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Protein

Endoplasmic reticulum membrane sensor NFE2L1

Gene

NFE2L1

Organism
Bos taurus (Bovine)
Status
Reviewed-Annotation score: -Experimental evidence at transcript leveli

Functioni

Endoplasmic reticulum membrane sensor NFE2L1: Endoplasmic reticulum membrane sensor that translocates into the nucleus in response to various stresses to act as a transcription factor (By similarity). Constitutes a precursor of the transcription factor NRF1 (By similarity). Able to detect various cellular stresses, such as cholesterol excess, oxidative stress or proteasome inhibition (By similarity). In response to stress, it is released from the endoplasmic reticulum membrane following cleavage by the protease DDI2 and translocates into the nucleus to form the transcription factor NRF1 (By similarity). Acts as a key sensor of cholesterol excess: in excess cholesterol conditions, the endoplasmic reticulum membrane form of the protein directly binds cholesterol via its CRAC motif, preventing cleavage and release of the transcription factor NRF1, thereby allowing expression of genes promoting cholesterol removal, such as CD36 (By similarity). Involved in proteasome homeostasis: in response to proteasome inhibition, it is released from the endoplasmic reticulum membrane, translocates to the nucleus and activates expression of genes encoding proteasome subunits (By similarity).By similarity
Transcription factor NRF1: CNC-type bZIP family transcription factor that translocates to the nucleus and regulates expression of target genes in response to various stresses. Heterodimerizes with small-Maf proteins (MAFF, MAFG or MAFK) and binds DNA motifs including the antioxidant response elements (AREs), which regulate expression of genes involved in oxidative stress response. Activates or represses expression of target genes, depending on the context (By similarity). Plays a key role in cholesterol homeostasis by acting as a sensor of cholesterol excess: in low cholesterol conditions, translocates into the nucleus and represses expression of genes involved in defense against cholesterol excess, such as CD36 (By similarity). In excess cholesterol conditions, the endoplasmic reticulum membrane form of the protein directly binds cholesterol via its CRAC motif, preventing cleavage and release of the transcription factor NRF1, thereby allowing expression of genes promoting cholesterol removal (By similarity). Critical for redox balance in response to oxidative stress: acts by binding the AREs motifs on promoters and mediating activation of oxidative stress response genes, such as GCLC, GCLM, GSS, MT1 and MT2 (By similarity). Plays an essential role during fetal liver hematopoiesis: probably has a protective function against oxidative stress and is involved in lipid homeostasis in the liver (By similarity). Involved in proteasome homeostasis: in response to proteasome inhibition, mediates the 'bounce-back' of proteasome subunits by translocating into the nucleus and activating expression of genes encoding proteasome subunits (By similarity). Also involved in regulating glucose flux (By similarity). Together with CEBPB; represses expression of DSPP during odontoblast differentiation. In response to ascorbic acid induction, activates expression of SP7/Osterix in osteoblasts (By similarity).By similarity

GO - Molecular functioni

GO - Biological processi

  • cell redox homeostasis Source: UniProtKB
  • cellular response to cholesterol Source: UniProtKB
  • cellular response to oxidative stress Source: UniProtKB
  • cholesterol homeostasis Source: UniProtKB
  • cholesterol metabolic process Source: UniProtKB-KW
  • erythrocyte differentiation Source: Ensembl
  • lipid homeostasis Source: UniProtKB
  • negative regulation of transcription by RNA polymerase II Source: UniProtKB
  • negative regulation of transcription from RNA polymerase II promoter in response to stress Source: UniProtKB
  • positive regulation of transcription, DNA-templated Source: GO_Central
  • positive regulation of transcription from RNA polymerase II promoter in response to stress Source: UniProtKB
  • regulation of odontoblast differentiation Source: UniProtKB
  • regulation of transcription by RNA polymerase II Source: GO_Central

Keywordsi

Molecular functionActivator, DNA-binding, Repressor
Biological processCholesterol metabolism, Lipid metabolism, Steroid metabolism, Sterol metabolism, Transcription, Transcription regulation
LigandLipid-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Endoplasmic reticulum membrane sensor NFE2L1Curated
Alternative name(s):
Nuclear factor erythroid 2-related factor 1By similarity
Short name:
NF-E2-related factor 1By similarity
Short name:
NFE2-related factor 1By similarity
Nuclear factor, erythroid derived 2, like 1By similarity
Cleaved into the following chain:
Transcription factor NRF1By similarity
Gene namesi
Name:NFE2L1By similarity
Synonyms:NRF1By similarity
OrganismiBos taurus (Bovine)
Taxonomic identifieri9913 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCetartiodactylaRuminantiaPecoraBovidaeBovinaeBos
Proteomesi
  • UP000009136 Componenti: Chromosome 19

