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Q16621 (NFE2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 136. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Transcription factor NF-E2 45 kDa subunit
Alternative name(s):
Leucine zipper protein NF-E2
Nuclear factor, erythroid-derived 2 45 kDa subunit
p45 NF-E2
Gene names
Name:NFE2
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length373 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Component of the NF-E2 complex essential for regulating erythroid and megakaryocytic maturation and differentiation. Binds to the hypersensitive site 2 (HS2) of the beta-globin control region (LCR). This subunit (NFE2) recognizes the TCAT/C sequence of the AP-1-like core palindrome present in a number of erythroid and megakaryocytic gene promoters. Requires MAFK or other small MAF proteins for binding to the NF-E2 motif. May play a role in all aspects of hemoglobin production from globin and heme synthesis to procurement of iron. Ref.8 Ref.9

Subunit structure

Homodimer; can bind DNA as a homodimer. Erythroid transcription activator nuclear factor erythroid-derived 2 (NF-E2), composed of a heterodimer of NFE2 and MAFK, possesses transactivation activity on beta-globin. Also forms high affinity heterodimer with MAFG; the interaction promotes erythropoiesis. Interacts (via the PXY motif 1) with ITCH (via the WW 1 domain); the interaction promotes 'Lys63'-linked ubiquitination of NFE2, translocates it to the cytoplasm and inhibits its transactivation activity. Interacts with KMT2D/MLL2; the interaction promotes transactivation of the beta-globin locus By similarity. Interacts with MAPK8 (phosphorylated form); the interaction leads to phosphorylation of NFE2 in undifferentiated cells By similarity. Ref.8 Ref.10

Subcellular location

NucleusPML body. Cytoplasm. Note: The sumoylated form locates to the nuclear bodies PML oncogenic domains (PODs). Translocated to the cytoplasm through interaction with ITCH. Ref.9 Ref.10

Tissue specificity

Expressed in hematopoietic cells and also in colon and testis.

Domain

The PXY motifs are required for binding WW domains. PXY1 is required to promote transactivation of beta-globin and for hyperacetylation of histone H3, but not for binding to the HS2 promoter site By similarity.

Post-translational modification

Phosphorylated on serine residues By similarity. In undifferentiated erythrocytes, phosphorylated by MAPK8 which then leads to ubiquitination and protein degradation By similarity.

Sumoylated. Sumoylation is required for translocation to nuclear bodies PODs, anchoring to the gene loci, and transactivation of the beta-globin gene. Ref.9

Ubiquitinated mainly by 'Lys63'-linked ubiquitin. Polyubiquitination with 'Lys63'-linked ubiquitin by ITCH retains NFE2 in the cytoplasm preventing its transactivation activity. In undifferentiated erythrocyte, ubiquitinated after MAPK8-mediatd phosphorylation leading to protein degradation By similarity. Ref.10

Sequence similarities

Belongs to the bZIP family. CNC subfamily.

Contains 1 bZIP (basic-leucine zipper) domain.

Ontologies

Keywords
   Biological processTranscription
Transcription regulation
   Cellular componentCytoplasm
Nucleus
   LigandDNA-binding
   Molecular functionActivator
   PTMIsopeptide bond
Phosphoprotein
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processblood circulation

Traceable author statement Ref.2. Source: ProtInc

blood coagulation

Traceable author statement. Source: Reactome

cell-cell signaling

Inferred from electronic annotation. Source: Ensembl

hemostasis

Traceable author statement PubMed 7774011. Source: ProtInc

labyrinthine layer blood vessel development

Inferred from electronic annotation. Source: Ensembl

multicellular organismal development

Traceable author statement PubMed 7774011. Source: ProtInc

negative regulation of bone mineralization

Inferred from electronic annotation. Source: Ensembl

negative regulation of syncytium formation by plasma membrane fusion

Inferred from electronic annotation. Source: Ensembl

nucleosome disassembly

Traceable author statement PubMed 9305852. Source: BHF-UCL

positive regulation of peptidyl-lysine acetylation

Inferred from electronic annotation. Source: Ensembl

positive regulation of transcription, DNA-templated

Traceable author statement PubMed 9305852. Source: BHF-UCL

regulation of transcription from RNA polymerase II promoter

Traceable author statement Ref.2. Source: ProtInc

transcription, DNA-templated

Traceable author statement PubMed 9305852. Source: BHF-UCL

   Cellular_componentPML body

Inferred from electronic annotation. Source: UniProtKB-SubCell

actin cytoskeleton

Inferred from direct assay. Source: HPA

cytoplasm

Inferred from electronic annotation. Source: UniProtKB-SubCell

nucleoplasm

Traceable author statement. Source: Reactome

nucleus

Inferred from direct assay. Source: HPA

   Molecular_functionWW domain binding

Inferred from physical interaction PubMed 9305852. Source: BHF-UCL

protein N-terminus binding

Inferred from physical interaction PubMed 11863372. Source: UniProtKB

sequence-specific DNA binding

Traceable author statement PubMed 9305852. Source: BHF-UCL

sequence-specific DNA binding transcription factor activity

Traceable author statement PubMed 7774011Ref.2. Source: ProtInc

transcription coactivator activity

Traceable author statement Ref.2. Source: ProtInc

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 373373Transcription factor NF-E2 45 kDa subunit
PRO_0000076446

Regions

Domain266 – 32964bZIP
Region1 – 206206Transactivation domain
Region1 – 8383Required for interaction with MAPK8 By similarity
Region268 – 28720Basic motif By similarity
Region291 – 2988Leucine-zipper By similarity
Motif61 – 655PXY motif 1
Motif79 – 835PXY motif 2
Compositional bias59 – 624Poly-Pro
Compositional bias77 – 826Poly-Pro

Amino acid modifications

Modified residue1571Phosphoserine; by MAPK8 By similarity
Modified residue1701Phosphoserine; by PKA By similarity
Cross-link368Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO-1) Ref.9

Experimental info

Mutagenesis3681K → R: 60% loss of DNA-binding and 5-fold loss of transactivation activity. Almost no colocalization with nuclear bodies. Ref.9
Sequence conflict334 – 3352FQ → LE in AAA35612. Ref.2

Secondary structure

......... 373
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q16621 [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: A9821170FB2ED67C

FASTA37341,473
        10         20         30         40         50         60 
MSPCPPQQSR NRVIQLSTSE LGEMELTWQE IMSITELQGL NAPSEPSFEP QAPAPYLGPP 

        70         80         90        100        110        120 
PPTTYCPCSI HPDSGFPLPP PPYELPASTS HVPDPPYSYG NMAIPVSKPL SLSGLLSEPL 

       130        140        150        160        170        180 
QDPLALLDIG LPAGPPKPQE DPESDSGLSL NYSDAESLEL EGTEAGRRRS EYVEMYPVEY 

       190        200        210        220        230        240 
PYSLMPNSLA HSNYTLPAAE TPLALEPSSG PVRAKPTARG EAGSRDERRA LAMKIPFPTD 

       250        260        270        280        290        300 
KIVNLPVDDF NELLARYPLT ESQLALVRDI RRRGKNKVAA QNCRKRKLET IVQLERELER 

       310        320        330        340        350        360 
LTNERERLLR ARGEADRTLE VMRQQLTELY RDIFQHLRDE SGNSYSPEEY ALQQAADGTI 

