ID   NF2L2_HUMAN             Reviewed;         605 AA.
AC   Q16236; B2RBU2; Q53RW6; Q59HH2; Q96F71;
DT   15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT   25-NOV-2002, sequence version 3.
DT   13-JUL-2010, entry version 102.
DE   RecName: Full=Nuclear factor erythroid 2-related factor 2;
DE            Short=NF-E2-related factor 2;
DE            Short=NFE2-related factor 2;
DE   AltName: Full=Nuclear factor, erythroid derived 2, like 2;
DE   AltName: Full=HEBP1;
GN   Name=NFE2L2; Synonyms=NRF2;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC   Catarrhini; Hominidae; Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Tongue;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA   Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA   Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA   Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA   Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA   Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA   Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA   Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA   Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA   Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA   Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA   Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA   Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA   Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA   Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA   Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA   Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA   Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA   Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA   Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   TISSUE=Myeloid leukemia cell;
RA   Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA   Ohara O., Nagase T., Kikuno R.F.;
RL   Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15815621; DOI=10.1038/nature03466;
RA   Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA   Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA   Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA   Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA   Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA   Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA   Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA   Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA   Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA   Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA   McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA   Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA   Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA   Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA   Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA   Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA   Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA   Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA   Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA   Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA   McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA   Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA   Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA   Waterston R.H., Wilson R.K.;
RT   "Generation and annotation of the DNA sequences of human chromosomes 2
RT   and 4.";
RL   Nature 434:724-731(2005).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA   Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA   Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA   Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA   Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA   Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA   Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA   Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Lung;
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
RT   project: the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-202 (ISOFORM 1).
RC   TISSUE=Melanoma;
RX   PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA   Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA   Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA   Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA   Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT   "The full-ORF clone resource of the German cDNA consortium.";
RL   BMC Genomics 8:399-399(2007).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 4-605 (ISOFORM 1).
RC   TISSUE=Fetal liver;
RX   MEDLINE=95024074; PubMed=7937919; DOI=10.1073/pnas.91.21.9926;
RA   Moi P., Chan K., Asunis I., Cao A., Kan Y.W.;
RT   "Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic
RT   leucine zipper transcriptional activator that binds to the tandem NF-
RT   E2/AP1 repeat of the beta-globin locus control region.";
RL   Proc. Natl. Acad. Sci. U.S.A. 91:9926-9930(1994).
RN   [8]
RP   FUNCTION, SUBCELLULAR LOCATION, AND PHOSPHORYLATION BY PKC.
RX   PubMed=11035812; DOI=10.1073/pnas.220418997;
RA   Huang H.-C., Nguyen T., Pickett C.B.;
RT   "Regulation of the antioxidant response element by protein kinase C-
RT   mediated phosphorylation of NF-E2-related factor 2.";
RL   Proc. Natl. Acad. Sci. U.S.A. 97:12475-12480(2000).
RN   [9]
RP   INTERACTION WITH PMF1.
RX   PubMed=11256947; DOI=10.1042/0264-6021:3550045;
RA   Wang Y., Devereux W., Stewart T.M., Casero R.A. Jr.;
RT   "Characterization of the interaction between the transcription factors
RT   human polyamine modulated factor (PMF-1) and NF-E2-related factor 2
RT   (Nrf-2) in the transcriptional regulation of the spermidine/spermine
RT   N1-acetyltransferase (SSAT) gene.";
RL   Biochem. J. 355:45-49(2001).
RN   [10]
RP   INTERACTION WITH PGAM5 AND KEAP1.
RX   PubMed=18387606; DOI=10.1016/j.yexcr.2008.02.014;
RA   Lo S.-C., Hannink M.;
RT   "PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to
RT   mitochondria.";
RL   Exp. Cell Res. 314:1789-1803(2008).
RN   [11]
RP   X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 69-84 IN COMPLEX WITH KEAP1,
RP   AND MUTAGENESIS OF THR-80.
RX   PubMed=16888629; DOI=10.1038/sj.emboj.7601243;
RA   Lo S.-C., Li X., Henzl M.T., Beamer L.J., Hannink M.;
RT   "Structure of the Keap1:Nrf2 interface provides mechanistic insight
RT   into Nrf2 signaling.";
RL   EMBO J. 25:3605-3617(2006).
