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Protein

Cyclic AMP-dependent transcription factor ATF-4

Gene

ATF4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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

HGNCiHGNC:786. ATF4.

Subcellular locationi

GO - Cellular componenti

  • ATF1-ATF4 transcription factor complex Source: ParkinsonsUK-UCL
  • ATF4-CREB1 transcription factor complex Source: ParkinsonsUK-UCL
  • CHOP-ATF4 complex Source: ParkinsonsUK-UCL
  • cytoplasm Source: ParkinsonsUK-UCL
  • dendrite membrane Source: Ensembl
  • Lewy body core Source: ParkinsonsUK-UCL
  • microtubule organizing center Source: UniProtKB-SubCell
  • neuron projection Source: ParkinsonsUK-UCL
  • nuclear periphery Source: ParkinsonsUK-UCL
  • nucleoplasm Source: Reactome
  • nucleus Source: ParkinsonsUK-UCL

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
Modified residuei213PhosphothreonineBy similarity1
Modified residuei219PhosphoserineBy similarity1
Modified residuei224PhosphoserineBy similarity1
Modified residuei231PhosphoserineBy similarity1
Modified residuei235PhosphoserineBy similarity1
Modified residuei248PhosphoserineBy similarity1
Cross-linki267Glycyl 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.

PTM databases

iPTMnetiP18848.
PhosphoSitePlusiP18848.

Expressioni

Gene expression databases

BgeeiENSG00000128272.
CleanExiHS_ATF4.
ExpressionAtlasiP18848. baseline and differential.
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

Show more details

GO - Molecular functioni

  • leucine zipper domain binding Source: ParkinsonsUK-UCL
  • protein C-terminus binding Source: Ensembl
  • protein heterodimerization activity Source: ParkinsonsUK-UCL
  • RNA polymerase II transcription factor binding Source: ParkinsonsUK-UCL

Protein-protein interaction databases

BioGridi106958. 75 interactors.
DIPiDIP-354N.
IntActiP18848. 54 interactors.
MINTiMINT-146610.
STRINGi9606.ENSP00000336790.

Structurei

Secondary structure

1351
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi288 – 340Combined sources53

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...

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:SF22. PTHR13044:SF22. 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.

Keywords - Coding sequence diversityi

Polymorphism

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.

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: July 5, 2017
This is version 192 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. Human chromosome 22
    Human chromosome 22: 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