NFE2_HUMAN
ID NFE2_HUMAN Reviewed; 373 AA.
AC Q16621; Q07720; Q6ICV9;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 200.
DE RecName: Full=Transcription factor NF-E2 45 kDa subunit;
DE AltName: Full=Leucine zipper protein NF-E2;
DE AltName: Full=Nuclear factor, erythroid-derived 2 45 kDa subunit;
DE AltName: Full=p45 NF-E2;
GN Name=NFE2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=8248255; DOI=10.1073/pnas.90.23.11366;
RA Chan J.Y., Han X.L., Kan Y.W.;
RT "Isolation of cDNA encoding the human NF-E2 protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:11366-11370(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=8355703; DOI=10.1128/mcb.13.9.5604-5612.1993;
RA Ney P.A., Andrews N.C., Jane S.M., Safer B., Purucker M.E., Weremowicz S.,
RA Goff S.C., Orkin S.H., Neinhuis A.W.;
RT "Purification of the human NF-E2 complex: cDNA cloning of the hematopoietic
RT cell-specific subunit and evidence for an associated partner.";
RL Mol. Cell. Biol. 13:5604-5612(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Fetal liver;
RX PubMed=7724591; DOI=10.1073/pnas.92.8.3511;
RA Pischedda C., Cocco S., Melis A., Marini M.G., Kan Y.W., Cao A., Moi P.;
RT "Isolation of a differentially regulated splicing isoform of human NF-E2.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:3511-3515(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG SeattleSNPs variation discovery resource;
RL Submitted (JAN-2006) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP INTERACTION WITH MAFG, AND FUNCTION.
RX PubMed=11154691; DOI=10.1074/jbc.m007846200;
RA Hung H.-L., Kim A.Y., Hong W., Rakowski C., Blobel G.A.;
RT "Stimulation of NF-E2 DNA binding by CREB-binding protein (CBP)-mediated
RT acetylation.";
RL J. Biol. Chem. 276:10715-10721(2001).
RN [9]
RP SUMOYLATION AT LYS-368, SUBCELLULAR LOCATION, FUNCTION, MUTAGENESIS OF
RP LYS-368, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=16287851; DOI=10.1128/mcb.25.23.10365-10378.2005;
RA Shyu Y.-C., Lee T.-L., Ting C.-Y., Wen S.-C., Hsieh L.-J., Li Y.-C.,
RA Hwang J.-L., Lin C.-C., Shen C.-K.J.;
RT "Sumoylation of p45/NF-E2: nuclear positioning and transcriptional
RT activation of the mammalian beta-like globin gene locus.";
RL Mol. Cell. Biol. 25:10365-10378(2005).
RN [10]
RP INTERACTION WITH ITCH, SUBCELLULAR LOCATION, AND UBIQUITINATION.
RX PubMed=18718448; DOI=10.1016/j.bbrc.2008.07.164;
RA Lee T.-L., Shyu Y.-C., Hsu T.-Y., Shen C.-K.J.;
RT "Itch regulates p45/NF-E2 in vivo by Lys63-linked ubiquitination.";
RL Biochem. Biophys. Res. Commun. 375:326-330(2008).
RN [11]
RP STRUCTURE BY NMR OF 214-293.
RG Northeast structural genomics consortium (NESG);
RT "Northeast structural genomics consortium target HR4653B.";
RL Submitted (NOV-2010) to the PDB data bank.
CC -!- FUNCTION: Component of the NF-E2 complex essential for regulating
CC erythroid and megakaryocytic maturation and differentiation. Binds to
CC the hypersensitive site 2 (HS2) of the beta-globin control region
CC (LCR). This subunit (NFE2) recognizes the TCAT/C sequence of the AP-1-
CC like core palindrome present in a number of erythroid and
CC megakaryocytic gene promoters. Requires MAFK or other small MAF
CC proteins for binding to the NF-E2 motif. May play a role in all aspects
CC of hemoglobin production from globin and heme synthesis to procurement
CC of iron. {ECO:0000269|PubMed:11154691, ECO:0000269|PubMed:16287851}.