Organism-specific databases

VGNCiVGNC:32035 NFE2L1

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Transmembranei7 – 24Helical; Signal-anchor for type II membrane proteinSequence analysisAdd BLAST18

Keywords - Cellular componenti

Endoplasmic reticulum, Membrane, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00003419461 – 763Endoplasmic reticulum membrane sensor NFE2L1Add BLAST763
ChainiPRO_0000443102104 – 763Transcription factor NRF1By similarityAdd BLAST660

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi338N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi350N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi413N-linked (GlcNAc...) asparagineSequence analysis1
Modified residuei519Phosphoserine; by CK2By similarity1
Modified residuei590Phosphoserine; by PKABy similarity1

Post-translational modificationi

Endoplasmic reticulum membrane sensor NFE2L1: Cleaved at Leu-104 by the aspartyl protease DDI2 following retrotranslocation, releasing the protein from the endoplasmic reticulum membrane and forming the transcription factor NRF1 that translocates into the nucleus. Ubiquitination is prerequisite for cleavage by aspartyl protease DDI2.By similarity
Endoplasmic reticulum membrane sensor NFE2L1: N-glycosylated in normal conditions, when it has a single-pass type II membrane protein topology, with the DNA-binding domain facing the endoplasmic reticulum lumen (By similarity). Deglycosylated during retrotranslocation to the cytosolic side of the membrane, to have a single-pass type III membrane protein topology with the major part of the protein facing the cytosol (By similarity).By similarity
Endoplasmic reticulum membrane sensor NFE2L1: Ubiquitinated by the SCF(FBXW7) complex and SYVN1/HRD1, leading to its degradation by the proteasome (By similarity). Ubiquitinated during retrotranslocation to the cytosolic side of the membrane: ubiquitination does not lead to degradation and is required for processing by the aspartyl protease DDI2 and subsequent release from the endoplasmic reticulum membrane (By similarity).By similarity
Transcription factor NRF1: Phosphorylation by CK2 at Ser-519 inhibits transcription factor activity, possibly by affecting DNA-binding activity (By similarity). Phosphorylation at Ser-590 is required for interaction with CEBPB (By similarity).By similarity
Transcription factor NRF1: Ubiquitinated by the SCF(BTRC) complex in the nucleus, leading to its degradation by the proteasome.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei103 – 104Cleavage; by DDI2By similarity2

Keywords - PTMi

Glycoprotein, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiA5D7E9
PRIDEiA5D7E9

Expressioni

Gene expression databases

BgeeiENSBTAG00000013653

Interactioni

Subunit structurei

Interacts with KEAP1 (By similarity). Endoplasmic reticulum membrane sensor NFE2L1: Interacts (via CPD region) with FBXW7; leading to its ubiquitination and degradation (By similarity). Endoplasmic reticulum membrane sensor NFE2L1: Interacts with SYVN1/HRD1; leading to its ubiquitination and degradation (By similarity). Endoplasmic reticulum membrane sensor NFE2L1: Interacts (when ubiquitinated) with DDI2; leading to its cleavage (By similarity). Transcription factor NRF1: Interacts (via the bZIP domain) with small MAF protein (MAFF, MAFG or MAFK); required for binding to antioxidant response elements (AREs) on DNA (By similarity). Transcription factor NRF1: Interacts (via Destruction motif) with BTRC; leading to its ubiquitination and degradation (By similarity). Transcription factor NRF1: Interacts with CEBPB; the heterodimer represses expression of DSPP during odontoblast differentiation (By similarity).By similarity

GO - Molecular functioni

Protein-protein interaction databases

STRINGi9913.ENSBTAP00000018147

Structurei

3D structure databases

ProteinModelPortaliA5D7E9
SMRiA5D7E9
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini645 – 708bZIPPROSITE-ProRule annotationAdd BLAST64

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni180 – 188Cholesterol recognition/amino acid consensus (CRAC) regionBy similarity9
Regioni369 – 373CPDBy similarity5
Regioni647 – 666Basic motifPROSITE-ProRule annotationAdd BLAST20
Regioni673 – 687Leucine-zipperPROSITE-ProRule annotationAdd BLAST15

