X-ray; 1.72 A; A=322-624.
DR PDB; 6ZEW; X-ray; 1.38 A; A=322-624.
DR PDB; 6ZEX; X-ray; 1.98 A; A=322-624.
DR PDB; 6ZEY; X-ray; 1.80 A; A=322-624.
DR PDB; 6ZEZ; X-ray; 2.55 A; A=322-624.
DR PDB; 6ZF0; X-ray; 1.60 A; A=322-624.
DR PDB; 6ZF1; X-ray; 1.74 A; A=322-624.
DR PDB; 6ZF2; X-ray; 2.20 A; A=322-624.
DR PDB; 6ZF3; X-ray; 1.28 A; A=322-624.
DR PDB; 6ZF4; X-ray; 1.21 A; A=322-624.
DR PDB; 6ZF5; X-ray; 1.29 A; A=322-624.
DR PDB; 6ZF6; X-ray; 1.38 A; A=322-624.
DR PDB; 6ZF7; X-ray; 1.37 A; A=322-624.
DR PDB; 6ZF8; X-ray; 1.75 A; A=322-624.
DR PDB; 7C5E; X-ray; 1.75 A; A=324-616.
DR PDB; 7C60; X-ray; 1.95 A; A=324-616.
DR PDB; 7ECA; X-ray; 2.00 A; A=309-624.
DR PDB; 7P58; X-ray; 1.89 A; A=322-624.
DR PDB; 7P5E; X-ray; 1.87 A; A=322-624.
DR PDB; 7P5F; X-ray; 1.88 A; A=322-624.
DR PDB; 7P5I; X-ray; 1.86 A; A=322-624.
DR PDB; 7P5K; X-ray; 1.79 A; A=322-624.
DR PDB; 7P5N; X-ray; 1.89 A; A=322-624.
DR PDB; 7P5P; X-ray; 1.85 A; A=322-624.
DR PDBsum; 1X2J; -.
DR PDBsum; 1X2R; -.
DR PDBsum; 2DYH; -.
DR PDBsum; 2Z32; -.
DR PDBsum; 3ADE; -.
DR PDBsum; 3WDZ; -.
DR PDBsum; 3WN7; -.
DR PDBsum; 4ZY3; -.
DR PDBsum; 5CGJ; -.
DR PDBsum; 5FNQ; -.
DR PDBsum; 5FNR; -.
DR PDBsum; 5FNS; -.
DR PDBsum; 5FNT; -.
DR PDBsum; 5FNU; -.
DR PDBsum; 5FZJ; -.
DR PDBsum; 5FZN; -.
DR PDBsum; 6QMC; -.
DR PDBsum; 6QMD; -.
DR PDBsum; 6QME; -.
DR PDBsum; 6QMJ; -.
DR PDBsum; 6QMK; -.
DR PDBsum; 6ZEW; -.
DR PDBsum; 6ZEX; -.
DR PDBsum; 6ZEY; -.
DR PDBsum; 6ZEZ; -.
DR PDBsum; 6ZF0; -.
DR PDBsum; 6ZF1; -.
DR PDBsum; 6ZF2; -.
DR PDBsum; 6ZF3; -.
DR PDBsum; 6ZF4; -.
DR PDBsum; 6ZF5; -.
DR PDBsum; 6ZF6; -.
DR PDBsum; 6ZF7; -.
DR PDBsum; 6ZF8; -.
DR PDBsum; 7C5E; -.
DR PDBsum; 7C60; -.
DR PDBsum; 7ECA; -.
DR PDBsum; 7P58; -.
DR PDBsum; 7P5E; -.
DR PDBsum; 7P5F; -.
DR PDBsum; 7P5I; -.
DR PDBsum; 7P5K; -.
DR PDBsum; 7P5N; -.
DR PDBsum; 7P5P; -.
DR AlphaFoldDB; Q9Z2X8; -.
DR BMRB; Q9Z2X8; -.
DR SMR; Q9Z2X8; -.
DR BioGRID; 206135; 28.
DR CORUM; Q9Z2X8; -.
DR DIP; DIP-49698N; -.
DR ELM; Q9Z2X8; -.
DR IntAct; Q9Z2X8; 9.
DR MINT; Q9Z2X8; -.
DR STRING; 10090.ENSMUSP00000131029; -.
DR BindingDB; Q9Z2X8; -.
DR ChEMBL; CHEMBL3562164; -.
DR iPTMnet; Q9Z2X8; -.
DR PhosphoSitePlus; Q9Z2X8; -.
DR SwissPalm; Q9Z2X8; -.
