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Protein

Cyclic AMP-dependent transcription factor ATF-4

Gene

Atf4

Organism
Mus musculus (Mouse)
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. Binds to asymmetric CRE's as a heterodimer and to palindromic CRE's as a homodimer. Cooperates with FOXO1 in osteoblasts to regulate glucose homeostasis through suppression of beta-cell production and decrease in insulin production. Regulates the induction of DDIT3/CHOP and asparagine synthetase (ASNS) in response to 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.7 Publications

GO - Molecular functioni

GO - Biological processi

  • cellular response to amino acid starvation Source: UniProtKB
  • cellular response to glucose starvation Source: MGI
  • circadian regulation of gene expression Source: UniProtKB
  • circadian rhythm Source: UniProtKB
  • gamma-aminobutyric acid signaling pathway Source: Ensembl
  • gluconeogenesis Source: MGI
  • intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress Source: UniProtKB
  • mRNA transcription from RNA polymerase II promoter Source: UniProtKB
  • negative regulation of oxidative stress-induced neuron death Source: MGI
  • negative regulation of potassium ion transport Source: Ensembl
  • PERK-mediated unfolded protein response Source: ParkinsonsUK-UCL
  • positive regulation of gene expression Source: ParkinsonsUK-UCL
  • positive regulation of neuron apoptotic process Source: UniProtKB
  • positive regulation of transcription, DNA-templated Source: UniProtKB
  • positive regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  • positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress Source: ParkinsonsUK-UCL
  • positive regulation of transcription from RNA polymerase II promoter in response to oxidative stress Source: MGI
  • positive regulation of transcription from RNA polymerase I promoter Source: MGI
  • positive regulation of vascular endothelial growth factor production Source: MGI
  • regulation of transcription, DNA-templated Source: UniProtKB
  • regulation of transcription from RNA polymerase II promoter Source: MGI
  • response to endoplasmic reticulum stress Source: UniProtKB
  • response to manganese-induced endoplasmic reticulum stress Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Activator

Keywords - Biological processi

Biological rhythms, Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding

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
C/EBP-related ATF
Short name:
C/ATF
Tax-responsive enhancer element-binding protein 67 homolog
Short name:
TaxREB67 homolog
Gene namesi
Name:Atf4
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 15

Organism-specific databases

MGIiMGI:88096. 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: MGI
  • cytoplasm Source: UniProtKB
  • dendrite membrane Source: Ensembl
  • Lewy body core Source: MGI
  • microtubule organizing center Source: UniProtKB-SubCell
  • neuron projection Source: MGI
  • nuclear periphery Source: MGI
  • nucleus Source: UniProtKB
  • transcription factor complex Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Cytoskeleton, Membrane, Nucleus

Pathology & Biotechi

Disruption phenotypei

Null mice exhibit an increase in serum insulin levels and low blood glucose levels. There is a decrease in total fat content, gonadal fat, lean mass and body weight. Serum levels of osteocalcin/BGLAP are decreased. PBK/AKT1-mediated phosphorylation of FOXO1 at 'Ser-258' is increased with a subsequent decrease of FOXO1-mediated transcriptional activity.1 Publication

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi212 – 2121T → A: Promotes stabilization due to impaired ubiquitination; when associated with A-223; A-230; A-234 and A-247. 1 Publication
Mutagenesisi218 – 2181S → A: Promotes stabilization due to impaired ubiquitination. 1 Publication
Mutagenesisi223 – 2231S → A: Promotes stabilization due to impaired ubiquitination; when associated with A-212; A-230; A-234 and A-247. 1 Publication
Mutagenesisi230 – 2301S → A: Promotes stabilization due to impaired ubiquitination; when associated with A-212; A-223; A-234 and A-247. 1 Publication
Mutagenesisi234 – 2341S → A: Promotes stabilization due to impaired ubiquitination; when associated with A-212; A-223; A-230 and A-247. 1 Publication
Mutagenesisi247 – 2471S → A: Promotes stabilization due to impaired ubiquitination; when associated with A-212; A-223; A-230 and A-234. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 349349Cyclic AMP-dependent transcription factor ATF-4PRO_0000076585Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei212 – 2121Phosphothreonine1 Publication
Modified residuei218 – 2181Phosphoserine1 Publication
Modified residuei223 – 2231Phosphoserine1 Publication
Modified residuei230 – 2301Phosphoserine1 Publication
Modified residuei234 – 2341Phosphoserine1 Publication
Modified residuei247 – 2471Phosphoserine1 Publication

Post-translational modificationi

Ubiquitinated by SCF(BTRC) in response to mTORC1 signal, followed by proteasomal degradation and leading to down-regulate expression of SIRT4.1 Publication
Phosphorylated by NEK6 (By similarity). Phosphorylated on the betaTrCP degron motif at Ser-218, followed by phosphorylation at Thr-212, Ser-223, Ser-230, Ser-234 and Ser-247, promoting interaction with BTRC and ubiquitination. Phosphorylation is promoted by mTORC1.By similarity1 Publication

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ06507.
PRIDEiQ06507.

PTM databases

iPTMnetiQ06507.
PhosphoSiteiQ06507.

