Q16621 (NFE2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	373 AA.
Sequence status	Complete.
Protein existence	Evidence 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 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	Nucleus › PML 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 process	Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Ligand	DNA-binding
Molecular function	Activator
PTM	Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	blood circulation Traceable author statement Ref.2. Source: ProtInc blood coagulation Traceable author statement. Source: Reactome cell-cell signaling Inferred from electronic annotation. Source: Compara multicellular organismal development Traceable author statement PubMed 7774011. Source: ProtInc negative regulation of bone mineralization Inferred from electronic annotation. Source: Compara nucleosome disassembly Traceable author statement PubMed 9305852. Source: BHF-UCL positive regulation of transcription, DNA-dependent 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-dependent Traceable author statement PubMed 9305852. Source: BHF-UCL
Cellular_component	PML 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
Molecular_function	WW domain binding Inferred from direct assay PubMed 9305852. Source: MGI 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 key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 373

373

Transcription factor NF-E2 45 kDa subunit

PRO_0000076446

Regions

Domain

266 – 329

64

bZIP

Region

1 – 206

206

Transactivation domain

Region

1 – 83

83

Required for interaction with MAPK8 By similarity

Region

268 – 287

20

Basic motif By similarity

Region

291 – 298

8

Leucine-zipper By similarity

Motif

61 – 65

5

PXY motif 1

Motif

79 – 83

5

PXY motif 2

Compositional bias

59 – 62

4

Poly-Pro

Compositional bias

77 – 82

6

Poly-Pro

Amino acid modifications

Modified residue

157

1

Phosphoserine; by MAPK8 By similarity

Modified residue

170

1

Phosphoserine; by PKA By similarity

Cross-link

368

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO-1) Ref.9

Experimental info

Mutagenesis

368

1

K → R: 60% loss of DNA-binding and 5-fold loss of transactivation activity. Almost no colocalization with nuclear bodies. Ref.9

Sequence conflict

334 – 335

2

FQ → LE in AAA35612. Ref.2

Secondary structure

1

.

.

.

.

.

.

.

.

.

373

Helix Strand Turn

Details...

Helix

225 – 233

9

Helix

239 – 244

6

Helix

247 – 256

10

Helix

261 – 279

19

Sequences

	Sequence		Length	Mass (Da)
	Q16621 [UniParc]. Last modified November 1, 1996. Version 1. Checksum: A9821170FB2ED67C	FASTA	373	41,473
	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

References

	« Hide 'large scale' referencesShow '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, MASS SPECTROMETRY, MUTAGENESIS OF LYS-368.
[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.
+	Additional computationally mapped references.

Web resources

SeattleSNPs

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.

IPI

IPI00003367.

PIR

A49671.
A54692.

RefSeq

NP_001129495.1. NM_001136023.2.
NP_001248390.1. NM_001261461.1.
NP_006154.1. NM_006163.2.

UniGene

Hs.75643.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1LVX	model	-	A	221-294	[»]
2KZ5	NMR	-	A	214-293	[»]

ProteinModelPortal

Q16621.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-57844N.

IntAct

Q16621. 3 interactions.

MINT

MINT-3032845.

STRING

9606.ENSP00000312436.

PTM databases

PhosphoSite

Q16621.

Polymorphism databases

DMDM

6831585.

Proteomic databases

PaxDb

Q16621.

PRIDE

Q16621.

Protocols and materials databases

DNASU

4778.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000312156; ENSP00000312436; ENSG00000123405.
ENST00000435572; ENSP00000397185; ENSG00000123405.
ENST00000540264; ENSP00000439120; ENSG00000123405.
ENST00000553070; ENSP00000447558; ENSG00000123405.

GeneID

4778.

KEGG

hsa:4778.

UCSC

uc001sfq.3. human.

Organism-specific databases

CTD

4778.

GeneCards

GC12M054685.

HGNC

HGNC:7780. NFE2.

HPA

HPA001914.

MIM

601490. gene.

neXtProt

NX_Q16621.

PharmGKB

PA31586.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG326795.

HOGENOM

HOG000234410.

HOVERGEN

HBG002901.

InParanoid

Q16621.

KO

K09039.

OMA

LETIVQL.

OrthoDB

EOG42FSJ4.

PhylomeDB

Q16621.

Enzyme and pathway databases

Reactome

REACT_604. Hemostasis.

Gene expression databases

ArrayExpress

Q16621.

Bgee

Q16621.

CleanEx

HS_NFE2.

Genevestigator

Q16621.

GermOnline

ENSG00000123405. Homo sapiens.

Family and domain databases

Gene3D

1.10.880.10. 1 hit.

InterPro

IPR004827. bZIP.
IPR008917. Euk_TF_DNA-bd.
[Graphical view]

Pfam

PF00170. bZIP_1. 1 hit.
[Graphical view]

SMART

SM00338. BRLZ. 1 hit.
[Graphical view]

SUPFAM

SSF47454. Euk_transcr_DNA. 1 hit.

PROSITE

PS50217. BZIP. 1 hit.
PS00036. BZIP_BASIC. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

Q16621.

GenomeRNAi

4778.

NextBio

18424.

SOURCE

Search...

Entry information

Entry name

NFE2_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 127 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.