DR EPD; Q9Z2X8; -.
DR MaxQB; Q9Z2X8; -.
DR PaxDb; Q9Z2X8; -.
DR PeptideAtlas; Q9Z2X8; -.
DR PRIDE; Q9Z2X8; -.
DR ProteomicsDB; 263429; -.
DR Antibodypedia; 1418; 714 antibodies from 39 providers.
DR DNASU; 50868; -.
DR Ensembl; ENSMUST00000049567; ENSMUSP00000062467; ENSMUSG00000003308.
DR Ensembl; ENSMUST00000164812; ENSMUSP00000131029; ENSMUSG00000003308.
DR Ensembl; ENSMUST00000193982; ENSMUSP00000141840; ENSMUSG00000003308.
DR Ensembl; ENSMUST00000194542; ENSMUSP00000141807; ENSMUSG00000003308.
DR GeneID; 50868; -.
DR KEGG; mmu:50868; -.
DR UCSC; uc009oko.2; mouse.
DR CTD; 9817; -.
DR MGI; MGI:1858732; Keap1.
DR VEuPathDB; HostDB:ENSMUSG00000003308; -.
DR eggNOG; KOG4441; Eukaryota.
DR GeneTree; ENSGT00940000159543; -.
DR HOGENOM; CLU_004253_14_2_1; -.
DR InParanoid; Q9Z2X8; -.
DR OMA; CYHPEND; -.
DR OrthoDB; 746011at2759; -.
DR PhylomeDB; Q9Z2X8; -.
DR TreeFam; TF329218; -.
DR Reactome; R-MMU-5689880; Ub-specific processing proteases.
DR Reactome; R-MMU-8951664; Neddylation.
DR Reactome; R-MMU-9755511; KEAP1-NFE2L2 pathway.
DR Reactome; R-MMU-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 50868; 23 hits in 77 CRISPR screens.
DR ChiTaRS; Keap1; mouse.
DR EvolutionaryTrace; Q9Z2X8; -.
DR PRO; PR:Q9Z2X8; -.
DR Proteomes; UP000000589; Chromosome 9.
DR RNAct; Q9Z2X8; protein.
DR Bgee; ENSMUSG00000003308; Expressed in supraoptic nucleus and 240 other tissues.
DR ExpressionAtlas; Q9Z2X8; baseline and differential.
DR Genevisible; Q9Z2X8; MM.
DR GO; GO:0005884; C:actin filament; IDA:CACAO.
DR GO; GO:0005912; C:adherens junction; ISO:MGI.
DR GO; GO:0034451; C:centriolar satellite; ISO:MGI.
DR GO; GO:0031463; C:Cul3-RING ubiquitin ligase complex; IDA:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:MGI.
DR GO; GO:0005925; C:focal adhesion; ISO:MGI.
DR GO; GO:0016234; C:inclusion body; IDA:UniProtKB.
DR GO; GO:0030496; C:midbody; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISO:MGI.
DR GO; GO:0032991; C:protein-containing complex; IMP:CAFA.
DR GO; GO:0097718; F:disordered domain specific binding; IPI:CAFA.
DR GO; GO:0042802; F:identical protein binding; IMP:CAFA.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; ISO:MGI.
DR GO; GO:0071322; P:cellular response to carbohydrate stimulus; ISO:MGI.
DR GO; GO:0071353; P:cellular response to interleukin-4; IDA:MGI.
DR GO; GO:0034599; P:cellular response to oxidative stress; IDA:UniProtKB.
DR GO; GO:0042994; P:cytoplasmic sequestering of transcription factor; ISO:MGI.
DR GO; GO:0001701; P:in utero embryonic development; IMP:MGI.
DR GO; GO:0010629; P:negative regulation of gene expression; ISO:MGI.
DR GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB.
DR GO; GO:0010506; P:regulation of autophagy; IDA:UniProtKB.
DR GO; GO:0045604; P:regulation of epidermal cell differentiation; IMP:MGI.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; IMP:MGI.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IDA:UniProtKB.
DR Gene3D; 2.120.10.80; -; 1.
DR Gene3D; 3.30.710.10; -; 1.
DR IDEAL; IID50109; -.
DR InterPro; IPR011705; BACK.
DR InterPro; IPR017096; BTB-kelch_protein.
DR InterPro; IPR000210; BTB/POZ_dom.
DR InterPro; IPR030563; KEAP1.
DR InterPro; IPR015915; Kelch-typ_b-propeller.
DR InterPro; IPR006652; Kelch_1.