Expressioni

Developmental stagei

At E16.5, expressed in osteoblasts surrounding newly formed trabecular bone. At postnatal day 2, detected in most osteoblasts and lining cells. By postnatal week 4, is detected in fewer osteoblasts, but remains present in lining cells (at protein level).1 Publication

Inductioni

By ER stress. Expressed in a circadian manner in the liver with an increased expression seen during the light phase. Expressed in a circadian manner in the midbrain with an increased expression seen during the dark phase (at protein level). Expressed in a circadian manner also in the suprachiasmatic nucleus (SCN) of the brain, cerebral cortex, kidney and small intestine.3 Publications

Gene expression databases

BgeeiENSMUSG00000042406.
CleanExiMM_ATF4.
GenevisibleiQ06507. MM.

Interactioni

Subunit structurei

Binds DNA as a homodimer and as a heterodimer (By similarity). Interacts with CEBPB and binds DNA as a heterodimer with CEBPB (PubMed:11018027). Interacts with CEP290 (via an N-terminal region). Interacts with NEK6, DAPK2 (isoform 2) and ZIPK/DAPK3. Interacts (via its leucine zipper domain) with GABBR1 and GABBR2 (via their C-termini) (By similarity). Forms a heterodimer with TXLNG in osteoblasts (PubMed:15911876). 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 (PubMed:22298775). Interacts with SATB2; the interaction results in enhanced DNA binding and transactivation by these transcription factors (PubMed:16751105). Interacts with DDIT3/CHOP (By similarity). Interacts with FAM175B (PubMed:22974638).By similarity5 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Dapk3O547843EBI-77383,EBI-77359
Trib3Q8K4K23EBI-77383,EBI-448962

GO - Molecular functioni

Protein-protein interaction databases

BioGridi198235. 11 interactions.
DIPiDIP-30969N.
IntActiQ06507. 6 interactions.
STRINGi10090.ENSMUSP00000105234.

Structurei

3D structure databases

ProteinModelPortaliQ06507.
SMRiQ06507. Positions 284-339.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini276 – 33964bZIPPROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni278 – 29821Basic motifPROSITE-ProRule annotationAdd
BLAST
Regioni303 – 33937Interaction with GABBR1By similarityAdd
BLAST
Regioni304 – 33229Leucine-zipperPROSITE-ProRule annotationAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi214 – 22310BetaTrCP degron motif

Domaini

The BetaTrCP degron motif promotes binding to BTRC when phosphorylated.1 Publication

Sequence similaritiesi

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

Phylogenomic databases

eggNOGiKOG4571. Eukaryota.
ENOG4111ZXT. LUCA.
GeneTreeiENSGT00530000063801.
HOVERGENiHBG004301.
InParanoidiQ06507.
KOiK04374.
OMAiAFSGMDW.
OrthoDBiEOG091G0FNW.
TreeFamiTF316136.

Family and domain databases

InterProiIPR029811. ATF4.
IPR004827. bZIP.
[Graphical view]
PANTHERiPTHR13044:SF2. PTHR13044:SF2. 1 hit.
PfamiPF00170. bZIP_1. 1 hit.
[Graphical view]
SMARTiSM00338. BRLZ. 1 hit.
[Graphical view]
PROSITEiPS50217. BZIP. 1 hit.
PS00036. BZIP_BASIC. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q06507-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MTEMSFLNSE VLAGDLMSPF DQSGLGAEES LGLLDDYLEV AKHLKPHGFS
60 70 80 90 100
SDKAGSSEWP AMDDGLASAS DTGKEDAFSG TDWMLEKMDL KEFDFDALFR
110 120 130 140 150
MDDLETMPDE LLTTLDDTCD LFAPLVQETN KEPPQTVNPI GHLPESLIKV
160 170 180 190 200
DQVAPFTFLQ PFPCSPGVLS STPEHSFSLE LGSEVDISEG DRKPDSAAYI
210 220 230 240 250
TLIPPCVKEE DTPSDNDSGI CMSPESYLGS PQHSPSTSRA PPDNLPSPGG
260 270 280 290 300
SRGSPRPKPY DPPGVSLTAK VKTEKLDKKL KKMEQNKTAA TRYRQKKRAE
310 320 330 340
QEALTGECKE LEKKNEALKE KADSLAKEIQ YLKDLIEEVR KARGKKRVP
Length:349
Mass (Da):38,355
Last modified:July 27, 2011 - v2
Checksum:i0C3F895755B1C7B9
GO

Sequence cautioni

The sequence AAA53043 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti345 – 3451K → Q in AAA40476 (PubMed:8506317).Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L13791 mRNA. Translation: AAA40476.1.
M94087 mRNA. Translation: AAA53043.1. Different initiation.
AK138657 mRNA. Translation: BAE23736.1.
AK144777 mRNA. Translation: BAE26060.1.
AK146193 mRNA. Translation: BAE26967.1.
AK156298 mRNA. Translation: BAE33662.1.
CH466550 Genomic DNA. Translation: EDL04604.1.
CH466550 Genomic DNA. Translation: EDL04605.1.
BC085169 mRNA. Translation: AAH85169.1.
CCDSiCCDS37145.1.
RefSeqiNP_001274109.1. NM_001287180.1.
NP_033846.2. NM_009716.3.
UniGeneiMm.641.

Genome annotation databases

EnsembliENSMUST00000109605; ENSMUSP00000105234; ENSMUSG00000042406.
GeneIDi11911.
KEGGimmu:11911.
UCSCiuc007wvl.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L13791 mRNA. Translation: AAA40476.1.
M94087 mRNA. Translation: AAA53043.1. Different initiation.
AK138657 mRNA. Translation: BAE23736.1.
AK144777 mRNA. Translation: BAE26060.1.
AK146193 mRNA. Translation: BAE26967.1.
AK156298 mRNA. