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Protein

Cyclic AMP-dependent transcription factor ATF-4

Gene

ATF4

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

Functioni

Transcriptional activator. Binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3'), a sequence present in many viral and cellular promoters. Cooperates with FOXO1 in osteoblasts to regulate glucose homeostasis through suppression of beta-cell production and decrease in insulin production (By similarity). It binds to a Tax-responsive enhancer element in the long terminal repeat of HTLV-I. Regulates the induction of DDIT3/CHOP and asparagine synthetase (ASNS) in response to endoplasmic reticulum (ER) stress. In concert with DDIT3/CHOP, activates the transcription of TRIB3 and promotes ER stress-induced neuronal apoptosis by regulating the transcriptional induction of BBC3/PUMA. Activates transcription of SIRT4. Regulates the circadian expression of the core clock component PER2 and the serotonin transporter SLC6A4. Binds in a circadian time-dependent manner to the cAMP response elements (CRE) in the SLC6A4 and PER2 promoters and periodically activates the transcription of these genes. During ER stress response, activates the transcription of NLRP1, possibly in concert with other factors (PubMed:26086088).By similarity4 Publications

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionActivator, DNA-binding
Biological processBiological rhythms, Transcription, Transcription regulation

Enzyme and pathway databases

ReactomeiR-HSA-380994 ATF4 activates genes
R-HSA-381042 PERK regulates gene expression
R-HSA-381183 ATF6 (ATF6-alpha) activates chaperone genes
SIGNORiP18848

Names & Taxonomyi

Protein namesi
Recommended name:
Cyclic AMP-dependent transcription factor ATF-4
Short name:
cAMP-dependent transcription factor ATF-4
Alternative name(s):
Activating transcription factor 4
Cyclic AMP-responsive element-binding protein 2
Short name:
CREB-2
Short name:
cAMP-responsive element-binding protein 2
DNA-binding protein TAXREB67
Tax-responsive enhancer element-binding protein 67
Short name:
TaxREB67
Gene namesi
Name:ATF4
Synonyms:CREB2, TXREB
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 22

Organism-specific databases

EuPathDBiHostDB:ENSG00000128272.14
HGNCiHGNC:786 ATF4
MIMi604064 gene
neXtProtiNX_P18848

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

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Cytoskeleton, Membrane, Nucleus

Pathology & Biotechi

Organism-specific databases

DisGeNETi468
OpenTargetsiENSG00000128272
PharmGKBiPA25086

Chemistry databases

DrugBankiDB00852 Pseudoephedrine

Polymorphism and mutation databases

BioMutaiATF4
DMDMi116241262

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000765841 – 351Cyclic AMP-dependent transcription factor ATF-4Add BLAST351

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Cross-linki53Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
Modified residuei213PhosphothreonineBy similarity1
Modified residuei219PhosphoserineBy similarity1
Modified residuei224PhosphoserineBy similarity1
Modified residuei231PhosphoserineBy similarity1
Modified residuei235PhosphoserineBy similarity1
Modified residuei248PhosphoserineBy similarity1
Cross-linki259Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
Cross-linki267Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
Cross-linki272Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources

Post-translational modificationi

Ubiquitinated by SCF(BTRC) in response to mTORC1 signal, followed by proteasomal degradation and leading to down-regulate expression of SIRT4.By similarity
Phosphorylated by NEK6 (By similarity). Phosphorylated on the betaTrCP degron motif at Ser-219, followed by phosphorylation at Thr-213, Ser-224, Ser-231, Ser-235 and Ser-248, promoting interaction with BTRC and ubiquitination. Phosphorylation is promoted by mTORC1 (By similarity).By similarity
Phosphorylated by NEK6.1 Publication

Keywords - PTMi

Isopeptide bond, Lipoprotein, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiP18848
PaxDbiP18848
PeptideAtlasiP18848
PRIDEiP18848
ProteomicsDBi53615

PTM databases

iPTMnetiP18848
PhosphoSitePlusiP18848

Expressioni

Gene expression databases

BgeeiENSG00000128272 Expressed in 103 organ(s), highest expression level in lower esophagus
CleanExiHS_ATF4
GenevisibleiP18848 HS

Organism-specific databases

HPAiCAB011596

Interactioni

Subunit structurei

Binds DNA as a homodimer and as a heterodimer (PubMed:11018027). Interacts with CEBPB and binds DNA as a heterodimer with CEBPB (PubMed:11018027). Interacts (via its leucine zipper domain) with GABBR1 and GABBR2 (via their C-termini). Interacts (via its DNA binding domain) with FOXO1 (C-terminal half); the interaction occurs in osteoblasts and regulates glucose homeostasis through suppression of beta-cell proliferation and a decrease in insulin production. Interacts with SATB2; the interaction results in enhanced DNA binding and transactivation by these transcription factors (By similarity). Interacts with CEP290 (via an N-terminal region) (PubMed:16682973). Interacts with NEK6, DAPK2 (isoform 2) and ZIPK/DAPK3 (PubMed:20873783, PubMed:21408167). Forms a heterodimer with TXLNG in osteoblasts (PubMed:15911876). Interacts with DDIT3/CHOP (PubMed:18940792). Interacts with ABRAXAS2 (PubMed:22974638).By similarity7 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi106958, 76 interactors
ComplexPortaliCPX-8 ATF4-CREB1 transcription factor complex
CPX-9 ATF1-ATF4 transcription factor complex
CORUMiP18848
DIPiDIP-354N
ELMiP18848
IntActiP18848, 59 interactors
MINTiP18848
STRINGi9606.ENSP00000336790