DR InterPro; IPR011333; SKP1/BTB/POZ_sf.
DR PANTHER; PTHR24412:SF162; PTHR24412:SF162; 1.
DR Pfam; PF07707; BACK; 1.
DR Pfam; PF00651; BTB; 1.
DR Pfam; PF01344; Kelch_1; 6.
DR PIRSF; PIRSF037037; Kelch-like_protein_gigaxonin; 1.
DR SMART; SM00875; BACK; 1.
DR SMART; SM00225; BTB; 1.
DR SMART; SM00612; Kelch; 6.
DR SUPFAM; SSF117281; SSF117281; 1.
DR SUPFAM; SSF54695; SSF54695; 1.
DR PROSITE; PS50097; BTB; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cytoplasm; Kelch repeat; Nucleus; Reference proteome; Repeat;
KW S-nitrosylation; Thioether bond; Ubl conjugation; Ubl conjugation pathway.
FT CHAIN 1..624
FT /note="Kelch-like ECH-associated protein 1"
FT /id="PRO_0000119094"
FT DOMAIN 77..149
FT /note="BTB"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00037"
FT DOMAIN 184..286
FT /note="BACK"
FT REPEAT 327..372
FT /note="Kelch 1"
FT REPEAT 373..423
FT /note="Kelch 2"
FT REPEAT 424..470
FT /note="Kelch 3"
FT REPEAT 471..517
FT /note="Kelch 4"
FT REPEAT 519..564
FT /note="Kelch 5"
FT REPEAT 565..611
FT /note="Kelch 6"
FT SITE 151
FT /note="Sensor for electrophilic agents"
FT /evidence="ECO:0000269|PubMed:18268004,
FT ECO:0000269|PubMed:22014577, ECO:0000269|PubMed:26527616"
FT SITE 257
FT /note="Sensor for electrophilic agents"
FT /evidence="ECO:0000250|UniProtKB:Q14145"
FT SITE 273
FT /note="Sensor for electrophilic agents"
FT /evidence="ECO:0000269|PubMed:14764894,
FT ECO:0000269|PubMed:26527616"
FT SITE 288
FT /note="Sensor for electrophilic agents"
FT /evidence="ECO:0000269|PubMed:14764894,
FT ECO:0000269|PubMed:22014577, ECO:0000269|PubMed:26527616"
FT SITE 434
FT /note="Sensor for electrophilic agents"
FT /evidence="ECO:0000269|PubMed:20498371"
FT MOD_RES 38
FT /note="S-(2-succinyl)cysteine"
FT /evidence="ECO:0000269|PubMed:22014577"
FT MOD_RES 151
FT /note="S-(2,3-dicarboxypropyl)cysteine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q14145"
FT MOD_RES 151
FT /note="S-(2-succinyl)cysteine; alternate"
FT /evidence="ECO:0000269|PubMed:22014577"
FT MOD_RES 151
FT /note="S-nitrosocysteine; alternate"
FT /evidence="ECO:0000269|PubMed:20956331"
FT MOD_RES 241
FT /note="S-(2-succinyl)cysteine"
FT /evidence="ECO:0000269|PubMed:22014577"
FT MOD_RES 257
FT /note="S-(2,3-dicarboxypropyl)cysteine"
FT /evidence="ECO:0000250|UniProtKB:Q14145"
FT MOD_RES 273
FT /note="S-(2,3-dicarboxypropyl)cysteine"
FT /evidence="ECO:0000250|UniProtKB:Q14145"
FT MOD_RES 288
FT /note="S-(2,3-dicarboxypropyl)cysteine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q14145"
FT MOD_RES 288
FT /note="S-(2-succinyl)cysteine; alternate"
FT /evidence="ECO:0000269|PubMed:22014577"
FT MOD_RES 319
FT /note="S-(2-succinyl)cysteine"
FT /evidence="ECO:0000269|PubMed:22014577"
FT MOD_RES 434
FT /note="S-cGMP-cysteine"
FT /evidence="ECO:0000269|PubMed:20498371"
FT MOD_RES 613
FT /note="S-(2-succinyl)cysteine"
FT /evidence="ECO:0000269|PubMed:22014577"
FT CROSSLNK 135
FT /note="N5-[4-(S-L-cysteinyl)-5-methyl-1H-imidazol-2-yl]-L-
FT ornithine (Arg-Cys) (interchain with C-151 in KEAP1)"
FT /evidence="ECO:0000250|UniProtKB:Q14145"
FT CROSSLNK 151
FT /note="N5-[4-(S-L-cysteinyl)-5-methyl-1H-imidazol-2-yl]-L-
FT ornithine (Cys-Arg) (interchain with R-135 in KEAP1)"
FT /evidence="ECO:0000250|UniProtKB:Q14145"
FT MUTAGEN 71
FT /note="R->G: Abolished ability to ubiquitinate NFE2L2/NRF2
FT without affecting homodimerization."