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi466 – 470Destruction motifBy similarity5
Motifi752 – 759Nuclear localization signalSequence analysis8

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi465 – 521Ser-richAdd BLAST57

Domaini

The cholesterol recognition/amino acid consensus (CRAC) region directly binds cholesterol, as well as campesterol and 27-hydroxycholesterol. Has much lower affinity for epicholesterol.By similarity

Sequence similaritiesi

Belongs to the bZIP family. CNC subfamily.Curated

Keywords - Domaini

Signal-anchor, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG3863 Eukaryota
ENOG410ZGMS LUCA
GeneTreeiENSGT00910000144085
HOVERGENiHBG052609
InParanoidiA5D7E9
KOiK09040
OMAiHKHSGPS
OrthoDBiEOG091G02EB
TreeFamiTF326681

Family and domain databases

InterProiView protein in InterPro
IPR004827 bZIP
IPR004826 bZIP_Maf
IPR029847 Nrf1_NFE2L1
IPR008917 TF_DNA-bd_sf
PANTHERiPTHR24411:SF31 PTHR24411:SF31, 1 hit
PfamiView protein in Pfam
PF03131 bZIP_Maf, 1 hit
SMARTiView protein in SMART
SM00338 BRLZ, 1 hit
SUPFAMiSSF47454 SSF47454, 1 hit
PROSITEiView protein in PROSITE
PS50217 BZIP, 1 hit
PS00036 BZIP_BASIC, 1 hit

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

A5D7E9-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MLSLKKYLTE GLLQFTILLS LIGVRVDVDT YLTSQLPPLR EIILGPSSAY
60 70 80 90 100
TQTQFHNLRN TLDGYGIHPK SIDLDNYFTA RRLLNQVRAL DRFQVPTTEV
110 120 130 140 150
NAWLVHRDPE GSVSGSQPSS GLALESSSGL QDVTGPDNGV RESETEQGFS
160 170 180 190 200
EDLEDLGAVA PPVSGDLTKE DIDLGAGREI FDYSHRQKEQ DVDKELRDGA
210 220 230 240 250
EQEDTWPGEG AEALARNLLV DGETGESFPA QVPGGEDQTA LSLEECLRLL
260 270 280 290 300
EATCPFGENA EFPADISSIT EAVPSESEPP GLQNNLLSPL LTGTESPFDL
310 320 330 340 350
EQQWQDLMSI MEMQAMEVNT STSEVLYNAP PGDPLSTNYS LAPNTPINQN
360 370 380 390 400
VSLHQASLGG CSQDFSLFSP EVESLPVASS STLLPLVPSN STSLNSTFGS
410 420 430 440 450
TNLAGLFFPP QLNGTANDTA GPELPDPLGG LLDEAMLDEI SLMDLAIEEG
460 470 480 490 500
FNPVQASQLE EEFDSDSGLS LDSSHSPSSL SSSEGSSSSS SSSSSSSSSS
510 520 530 540 550
ASSSASSSFS EEGAVGYSSD SETLDLEEAE GAVGYQPEYS KFCRMSYQDP
560 570 580 590 600
SQLSCLPYLE HVGHNHTYNM APSALDSADL PPPSTLKKGS KEKQADFLDK
610 620 630 640 650
QMSRDEHRAR AMKIPFTNDK IINLPVEEFN ELLSKYQLSE AQLSLIRDIR
660 670 680 690 700
RRGKNKMAAQ NCRKRKLDTI LNLERDVEDL QRDKARLLRE KVEFLRSLRQ
710 720 730 740 750
MKQKVQSLYQ EVFGRLRDEN GRPYSPSQYA LQYAGDGSVL LIPRTLADQQ
760
ARRQERKPKD RRK
Length:763
Mass (Da):83,607
Last modified:June 12, 2007 - v1
Checksum:i3C78D811BE63A378
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BC140530 mRNA Translation: AAI40531.1
RefSeqiNP_001095985.1, NM_001102515.1
XP_005220649.1, XM_005220592.3
UniGeneiBt.28567

Genome annotation databases

EnsembliENSBTAT00000018147; ENSBTAP00000018147; ENSBTAG00000013653
GeneIDi534582
KEGGibta:534582

Similar proteinsi

Entry informationi

Entry nameiNF2L1_BOVIN
AccessioniPrimary (citable) accession number: A5D7E9
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 1, 2008
Last sequence update: June 12, 2007
Last modified: May 23, 2018
This is version 74 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

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