CC -!- SUBUNIT: Homodimer; can bind DNA as a homodimer. Erythroid
CC transcription activator nuclear factor erythroid-derived 2 (NF-E2),
CC composed of a heterodimer of NFE2 and MAFK, possesses transactivation
CC activity on beta-globin. Also forms high affinity heterodimer with
CC MAFG; the interaction promotes erythropoiesis. Interacts (via the PXY
CC motif 1) with ITCH (via the WW 1 domain); the interaction promotes
CC 'Lys63'-linked ubiquitination of NFE2, translocates it to the cytoplasm
CC and inhibits its transactivation activity. Interacts with KMT2D/MLL2;
CC the interaction promotes transactivation of the beta-globin locus (By
CC similarity). Interacts with MAPK8 (phosphorylated form); the
CC interaction leads to phosphorylation of NFE2 in undifferentiated cells
CC (By similarity). {ECO:0000250}.
CC -!- INTERACTION:
CC Q16621; Q9Y297: BTRC; NbExp=3; IntAct=EBI-726369, EBI-307461;
CC Q16621; P22607: FGFR3; NbExp=3; IntAct=EBI-726369, EBI-348399;
CC Q16621; Q53GS7: GLE1; NbExp=3; IntAct=EBI-726369, EBI-1955541;
CC Q16621; P06396: GSN; NbExp=3; IntAct=EBI-726369, EBI-351506;
CC Q16621; Q16621: NFE2; NbExp=2; IntAct=EBI-726369, EBI-726369;
CC Q16621; Q9Y4A8: NFE2L3; NbExp=4; IntAct=EBI-726369, EBI-10890629;
CC Q16621; Q7Z699: SPRED1; NbExp=3; IntAct=EBI-726369, EBI-5235340;
CC Q16621; Q9Y649; NbExp=3; IntAct=EBI-726369, EBI-25900580;
CC Q16621; Q9DGW5: MDV005; Xeno; NbExp=2; IntAct=EBI-726369, EBI-10889526;
CC -!- SUBCELLULAR LOCATION: Nucleus, PML body. Cytoplasm. Note=The sumoylated
CC form locates to the nuclear bodies PML oncogenic domains (PODs).
CC Translocated to the cytoplasm through interaction with ITCH.
CC -!- TISSUE SPECIFICITY: Expressed in hematopoietic cells and also in colon
CC and testis.
CC -!- DOMAIN: The PXY motifs are required for binding WW domains. PXY1 is
CC required to promote transactivation of beta-globin and for
CC hyperacetylation of histone H3, but not for binding to the HS2 promoter
CC site (By similarity). {ECO:0000250}.
CC -!- PTM: Phosphorylated on serine residues. In undifferentiated
CC erythrocytes, phosphorylated by MAPK8 which then leads to
CC ubiquitination and protein degradation. {ECO:0000250}.
CC -!- PTM: Sumoylated. Sumoylation is required for translocation to nuclear
CC bodies PODs, anchoring to the gene loci, and transactivation of the
CC beta-globin gene. {ECO:0000269|PubMed:16287851}.
CC -!- PTM: Ubiquitinated mainly by 'Lys63'-linked ubiquitin.
CC Polyubiquitination with 'Lys63'-linked ubiquitin by ITCH retains NFE2
CC in the cytoplasm preventing its transactivation activity. In
CC undifferentiated erythrocyte, ubiquitinated after MAPK8-mediatd
CC phosphorylation leading to protein degradation (By similarity).
CC {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the bZIP family. CNC subfamily. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/nfe2/";
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DR EMBL; L24122; AAA16118.1; -; mRNA.
DR EMBL; L13974; AAA35612.1; -; mRNA.
DR EMBL; S77763; AAB34115.1; -; mRNA.
DR EMBL; CR450284; CAG29280.1; -; mRNA.
DR EMBL; BT007288; AAP35952.1; -; mRNA.
DR EMBL; DQ367844; ABC79302.1; -; Genomic_DNA.
DR EMBL; BC005044; AAH05044.1; -; mRNA.
DR CCDS; CCDS8876.1; -.
DR PIR; A49671; A49671.
DR PIR; A54692; A54692.
DR RefSeq; NP_001129495.1; NM_001136023.2.
DR RefSeq; NP_001248390.1; NM_001261461.1.
DR RefSeq; NP_006154.1; NM_006163.2.
