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Protein

Nuclear factor erythroid 2-related factor 2

Gene

NFE2L2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Transcription activator that binds to antioxidant response (ARE) elements in the promoter regions of target genes. Important for the coordinated up-regulation of genes in response to oxidative stress. May be involved in the transcriptional activation of genes of the beta-globin cluster by mediating enhancer activity of hypersensitive site 2 of the beta-globin locus control region.1 Publication

GO - Molecular functioni

  • DNA binding Source: UniProtKB
  • protein domain specific binding Source: UniProtKB
  • RNA polymerase II activating transcription factor binding Source: BHF-UCL
  • RNA polymerase II distal enhancer sequence-specific DNA binding Source: Ensembl
  • transcriptional activator activity, RNA polymerase II distal enhancer sequence-specific binding Source: Ensembl
  • transcription factor activity, sequence-specific DNA binding Source: ParkinsonsUK-UCL
  • transcription regulatory region DNA binding Source: ParkinsonsUK-UCL
  • transcription regulatory region sequence-specific DNA binding Source: ParkinsonsUK-UCL

GO - Biological processi

  • cell redox homeostasis Source: Ensembl
  • cellular response to drug Source: Ensembl
  • cellular response to fluid shear stress Source: UniProtKB
  • cellular response to glucose starvation Source: Ensembl
  • cellular response to hydrogen peroxide Source: BHF-UCL
  • cellular response to laminar fluid shear stress Source: BHF-UCL
  • cellular response to oxidative stress Source: ParkinsonsUK-UCL
  • cellular response to tumor necrosis factor Source: BHF-UCL
  • endoplasmic reticulum unfolded protein response Source: ParkinsonsUK-UCL
  • inflammatory response Source: Ensembl
  • negative regulation of endothelial cell apoptotic process Source: BHF-UCL
  • negative regulation of hematopoietic stem cell differentiation Source: Ensembl
  • negative regulation of hydrogen peroxide-induced cell death Source: ParkinsonsUK-UCL
  • negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway Source: BHF-UCL
  • PERK-mediated unfolded protein response Source: ParkinsonsUK-UCL
  • positive regulation of blood coagulation Source: Ensembl
  • positive regulation of ER-associated ubiquitin-dependent protein catabolic process Source: ParkinsonsUK-UCL
  • positive regulation of gene expression Source: ParkinsonsUK-UCL
  • positive regulation of glucose import Source: Ensembl
  • positive regulation of glutathione biosynthetic process Source: Ensembl
  • positive regulation of reactive oxygen species metabolic process Source: Ensembl
  • positive regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  • positive regulation of transcription from RNA polymerase II promoter in response to oxidative stress Source: Ensembl
  • positive regulation of transcription from RNA polymerase II promoter in response to stress Source: BHF-UCL
  • proteasomal ubiquitin-independent protein catabolic process Source: UniProtKB
  • proteasome-mediated ubiquitin-dependent protein catabolic process Source: UniProtKB
  • protein ubiquitination Source: UniProtKB
  • regulation of embryonic development Source: Ensembl
  • regulation of removal of superoxide radicals Source: Ensembl
  • transcription from RNA polymerase II promoter Source: ProtInc
Complete GO annotation...

Keywords - Molecular functioni

Activator

Keywords - Biological processi

Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding

Enzyme and pathway databases

SignaLinkiQ16236.
SIGNORiQ16236.

Names & Taxonomyi

Protein namesi
Recommended name:
Nuclear factor erythroid 2-related factor 2
Short name:
NF-E2-related factor 2
Short name:
NFE2-related factor 2
Alternative name(s):
HEBP1
Nuclear factor, erythroid derived 2, like 2
Gene namesi
Name:NFE2L2
Synonyms:NRF2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 2

Organism-specific databases

HGNCiHGNC:7782. NFE2L2.

Subcellular locationi

  • Cytoplasmcytosol
  • Nucleus

  • Note: Cytosolic under unstressed conditions, translocates into the nucleus upon induction by electrophilic agents.

GO - Cellular componenti

  • centrosome Source: HPA
  • chromatin Source: Ensembl
  • cytoplasm Source: ParkinsonsUK-UCL
  • cytosol Source: BHF-UCL
  • nucleus Source: UniProtKB
  • plasma membrane Source: HPA
  • protein-DNA complex Source: ParkinsonsUK-UCL
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi80 – 801T → A: Loss of interaction with KEAP1. 1 Publication

Organism-specific databases

PharmGKBiPA31588.

Chemistry

ChEMBLiCHEMBL3038498.

Polymorphism and mutation databases

BioMutaiNFE2L2.
DMDMi25453452.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 605605Nuclear factor erythroid 2-related factor 2PRO_0000076449Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei40 – 401Phosphoserine; by PKCBy similarity
Modified residuei215 – 2151PhosphoserineCombined sources
Modified residuei596 – 5961N6-acetyllysine; by CREBBP1 Publication
Modified residuei599 – 5991N6-acetyllysine; by CREBBP1 Publication

Post-translational modificationi

Phosphorylation of Ser-40 by PKC in response to oxidative stress dissociates NFE2L2 from its cytoplasmic inhibitor KEAP1, promoting its translocation into the nucleus.By similarity
Acetylation at Lys-596 and Lys-599 increases nuclear localization whereas deacetylation by SIRT1 enhances cytoplasmic presence.1 Publication
Ubiquitinated by the KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex and subject to proteasomal degradation. Ubiquitination is inhibited by sulforaphane.1 Publication

Keywords - PTMi

Acetylation, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ16236.
MaxQBiQ16236.
PaxDbiQ16236.
PeptideAtlasiQ16236.
PRIDEiQ16236.

PTM databases

iPTMnetiQ16236.
PhosphoSiteiQ16236.

Miscellaneous databases

PMAP-CutDBQ16236.

Expressioni

Tissue specificityi

Widely expressed. Highest expression in adult muscle, kidney, lung, liver and in fetal muscle.

Inductioni

Down-regulated by ENC1 via a proteasomal ubiquitin-independent protein catabolic process.

Gene expression databases

BgeeiENSG00000116044.
CleanExiHS_NFE2L2.
ExpressionAtlasiQ16236. baseline and differential.
GenevisibleiQ16236. HS.

Organism-specific databases

HPAiCAB020317.
HPA002990.
HPA043438.

Interactioni

Subunit structurei

Heterodimer. Forms a ternary complex with PGAM5 and KEAP1. May bind DNA with an unknown protein. Interacts via its leucine-zipper domain with the coiled-coil domain of PMF1. Interacts with EEF1D at heat shock promoter elements (HSE). Interacts (via the bZIP domain) with MAFK; required for binding to antioxidant response (ARE) elements on DNA. Interacts with CHD6; involved in activation of the transcription.4 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
KEAP1Q1414517EBI-2007911,EBI-751001
MAFGO155253EBI-2007911,EBI-713514
TNNT1P138053EBI-2007911,EBI-726527
WACQ9BTA93EBI-2007911,EBI-749118

GO - Molecular functioni

  • protein domain specific binding Source: UniProtKB
  • RNA polymerase II activating transcription factor binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi110852. 64 interactions.
DIPiDIP-29971N.
IntActiQ16236. 11 interactions.
MINTiMINT-2844437.
STRINGi9606.ENSP00000380252.

Chemistry

BindingDBiQ16236.

Structurei

Secondary structure

1
605
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Turni78 – 803Combined sources
Helixi456 – 4649Combined sources
Helixi470 – 4756Combined sources
Helixi478 – 48710Combined sources
Helixi492 – 50413Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
2FLUX-ray1.50P69-84[»]
2LZ1NMR-A445-523[»]
3ZGCX-ray2.20C76-82[»]
4IFLX-ray1.80P69-84[»]
ProteinModelPortaliQ16236.
SMRiQ16236. Positions 449-523.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ16236.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini497 – 56064bZIPPROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni499 – 51820Basic motifPROSITE-ProRule annotationAdd
BLAST
Regioni522 – 5298Leucine-zipperPROSITE-ProRule annotation
Regioni591 – 5966Mediates interaction with CHD6 and is necessary to activate transcriptionBy similarity

Domaini

Acidic activation domain in the N-terminus, and DNA binding domain in the C-terminus.

Sequence similaritiesi

Belongs to the bZIP family. CNC subfamily.Curated
Contains 1 bZIP (basic-leucine zipper) domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiENOG410ISV3. Eukaryota.
ENOG41100FB. LUCA.
GeneTreeiENSGT00830000128250.
HOGENOMiHOG000234410.
HOVERGENiHBG052609.
InParanoidiQ16236.
KOiK05638.
OMAiALHIPFP.
OrthoDBiEOG091G02EB.
PhylomeDBiQ16236.
TreeFamiTF326681.

Family and domain databases

Gene3Di1.10.880.10. 1 hit.
InterProiIPR004827. bZIP.
IPR004826. bZIP_Maf.
IPR029845. Nrf2.
IPR008917. TF_DNA-bd.
[Graphical view]
PANTHERiPTHR24411:SF3. PTHR24411:SF3. 1 hit.
PfamiPF03131. bZIP_Maf. 1 hit.
[Graphical view]
SMARTiSM00338. BRLZ. 1 hit.
[Graphical view]
SUPFAMiSSF47454. SSF47454. 1 hit.
PROSITEiPS50217. BZIP. 1 hit.
PS00036. BZIP_BASIC. 1 hit.
[Graphical view]

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q16236-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MMDLELPPPG LPSQQDMDLI DILWRQDIDL GVSREVFDFS QRRKEYELEK
60 70 80 90 100
QKKLEKERQE QLQKEQEKAF FAQLQLDEET GEFLPIQPAQ HIQSETSGSA
110 120 130 140 150
NYSQVAHIPK SDALYFDDCM QLLAQTFPFV DDNEVSSATF QSLVPDIPGH
160 170 180 190 200
IESPVFIATN QAQSPETSVA QVAPVDLDGM QQDIEQVWEE LLSIPELQCL
210 220 230 240 250
NIENDKLVET TMVPSPEAKL TEVDNYHFYS SIPSMEKEVG NCSPHFLNAF
260 270 280 290 300
EDSFSSILST EDPNQLTVNS LNSDATVNTD FGDEFYSAFI AEPSISNSMP
310 320 330 340 350
SPATLSHSLS ELLNGPIDVS DLSLCKAFNQ NHPESTAEFN DSDSGISLNT
360 370 380 390 400
SPSVASPEHS VESSSYGDTL LGLSDSEVEE LDSAPGSVKQ NGPKTPVHSS
410 420 430 440 450
GDMVQPLSPS QGQSTHVHDA QCENTPEKEL PVSPGHRKTP FTKDKHSSRL
460 470 480 490 500
EAHLTRDELR AKALHIPFPV EKIINLPVVD FNEMMSKEQF NEAQLALIRD
510 520 530 540 550
IRRRGKNKVA AQNCRKRKLE NIVELEQDLD HLKDEKEKLL KEKGENDKSL
560 570 580 590 600
HLLKKQLSTL YLEVFSMLRD EDGKPYSPSE YSLQQTRDGN VFLVPKSKKP

DVKKN
Length:605
Mass (Da):67,827
Last modified:November 25, 2002 - v3
Checksum:i99FAFD811B6C1416
GO
Isoform 2 (identifier: Q16236-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-16: Missing.

Show »
Length:589
Mass (Da):66,076
Checksum:iC0154E60AC7C138C
GO
Isoform 3 (identifier: Q16236-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-16: Missing.
     135-141: Missing.

Note: No experimental confirmation available.
Show »
Length:582
Mass (Da):65,356
Checksum:i8C560533CEB5E2F8
GO

Sequence cautioni

The sequence AAB32188 differs from that shown. Reason: Erroneous initiation. Curated
The sequence BAD92023 differs from that shown. Reason: Erroneous initiation. Curated

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti72 – 721A → T in AAB32188 (PubMed:7937919).Curated
Sequence conflicti92 – 921I → T in AAB32188 (PubMed:7937919).Curated
Sequence conflicti178 – 1781D → Y in AL135266 (PubMed:15815621).Curated
Sequence conflicti521 – 5211N → D in BAG65350 (PubMed:14702039).Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti43 – 431R → Q.
Corresponds to variant rs35248500 [ dbSNP | Ensembl ].
VAR_032110
Natural varianti99 – 991S → P.
Corresponds to variant rs5031039 [ dbSNP | Ensembl ].
VAR_020322
Natural varianti268 – 2681V → M.
Corresponds to variant rs34154613 [ dbSNP | Ensembl ].
VAR_032111

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 1616Missing in isoform 2 and isoform 3. 2 PublicationsVSP_025045Add
BLAST
Alternative sequencei135 – 1417Missing in isoform 3. 1 PublicationVSP_046168

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK304555 mRNA. Translation: BAG65350.1.
AK314816 mRNA. Translation: BAG37339.1.
AB208786 mRNA. Translation: BAD92023.1. Different initiation.
AC019080 Genomic DNA. No translation available.
AC079305 Genomic DNA. Translation: AAY14710.1.
CH471058 Genomic DNA. Translation: EAX11062.1.
BC011558 mRNA. Translation: AAH11558.1.
AL135266 mRNA. No translation available.
S74017 mRNA. Translation: AAB32188.1. Different initiation.
CCDSiCCDS42782.1. [Q16236-1]
CCDS46457.1. [Q16236-2]
CCDS46458.1. [Q16236-3]
RefSeqiNP_001138884.1. NM_001145412.3. [Q16236-2]
NP_001138885.1. NM_001145413.3. [Q16236-3]
NP_001300829.1. NM_001313900.1. [Q16236-2]
NP_001300830.1. NM_001313901.1. [Q16236-2]
NP_006155.2. NM_006164.4. [Q16236-1]
UniGeneiHs.744006.

Genome annotation databases

EnsembliENST00000397062; ENSP00000380252; ENSG00000116044. [Q16236-1]
ENST00000397063; ENSP00000380253; ENSG00000116044. [Q16236-2]
ENST00000446151; ENSP00000411575; ENSG00000116044. [Q16236-3]
ENST00000464747; ENSP00000467401; ENSG00000116044. [Q16236-2]
GeneIDi4780.
KEGGihsa:4780.
UCSCiuc002ulg.6. human. [Q16236-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK304555 mRNA. Translation: BAG65350.1.
AK314816 mRNA. Translation: BAG37339.1.
AB208786 mRNA. Translation: BAD92023.1. Different initiation.
AC019080 Genomic DNA. No translation available.
AC079305 Genomic DNA. Translation: AAY14710.1.
CH471058 Genomic DNA. Translation: EAX11062.1.
BC011558 mRNA. Translation: AAH11558.1.
AL135266 mRNA. No translation available.
S74017 mRNA. Translation: AAB32188.1. Different initiation.
CCDSiCCDS42782.1. [Q16236-1]
CCDS46457.1. [Q16236-2]
CCDS46458.1. [Q16236-3]
RefSeqiNP_001138884.1. NM_001145412.3. [Q16236-2]
NP_001138885.1. NM_001145413.3. [Q16236-3]
NP_001300829.1. NM_001313900.1. [Q16236-2]
NP_001300830.1. NM_001313901.1. [Q16236-2]
NP_006155.2. NM_006164.4. [Q16236-1]
UniGeneiHs.744006.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
2FLUX-ray1.50P69-84[»]
2LZ1NMR-A445-523[»]
3ZGCX-ray2.20C76-82[»]
4IFLX-ray1.80P69-84[»]
ProteinModelPortaliQ16236.
SMRiQ16236. Positions 449-523.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi110852. 64 interactions.
DIPiDIP-29971N.
IntActiQ16236. 11 interactions.
MINTiMINT-2844437.
STRINGi9606.ENSP00000380252.

Chemistry

BindingDBiQ16236.
ChEMBLiCHEMBL3038498.

PTM databases

iPTMnetiQ16236.
PhosphoSiteiQ16236.

Polymorphism and mutation databases

BioMutaiNFE2L2.
DMDMi25453452.

Proteomic databases

EPDiQ16236.
MaxQBiQ16236.
PaxDbiQ16236.
PeptideAtlasiQ16236.
PRIDEiQ16236.

Protocols and materials databases

DNASUi4780.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000397062; ENSP00000380252; ENSG00000116044. [Q16236-1]
ENST00000397063; ENSP00000380253; ENSG00000116044. [Q16236-2]
ENST00000446151; ENSP00000411575; ENSG00000116044. [Q16236-3]
ENST00000464747; ENSP00000467401; ENSG00000116044. [Q16236-2]
GeneIDi4780.
KEGGihsa:4780.
UCSCiuc002ulg.6. human. [Q16236-1]

Organism-specific databases

CTDi4780.
GeneCardsiNFE2L2.
HGNCiHGNC:7782. NFE2L2.
HPAiCAB020317.
HPA002990.
HPA043438.
MIMi600492. gene.
neXtProtiNX_Q16236.
PharmGKBiPA31588.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410ISV3. Eukaryota.
ENOG41100FB. LUCA.
GeneTreeiENSGT00830000128250.
HOGENOMiHOG000234410.
HOVERGENiHBG052609.
InParanoidiQ16236.
KOiK05638.
OMAiALHIPFP.
OrthoDBiEOG091G02EB.
PhylomeDBiQ16236.
TreeFamiTF326681.

Enzyme and pathway databases

SignaLinkiQ16236.
SIGNORiQ16236.

Miscellaneous databases

ChiTaRSiNFE2L2. human.
EvolutionaryTraceiQ16236.
GeneWikiiNFE2L2.
GenomeRNAii4780.
PMAP-CutDBQ16236.
PROiQ16236.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000116044.
CleanExiHS_NFE2L2.
ExpressionAtlasiQ16236. baseline and differential.
GenevisibleiQ16236. HS.

Family and domain databases

Gene3Di1.10.880.10. 1 hit.
InterProiIPR004827. bZIP.
IPR004826. bZIP_Maf.
IPR029845. Nrf2.
IPR008917. TF_DNA-bd.
[Graphical view]
PANTHERiPTHR24411:SF3. PTHR24411:SF3. 1 hit.
PfamiPF03131. bZIP_Maf. 1 hit.
[Graphical view]
SMARTiSM00338. BRLZ. 1 hit.
[Graphical view]
SUPFAMiSSF47454. SSF47454. 1 hit.
PROSITEiPS50217. BZIP. 1 hit.
PS00036. BZIP_BASIC. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiNF2L2_HUMAN
AccessioniPrimary (citable) accession number: Q16236
Secondary accession number(s): B2RBU2
, B4E338, E9PGJ7, Q53RW6, Q59HH2, Q96F71
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: November 25, 2002
Last modified: September 7, 2016
This is version 166 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 2
    Human chromosome 2: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.