Structurei

Secondary structure

1351
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliP18848
SMRiP18848
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP18848

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini278 – 341bZIPPROSITE-ProRule annotationAdd BLAST64

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni280 – 300Basic motifPROSITE-ProRule annotationAdd BLAST21
Regioni305 – 341Interaction with GABBR1By similarityAdd BLAST37
Regioni306 – 334Leucine-zipperPROSITE-ProRule annotationAdd BLAST29

Coiled coil

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Coiled coili280 – 340Add BLAST61

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi215 – 224BetaTrCP degron motif10

Domaini

The BetaTrCP degron motif promotes binding to BTRC when phosphorylated.By similarity

Sequence similaritiesi

Belongs to the bZIP family.Curated

Keywords - Domaini

Coiled coil

Phylogenomic databases

eggNOGiKOG4571 Eukaryota
ENOG4111ZXT LUCA
GeneTreeiENSGT00530000063801
HOGENOMiHOG000004844
HOVERGENiHBG004301
InParanoidiP18848
KOiK04374
OMAiAFSGMDW
OrthoDBiEOG091G0FNW
PhylomeDBiP18848
TreeFamiTF316136

Family and domain databases

InterProiView protein in InterPro
IPR029811 ATF4
IPR004827 bZIP
PANTHERiPTHR13044:SF2 PTHR13044:SF2, 1 hit
PfamiView protein in Pfam
PF00170 bZIP_1, 1 hit
SMARTiView protein in SMART
SM00338 BRLZ, 1 hit
PROSITEiView protein in PROSITE
PS50217 BZIP, 1 hit
PS00036 BZIP_BASIC, 1 hit

Sequencei

Sequence statusi: Complete.

P18848-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MTEMSFLSSE VLVGDLMSPF DQSGLGAEES LGLLDDYLEV AKHFKPHGFS
60 70 80 90 100
SDKAKAGSSE WLAVDGLVSP SNNSKEDAFS GTDWMLEKMD LKEFDLDALL
110 120 130 140 150
GIDDLETMPD DLLTTLDDTC DLFAPLVQET NKQPPQTVNP IGHLPESLTK
160 170 180 190 200
PDQVAPFTFL QPLPLSPGVL SSTPDHSFSL ELGSEVDITE GDRKPDYTAY
210 220 230 240 250
VAMIPQCIKE EDTPSDNDSG ICMSPESYLG SPQHSPSTRG SPNRSLPSPG
260 270 280 290 300
VLCGSARPKP YDPPGEKMVA AKVKGEKLDK KLKKMEQNKT AATRYRQKKR
310 320 330 340 350
AEQEALTGEC KELEKKNEAL KERADSLAKE IQYLKDLIEE VRKARGKKRV

P
Length:351
Mass (Da):38,590
Last modified:October 17, 2006 - v3
Checksum:i3BBB7379DC3B0D07
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti284K → R no nucleotide entry (PubMed:2516827).Curated1
Sequence conflicti290T → R no nucleotide entry (PubMed:2516827).Curated1
Sequence conflicti329 – 331KEI → REK no nucleotide entry (PubMed:2516827).Curated3
Sequence conflicti338I → L no nucleotide entry (PubMed:2516827).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_02825322Q → P3 PublicationsCorresponds to variant dbSNP:rs4894Ensembl.1
Natural variantiVAR_029259258P → A. Corresponds to variant dbSNP:rs1803323Ensembl.1
Natural variantiVAR_014768322E → D. Corresponds to variant dbSNP:rs1803324Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D90209 mRNA Translation: BAA14234.1
M86842 mRNA Translation: AAA52071.1
CR456384 mRNA Translation: CAG30270.1
AL022312 Genomic DNA No translation available.
CH471095 Genomic DNA Translation: EAW60341.1
CH471095 Genomic DNA Translation: EAW60342.1
BC008090 mRNA Translation: AAH08090.1
BC011994 mRNA Translation: AAH11994.1
BC016855 mRNA Translation: AAH16855.1
BC022088 mRNA Translation: AAH22088.1
BC024775 mRNA Translation: AAH24775.1
BC044895 mRNA Translation: AAH44895.1
BC073754 mRNA Translation: AAH73754.1
BC073990 mRNA Translation: AAH73990.1
CCDSiCCDS13996.1
PIRiA45377
RefSeqiNP_001666.2, NM_001675.4
NP_877962.1, NM_182810.2
XP_016884296.1, XM_017028807.1
UniGeneiHs.496487