FT /evidence="ECO:0000269|PubMed:16790436"
FT MUTAGEN 151
FT /note="C->S: Substitution with a small side chain that
FT prevents covalent modification by an electrophile; promotes
FT constitutive ubiquitination of NFE2L2/NRF2 and subsequent
FT repression of phase 2 detoxifying enzymes. Knockin mice are
FT healthy and viable in normal conditions but do not activate
FT NFE2L2/NRF2 in response to oxidative stress."
FT /evidence="ECO:0000269|PubMed:18268004,
FT ECO:0000269|PubMed:20956331"
FT MUTAGEN 273
FT /note="C->A: Abolishes repression of NFE2L2/NRF2-dependent
FT gene expression. Knockin mice die approximately three weeks
FT after birth because of impaired ability of the BCR(KEAP1)
FT complex to ubiquitinate NFE2L2/NRF2; when associated with
FT A-288."
FT /evidence="ECO:0000269|PubMed:14764894"
FT MUTAGEN 273
FT /note="C->W,M: Retains ability to degrade NFE2L2/NRF2; when
FT associated with E-288."
FT /evidence="ECO:0000269|PubMed:26527616"
FT MUTAGEN 288
FT /note="C->A: Abolishes repression of NFE2L2/NRF2-dependent
FT gene expression. Slows down degradation of NFE2L2/NRF2.
FT Knockin mice die approximately three weeks after birth
FT because of impaired ability of the BCR(KEAP1) complex to
FT ubiquitinate NFE2L2/NRF2; when associated with A-273."
FT /evidence="ECO:0000269|PubMed:14764894"
FT MUTAGEN 288
FT /note="C->E,N,R: Retains ability to degrade NFE2L2/NRF2;
FT when associated with W-273. Abolishes ability to be
FT activated by 15-deoxy-delta(12,14)-prostaglandin J2."
FT /evidence="ECO:0000269|PubMed:26527616"
FT MUTAGEN 334
FT /note="Y->A: Impaired interaction with SQSTM1/p62."
FT /evidence="ECO:0000269|PubMed:20173742"
FT MUTAGEN 363
FT /note="S->A: Impaired interaction with SQSTM1/p62."
FT /evidence="ECO:0000269|PubMed:20173742"
FT MUTAGEN 380
FT /note="R->A: Impaired interaction with SQSTM1/p62.
FT Abolished interaction with SQSTM1/p62; when associated with
FT A-415 and A-483."
FT /evidence="ECO:0000269|PubMed:20173742,
FT ECO:0000269|PubMed:20421418"
FT MUTAGEN 380
FT /note="R->M: Impaired interaction with NFE2L2/NRF2."
FT /evidence="ECO:0000269|PubMed:16790436"
FT MUTAGEN 382
FT /note="N->A: Impaired interaction with SQSTM1/p62."
FT /evidence="ECO:0000269|PubMed:20173742"
FT MUTAGEN 415
FT /note="R->A: Impaired interaction with SQSTM1/p62.
FT Abolished interaction with SQSTM1/p62; when associated with
FT A-380 and A-483."
FT /evidence="ECO:0000269|PubMed:20173742,
FT ECO:0000269|PubMed:20421418"
FT MUTAGEN 415
FT /note="R->M: Impaired interaction with NFE2L2/NRF2."
FT /evidence="ECO:0000269|PubMed:16790436"
FT MUTAGEN 483
FT /note="R->A: Does not affect interaction with SQSTM1/p62.
FT Abolished interaction with SQSTM1/p62; when associated with
FT A-380 and A-415."
FT /evidence="ECO:0000269|PubMed:20173742,
FT ECO:0000269|PubMed:20421418"
FT MUTAGEN 483
FT /note="R->M: Impaired interaction with NFE2L2/NRF2."
FT /evidence="ECO:0000269|PubMed:16790436"
FT MUTAGEN 508
FT /note="S->A: Impaired interaction with SQSTM1/p62."
FT /evidence="ECO:0000269|PubMed:20173742"
FT MUTAGEN 530
FT /note="Q->A: Impaired interaction with SQSTM1/p62."
FT /evidence="ECO:0000269|PubMed:20173742"
FT MUTAGEN 555
FT /note="S->A: Impaired interaction with SQSTM1/p62."