DR RefSeq; XP_005268963.1; XM_005268906.4.
DR PDB; 2KZ5; NMR; -; A=214-293.
DR PDBsum; 2KZ5; -.
DR AlphaFoldDB; Q16621; -.
DR BMRB; Q16621; -.
DR SMR; Q16621; -.
DR BioGRID; 110850; 21.
DR ComplexPortal; CPX-6568; bZIP transcription factor complex, ATF4-NFE2.
DR ComplexPortal; CPX-6789; bZIP transcription factor complex, ATF7-NFE2.
DR DIP; DIP-57844N; -.
DR IntAct; Q16621; 25.
DR MINT; Q16621; -.
DR STRING; 9606.ENSP00000439120; -.
DR BindingDB; Q16621; -.
DR ChEMBL; CHEMBL4523303; -.
DR GlyGen; Q16621; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q16621; -.
DR PhosphoSitePlus; Q16621; -.
DR BioMuta; NFE2; -.
DR DMDM; 6831585; -.
DR EPD; Q16621; -.
DR MassIVE; Q16621; -.
DR MaxQB; Q16621; -.
DR PaxDb; Q16621; -.
DR PeptideAtlas; Q16621; -.
DR PRIDE; Q16621; -.
DR ProteomicsDB; 60962; -.
DR Antibodypedia; 907; 149 antibodies from 27 providers.
DR DNASU; 4778; -.
DR Ensembl; ENST00000312156.8; ENSP00000312436.4; ENSG00000123405.14.
DR Ensembl; ENST00000435572.7; ENSP00000397185.2; ENSG00000123405.14.
DR Ensembl; ENST00000540264.2; ENSP00000439120.2; ENSG00000123405.14.
DR Ensembl; ENST00000553070.5; ENSP00000447558.1; ENSG00000123405.14.
DR GeneID; 4778; -.
DR KEGG; hsa:4778; -.
DR MANE-Select; ENST00000435572.7; ENSP00000397185.2; NM_001136023.3; NP_001129495.1.
DR UCSC; uc001sfq.5; human.
DR CTD; 4778; -.
DR DisGeNET; 4778; -.
DR GeneCards; NFE2; -.
DR HGNC; HGNC:7780; NFE2.
DR HPA; ENSG00000123405; Group enriched (bone marrow, lymphoid tissue).
DR MIM; 601490; gene.
DR neXtProt; NX_Q16621; -.
DR OpenTargets; ENSG00000123405; -.
DR PharmGKB; PA31586; -.
DR VEuPathDB; HostDB:ENSG00000123405; -.
DR eggNOG; KOG3863; Eukaryota.
DR GeneTree; ENSGT00950000182892; -.
DR HOGENOM; CLU_058451_0_0_1; -.
DR InParanoid; Q16621; -.
DR OMA; ELYCDIF; -.
DR OrthoDB; 1095280at2759; -.
DR PhylomeDB; Q16621; -.
DR TreeFam; TF326681; -.
DR PathwayCommons; Q16621; -.
DR Reactome; R-HSA-8936459; RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function.
DR Reactome; R-HSA-983231; Factors involved in megakaryocyte development and platelet production.
DR SignaLink; Q16621; -.
DR SIGNOR; Q16621; -.
DR BioGRID-ORCS; 4778; 25 hits in 1096 CRISPR screens.
DR ChiTaRS; NFE2; human.
DR EvolutionaryTrace; Q16621; -.
DR GeneWiki; NFE2; -.
DR GenomeRNAi; 4778; -.
DR Pharos; Q16621; Tchem.
DR PRO; PR:Q16621; -.
DR Proteomes; UP000005640; Chromosome 12.
DR RNAct; Q16621; protein.
DR Bgee; ENSG00000123405; Expressed in blood and 97 other tissues.
DR ExpressionAtlas; Q16621; baseline and differential.
DR Genevisible; Q16621; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0016605; C:PML body; IEA:UniProtKB-SubCell.
DR GO; GO:0032993; C:protein-DNA complex; IDA:UniProtKB.
DR GO; GO:0090575; C:RNA polymerase II transcription regulator complex; IPI:ComplexPortal.
DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; TAS:ProtInc.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0047485; F:protein N-terminus binding; IPI:UniProtKB.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:0043565; F:sequence-specific DNA binding; TAS:BHF-UCL.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL.