CC   -!- FUNCTION: Transcription activator that binds to antioxidant
CC       response (ARE) elements in the promoter regions of target genes.
CC       Important for the coordinated up-regulation of genes in response
CC       to oxidative stress. May be involved in the transcriptional
CC       activation of genes of the beta-globin cluster by mediating
CC       enhancer activity of hypersensitive site 2 of the beta-globin
CC       locus control region.
CC   -!- SUBUNIT: Heterodimer. Forms a ternary complex with PGAM5 and
CC       KEAP1. May bind DNA with an unknown protein. Interacts via its
CC       leucine-zipper domain with the coiled-coil domain of PMF1.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol. Nucleus. Note=Cytosolic
CC       under unstressed conditions, translocates into the nucleus upon
CC       induction by electrophilic agents.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q16236-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q16236-2; Sequence=VSP_025045;
CC   -!- TISSUE SPECIFICITY: Widely expressed. Highest expression in adult
CC       muscle, kidney, lung, liver and in fetal muscle.
CC   -!- DOMAIN: Acidic activation domain in the N-terminus, and DNA
CC       binding domain in the C-terminus.
CC   -!- PTM: Phosphorylation of Ser-40 by PKC in response to oxidative
CC       stress dissociates NFE2L2 from its cytoplasmic inhibitor KEAP1,
CC       promoting its translocation into the nucleus (By similarity).
CC   -!- SIMILARITY: Belongs to the bZIP family. CNC subfamily.
CC   -!- SIMILARITY: Contains 1 bZIP domain.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAB32188.1; Type=Erroneous initiation;
CC       Sequence=BAD92023.1; Type=Erroneous initiation;
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DR   EMBL; AK314816; BAG37339.1; -; mRNA.
DR   EMBL; AB208786; BAD92023.1; ALT_INIT; mRNA.
DR   EMBL; AC079305; AAY14710.1; -; Genomic_DNA.
DR   EMBL; CH471058; EAX11062.1; -; Genomic_DNA.
DR   EMBL; BC011558; AAH11558.1; -; mRNA.
DR   EMBL; AL135266; -; NOT_ANNOTATED_CDS; mRNA.
DR   EMBL; S74017; AAB32188.1; ALT_INIT; mRNA.
DR   IPI; IPI00000712; -.
DR   IPI; IPI00915403; -.
DR   RefSeq; NP_001138884.1; -.
DR   RefSeq; NP_001138885.1; -.
DR   RefSeq; NP_006155.2; -.
DR   UniGene; Hs.155396; -.
DR   UniGene; Hs.666143; -.
DR   PDB; 2FLU; X-ray; 1.50 A; P=69-84.
DR   PDBsum; 2FLU; -.
DR   SMR; Q16236; 452-521.
DR   DIP; DIP-29971N; -.
DR   IntAct; Q16236; 1.
DR   MINT; MINT-2844437; -.
DR   STRING; Q16236; -.
DR   PhosphoSite; Q16236; -.
DR   PRIDE; Q16236; -.
DR   Ensembl; ENST00000397062; ENSP00000380252; ENSG00000116044; Homo sapiens.
DR   GeneID; 4780; -.
DR   KEGG; hsa:4780; -.
DR   UCSC; uc002ulf.2; human.
DR   UCSC; uc002ulh.2; human.
DR   CTD; 4780; -.
DR   GeneCards; GC02M177803; -.
DR   H-InvDB; HIX0019601; -.
DR   HGNC; HGNC:7782; NFE2L2.
DR   HPA; CAB020317; -.
DR   HPA; HPA002990; -.
DR   MIM; 600492; gene.
DR   PharmGKB; PA31588; -.
DR   eggNOG; prNOG09596; -.
DR   HOGENOM; HBG715034; -.
DR   HOVERGEN; HBG052609; -.
DR   InParanoid; Q16236; -.
DR   OMA; ALHIPFP; -.
DR   OrthoDB; EOG9J9QJJ; -.
DR   NextBio; 18432; -.
DR   PMAP-CutDB; Q16236; -.
DR   ArrayExpress; Q16236; -.
DR   Bgee; Q16236; -.
DR   CleanEx; HS_NFE2L2; -.
DR   Genevestigator; Q16236; -.