       370 
FLVPRGTKME ATD 

« Hide

References

« Hide 'large scale' references
[1]"Isolation of cDNA encoding the human NF-E2 protein."
Chan J.Y., Han X.L., Kan Y.W.
Proc. Natl. Acad. Sci. U.S.A. 90:11366-11370(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]"Purification of the human NF-E2 complex: cDNA cloning of the hematopoietic cell-specific subunit and evidence for an associated partner."
Ney P.A., Andrews N.C., Jane S.M., Safer B., Purucker M.E., Weremowicz S., Goff S.C., Orkin S.H., Neinhuis A.W.
Mol. Cell. Biol. 13:5604-5612(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]"Isolation of a differentially regulated splicing isoform of human NF-E2."
Pischedda C., Cocco S., Melis A., Marini M.G., Kan Y.W., Cao A., Moi P.
Proc. Natl. Acad. Sci. U.S.A. 92:3511-3515(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Fetal liver.
[4]"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)."
Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.
Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[5]"Cloning of human full-length CDSs in BD Creator(TM) system donor vector."
Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A.
Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[6]SeattleSNPs variation discovery resource
Submitted (JAN-2006) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[7]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Lung.
[8]"Stimulation of NF-E2 DNA binding by CREB-binding protein (CBP)-mediated acetylation."
Hung H.-L., Kim A.Y., Hong W., Rakowski C., Blobel G.A.
J. Biol. Chem. 276:10715-10721(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH MAFG, FUNCTION.
[9]"Sumoylation of p45/NF-E2: nuclear positioning and transcriptional activation of the mammalian beta-like globin gene locus."
Shyu Y.-C., Lee T.-L., Ting C.-Y., Wen S.-C., Hsieh L.-J., Li Y.-C., Hwang J.-L., Lin C.-C., Shen C.-K.J.
Mol. Cell. Biol. 25:10365-10378(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: SUMOYLATION AT LYS-368, SUBCELLULAR LOCATION, FUNCTION, MUTAGENESIS OF LYS-368, IDENTIFICATION BY MASS SPECTROMETRY.
[10]"Itch regulates p45/NF-E2 in vivo by Lys63-linked ubiquitination."
Lee T.-L., Shyu Y.-C., Hsu T.-Y., Shen C.-K.J.
Biochem. Biophys. Res. Commun. 375:326-330(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ITCH, SUBCELLULAR LOCATION, UBIQUITINATION.
[11]"Northeast structural genomics consortium target HR4653B."
Northeast structural genomics consortium (NESG)
Submitted (NOV-2010) to the PDB data bank
Cited for: STRUCTURE BY NMR OF 214-293.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
L24122 mRNA. Translation: AAA16118.1.
L13974 mRNA. Translation: AAA35612.1.
S77763 mRNA. Translation: AAB34115.1.
CR450284 mRNA. Translation: CAG29280.1.
BT007288 mRNA. Translation: AAP35952.1.
DQ367844 Genomic DNA. Translation: ABC79302.1.
BC005044 mRNA. Translation: AAH05044.1.
PIRA49671.
A54692.
RefSeqNP_001129495.1. NM_001136023.2.
NP_001248390.1. NM_001261461.1.
NP_006154.1. NM_006163.2.
XP_005268963.1. XM_005268906.2.
XP_005268964.1. XM_005268907.1.
UniGeneHs.75643.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1LVXmodel-A221-294[»]
2KZ5NMR-A214-293[»]
ProteinModelPortalQ16621.
SMRQ16621. Positions 187-330.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid110850. 20 interactions.
DIPDIP-57844N.
IntActQ16621. 5 interactions.
MINTMINT-3032845.
STRING9606.ENSP00000312436.

PTM databases

PhosphoSiteQ16621.

Polymorphism databases

DMDM6831585.

Proteomic databases

PaxDbQ16621.
PRIDEQ16621.

Protocols and materials databases

DNASU4778.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000312156; ENSP00000312436; ENSG00000123405.
ENST00000435572; ENSP00000397185; ENSG00000123405.
ENST00000540264; ENSP00000439120; ENSG00000123405.
ENST00000553070; ENSP00000447558; ENSG00000123405.
GeneID4778.
KEGGhsa:4778.
UCSCuc001sfq.4. human.

Organism-specific databases

CTD4778.
GeneCardsGC12M054685.
HGNCHGNC:7780. NFE2.
HPAHPA001914.
MIM601490. gene.
neXtProtNX_Q16621.
PharmGKBPA31586.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG326795.
HOGENOMHOG000234410.
HOVERGENHBG002901.
InParanoidQ16621.
KOK09039.
OMAPTDKIVN.
OrthoDBEOG715Q3N.
PhylomeDBQ16621.
TreeFamTF326681.

Enzyme and pathway databases

ReactomeREACT_604. Hemostasis.
SignaLinkQ16621.

Gene expression databases

ArrayExpressQ16621.
BgeeQ16621.
CleanExHS_NFE2.
GenevestigatorQ16621.

Family and domain databases

Gene3D1.10.880.10. 1 hit.
InterProIPR004827. bZIP.
IPR004826. bZIP_Maf.
IPR008917. TF_DNA-bd.
[Graphical view]
PfamPF03131. bZIP_Maf. 1 hit.
[Graphical view]
SMARTSM00338. BRLZ. 1 hit.
[Graphical view]
SUPFAMSSF47454. SSF47454. 1 hit.
PROSITEPS50217. BZIP. 1 hit.
PS00036. BZIP_BASIC. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceQ16621.
GeneWikiNFE2.
GenomeRNAi4778.
NextBio18424.
PROQ16621.
SOURCESearch...

Entry information

Entry nameNFE2_HUMAN
AccessionPrimary (citable) accession number: Q16621
Secondary accession number(s): Q07720, Q6ICV9
Entry history
Integrated into UniProtKB/Swiss-Prot: May 30, 2000
Last sequence update: November 1, 1996
Last modified: April 16, 2014
This is version 136 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome 12

Human chromosome 12: entries, gene names and cross-references to MIM