FT /evidence="ECO:0000269|PubMed:20173742"
FT MUTAGEN 599..601
FT /note="SGR->AAA: Decreases repression of NFE2L2/NRF2-
FT dependent gene expression."
FT /evidence="ECO:0000269|PubMed:16507366"
FT MUTAGEN 602..604
FT /note="SGV->AAA: Abolishes repression of NFE2L2/NRF2-
FT dependent gene expression."
FT /evidence="ECO:0000269|PubMed:16507366"
FT MUTAGEN 602
FT /note="S->A: Impaired interaction with SQSTM1/p62."
FT /evidence="ECO:0000269|PubMed:20173742"
FT MUTAGEN 605..608
FT /note="GVAV->AAAA: Decreases repression of NFE2L2/NRF2-
FT dependent gene expression."
FT /evidence="ECO:0000269|PubMed:16507366"
FT CONFLICT 43
FT /note="T -> A (in Ref. 4; BAE29559/BAE30980)"
FT /evidence="ECO:0000305"
FT CONFLICT 348
FT /note="S -> G (in Ref. 4; BAC32621)"
FT /evidence="ECO:0000305"
FT CONFLICT 361
FT /note="P -> T (in Ref. 4; BAE29559/BAE30980)"
FT /evidence="ECO:0000305"
FT CONFLICT 579
FT /note="D -> V (in Ref. 4; BAE32581/BAE33299)"
FT /evidence="ECO:0000305"
FT STRAND 326..331
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 334..338
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 342..345
FT /evidence="ECO:0007829|PDB:6ZF4"
FT TURN 347..349
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 352..354
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 366..370
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 373..377
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 380..383
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 386..389
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 393..396
FT /evidence="ECO:0007829|PDB:6ZF4"
FT TURN 398..400
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 403..405
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 417..421
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 424..428
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 440..444
FT /evidence="ECO:0007829|PDB:6ZF4"
FT TURN 445..448
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 449..452
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 464..468
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 471..475
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 480..483
FT /evidence="ECO:0007829|PDB:7C60"
FT STRAND 487..491
FT /evidence="ECO:0007829|PDB:6ZF4"
FT HELIX 492..494
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 496..500
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 511..515
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 518..522
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 527..530
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 534..538
FT /evidence="ECO:0007829|PDB:6ZF4"
FT TURN 539..542
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 543..546
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 554..556
FT /evidence="ECO:0007829|PDB:6ZEZ"
FT STRAND 558..562
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 565..569
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 574..577
FT /evidence="ECO:0007829|PDB:4ZY3"
FT STRAND 580..585
FT /evidence="ECO:0007829|PDB:6ZF4"
FT TURN 586..589
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 590..596
FT /evidence="ECO:0007829|PDB:6ZF4"
FT STRAND 605..610
FT /evidence="ECO:0007829|PDB:6ZF4"
SQ SEQUENCE 624 AA; 69553 MW; 4645DB0122FB5F54 CRC64;
MQPEPKLSGA PRSSQFLPLW SKCPEGAGDA VMYASTECKA EVTPSQDGNR TFSYTLEDHT
KQAFGVMNEL RLSQQLCDVT LQVKYEDIPA AQFMAHKVVL ASSSPVFKAM FTNGLREQGM
EVVSIEGIHP KVMERLIEFA YTASISVGEK CVLHVMNGAV MYQIDSVVRA CSDFLVQQLD
PSNAIGIANF AEQIGCTELH QRAREYIYMH FGEVAKQEEF FNLSHCQLAT LISRDDLNVR
CESEVFHACI DWVKYDCPQR RFYVQALLRA VRCHALTPRF LQTQLQKCEI LQADARCKDY
LVQIFQELTL HKPTQAVPCR APKVGRLIYT AGGYFRQSLS YLEAYNPSNG SWLRLADLQV
PRSGLAGCVV GGLLYAVGGR NNSPDGNTDS SALDCYNPMT NQWSPCASMS VPRNRIGVGV
IDGHIYAVGG SHGCIHHSSV ERYEPERDEW HLVAPMLTRR IGVGVAVLNR LLYAVGGFDG
TNRLNSAECY YPERNEWRMI TPMNTIRSGA GVCVLHNCIY AAGGYDGQDQ LNSVERYDVE
TETWTFVAPM RHHRSALGIT VHQGKIYVLG GYDGHTFLDS VECYDPDSDT WSEVTRMTSG
RSGVGVAVTM EPCRKQIDQQ NCTC