DR GO; GO:0050699; F:WW domain binding; IDA:MGI.
DR GO; GO:0007599; P:hemostasis; TAS:UniProtKB.
DR GO; GO:0140467; P:integrated stress response signaling; IC:ComplexPortal.
DR GO; GO:0006337; P:nucleosome disassembly; TAS:BHF-UCL.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; TAS:BHF-UCL.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR IDEAL; IID00477; -.
DR InterPro; IPR004827; bZIP.
DR InterPro; IPR004826; bZIP_Maf.
DR InterPro; IPR046347; bZIP_sf.
DR InterPro; IPR029853; NF-E2_p45.
DR InterPro; IPR008917; TF_DNA-bd_sf.
DR PANTHER; PTHR24411:SF26; PTHR24411:SF26; 1.
DR Pfam; PF03131; bZIP_Maf; 1.
DR SMART; SM00338; BRLZ; 1.
DR SUPFAM; SSF47454; SSF47454; 1.
DR SUPFAM; SSF57959; SSF57959; 1.
DR PROSITE; PS50217; BZIP; 1.
DR PROSITE; PS00036; BZIP_BASIC; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Activator; Cytoplasm; DNA-binding; Isopeptide bond; Nucleus;
KW Phosphoprotein; Reference proteome; Transcription;
KW Transcription regulation; Ubl conjugation.
FT CHAIN 1..373
FT /note="Transcription factor NF-E2 45 kDa subunit"
FT /id="PRO_0000076446"
FT DOMAIN 266..329
FT /note="bZIP"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 1..206
FT /note="Transactivation domain"
FT REGION 1..83
FT /note="Required for interaction with MAPK8"
FT /evidence="ECO:0000250"
FT REGION 127..150
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 205..226
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 268..287
FT /note="Basic motif"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 291..298
FT /note="Leucine-zipper"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT MOTIF 61..65
FT /note="PXY motif 1"
FT MOTIF 79..83
FT /note="PXY motif 2"
FT MOD_RES 157
FT /note="Phosphoserine; by MAPK8"
FT /evidence="ECO:0000250|UniProtKB:Q07279"
FT MOD_RES 170
FT /note="Phosphoserine; by PKA"
FT /evidence="ECO:0000250|UniProtKB:Q07279"
FT CROSSLNK 368
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1)"
FT /evidence="ECO:0000269|PubMed:16287851"
FT MUTAGEN 368
FT /note="K->R: 60% loss of DNA-binding and 5-fold loss of
FT transactivation activity. Almost no colocalization with
FT nuclear bodies."
FT /evidence="ECO:0000269|PubMed:16287851"
FT CONFLICT 334..335
FT /note="FQ -> LE (in Ref. 2; AAA35612)"
FT /evidence="ECO:0000305"
FT HELIX 225..233
FT /evidence="ECO:0007829|PDB:2KZ5"
FT HELIX 239..244
FT /evidence="ECO:0007829|PDB:2KZ5"
FT HELIX 247..256
FT /evidence="ECO:0007829|PDB:2KZ5"
FT HELIX 261..279
FT /evidence="ECO:0007829|PDB:2KZ5"
SQ SEQUENCE 373 AA; 41473 MW; A9821170FB2ED67C CRC64;
MSPCPPQQSR NRVIQLSTSE LGEMELTWQE IMSITELQGL NAPSEPSFEP QAPAPYLGPP
PPTTYCPCSI HPDSGFPLPP PPYELPASTS HVPDPPYSYG NMAIPVSKPL SLSGLLSEPL
QDPLALLDIG LPAGPPKPQE DPESDSGLSL NYSDAESLEL EGTEAGRRRS EYVEMYPVEY
PYSLMPNSLA HSNYTLPAAE TPLALEPSSG PVRAKPTARG EAGSRDERRA LAMKIPFPTD
KIVNLPVDDF NELLARYPLT ESQLALVRDI RRRGKNKVAA QNCRKRKLET IVQLERELER
LTNERERLLR ARGEADRTLE VMRQQLTELY RDIFQHLRDE SGNSYSPEEY ALQQAADGTI
FLVPRGTKME ATD