DR   GermOnline; ENSG00000116044; Homo sapiens.
DR   GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR   GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR   GO; GO:0046983; F:protein dimerization activity; IEA:InterPro.
DR   GO; GO:0019904; F:protein domain specific binding; IPI:UniProtKB.
DR   GO; GO:0043565; F:sequence-specific DNA binding; IEA:InterPro.
DR   GO; GO:0003700; F:transcription factor activity; TAS:ProtInc.
DR   GO; GO:0006366; P:transcription from RNA polymerase II promoter; TAS:ProtInc.
DR   InterPro; IPR011616; bZIP_1.
DR   InterPro; IPR008917; Euk_TF_DNA-bd.
DR   InterPro; IPR013089; Kelch_related.
DR   InterPro; IPR004827; TF_bZIP.
DR   PANTHER; PTHR23230; Kelch_related; 1.
DR   Pfam; PF00170; bZIP_1; 1.
DR   SMART; SM00338; BRLZ; 1.
DR   SUPFAM; SSF47454; Euk_transcr_DNA; 1.
DR   PROSITE; PS50217; BZIP; 1.
DR   PROSITE; PS00036; BZIP_BASIC; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Activator; Alternative splicing; Complete proteome;
KW   Cytoplasm; DNA-binding; Nucleus; Phosphoprotein; Polymorphism;
KW   Transcription; Transcription regulation.
FT   CHAIN         1    605       Nuclear factor erythroid 2-related factor
FT                                2.
FT                                /FTId=PRO_0000076449.
FT   DOMAIN      519    539       Leucine-zipper.
FT   DNA_BIND    502    517       Basic motif.
FT   MOD_RES      40     40       Phosphoserine; by PKC.
FT   VAR_SEQ       1     16       Missing (in isoform 2).
FT                                /FTId=VSP_025045.
FT   VARIANT      43     43       R -> Q (in dbSNP:rs35248500).
FT                                /FTId=VAR_032110.
FT   VARIANT      99     99       S -> P (in dbSNP:rs5031039).
FT                                /FTId=VAR_020322.
FT   VARIANT     268    268       V -> M (in dbSNP:rs34154613).
FT                                /FTId=VAR_032111.
FT   MUTAGEN      80     80       T->A: Loss of interaction with KEAP1.
FT   CONFLICT     72     72       A -> T (in Ref. 7; AAB32188).
FT   CONFLICT     92     92       I -> T (in Ref. 7; AAB32188).
FT   CONFLICT    178    178       D -> Y (in Ref. 3; AL135266).
FT   STRAND       75     77
SQ   SEQUENCE   605 AA;  67827 MW;  99FAFD811B6C1416 CRC64;
     MMDLELPPPG LPSQQDMDLI DILWRQDIDL GVSREVFDFS QRRKEYELEK QKKLEKERQE
     QLQKEQEKAF FAQLQLDEET GEFLPIQPAQ HIQSETSGSA NYSQVAHIPK SDALYFDDCM
     QLLAQTFPFV DDNEVSSATF QSLVPDIPGH IESPVFIATN QAQSPETSVA QVAPVDLDGM
     QQDIEQVWEE LLSIPELQCL NIENDKLVET TMVPSPEAKL TEVDNYHFYS SIPSMEKEVG
     NCSPHFLNAF EDSFSSILST EDPNQLTVNS LNSDATVNTD FGDEFYSAFI AEPSISNSMP
     SPATLSHSLS ELLNGPIDVS DLSLCKAFNQ NHPESTAEFN DSDSGISLNT SPSVASPEHS
     VESSSYGDTL LGLSDSEVEE LDSAPGSVKQ NGPKTPVHSS GDMVQPLSPS QGQSTHVHDA
     QCENTPEKEL PVSPGHRKTP FTKDKHSSRL EAHLTRDELR AKALHIPFPV EKIINLPVVD
     FNEMMSKEQF NEAQLALIRD IRRRGKNKVA AQNCRKRKLE NIVELEQDLD HLKDEKEKLL
     KEKGENDKSL HLLKKQLSTL YLEVFSMLRD EDGKPYSPSE YSLQQTRDGN VFLVPKSKKP
     DVKKN
//