Genome annotation databases

EnsembliENST00000337304; ENSP00000336790; ENSG00000128272
ENST00000396680; ENSP00000379912; ENSG00000128272
ENST00000404241; ENSP00000384587; ENSG00000128272
GeneIDi468
KEGGihsa:468
UCSCiuc003axz.4 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Cross-referencesi

Web resourcesi

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D90209 mRNA Translation: BAA14234.1
M86842 mRNA Translation: AAA52071.1
CR456384 mRNA Translation: CAG30270.1
AL022312 Genomic DNA No translation available.
CH471095 Genomic DNA Translation: EAW60341.1
CH471095 Genomic DNA Translation: EAW60342.1
BC008090 mRNA Translation: AAH08090.1
BC011994 mRNA Translation: AAH11994.1
BC016855 mRNA Translation: AAH16855.1
BC022088 mRNA Translation: AAH22088.1
BC024775 mRNA Translation: AAH24775.1
BC044895 mRNA Translation: AAH44895.1
BC073754 mRNA Translation: AAH73754.1
BC073990 mRNA Translation: AAH73990.1
CCDSiCCDS13996.1
PIRiA45377
RefSeqiNP_001666.2, NM_001675.4
NP_877962.1, NM_182810.2
XP_016884296.1, XM_017028807.1
UniGeneiHs.496487

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1CI6X-ray2.60A280-341[»]
ProteinModelPortaliP18848
SMRiP18848
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi106958, 76 interactors
ComplexPortaliCPX-8 ATF4-CREB1 transcription factor complex
CPX-9 ATF1-ATF4 transcription factor complex
CORUMiP18848
DIPiDIP-354N
ELMiP18848
IntActiP18848, 59 interactors
MINTiP18848
STRINGi9606.ENSP00000336790

Chemistry databases

DrugBankiDB00852 Pseudoephedrine

PTM databases

iPTMnetiP18848
PhosphoSitePlusiP18848

Polymorphism and mutation databases

BioMutaiATF4
DMDMi116241262

Proteomic databases

EPDiP18848
PaxDbiP18848
PeptideAtlasiP18848
PRIDEiP18848
ProteomicsDBi53615

Protocols and materials databases

DNASUi468
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000337304; ENSP00000336790; ENSG00000128272
ENST00000396680; ENSP00000379912; ENSG00000128272
ENST00000404241; ENSP00000384587; ENSG00000128272
GeneIDi468
KEGGihsa:468
UCSCiuc003axz.4 human

Organism-specific databases

CTDi468
DisGeNETi468
EuPathDBiHostDB:ENSG00000128272.14
GeneCardsiATF4
HGNCiHGNC:786 ATF4
HPAiCAB011596
MIMi604064 gene
neXtProtiNX_P18848
OpenTargetsiENSG00000128272
PharmGKBiPA25086
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG4571 Eukaryota
ENOG4111ZXT LUCA
GeneTreeiENSGT00530000063801
HOGENOMiHOG000004844
HOVERGENiHBG004301
InParanoidiP18848
KOiK04374
OMAiAFSGMDW
OrthoDBiEOG091G0FNW
PhylomeDBiP18848
TreeFamiTF316136

Enzyme and pathway databases

ReactomeiR-HSA-380994 ATF4 activates genes
R-HSA-381042 PERK regulates gene expression
R-HSA-381183 ATF6 (ATF6-alpha) activates chaperone genes
SIGNORiP18848

Miscellaneous databases

ChiTaRSiATF4 human
EvolutionaryTraceiP18848
GeneWikiiATF4
GenomeRNAii468
PROiPR:P18848
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000128272 Expressed in 103 organ(s), highest expression level in lower esophagus
CleanExiHS_ATF4
GenevisibleiP18848 HS

Family and domain databases

InterProiView protein in InterPro
IPR029811 ATF4
IPR004827 bZIP
PANTHERiPTHR13044:SF2 PTHR13044:SF2, 1 hit
PfamiView protein in Pfam
PF00170 bZIP_1, 1 hit
SMARTiView protein in SMART
SM00338 BRLZ, 1 hit
PROSITEiView protein in PROSITE
PS50217 BZIP, 1 hit
PS00036 BZIP_BASIC, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiATF4_HUMAN
AccessioniPrimary (citable) accession number: P18848
Secondary accession number(s): Q96AQ3, Q9UH31
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1990
Last sequence update: October 17, 2006
Last modified: September 12, 2018
This is version 205 of the entry and version 3 of the sequence. See 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. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  2. SIMILARITY comments
    Index of protein domains and families
  3. Human chromosome 22
    Human chromosome 22: entries, gene names and cross-references to MIM
  4. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  5. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  6. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
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Main funding by: National Institutes of Health

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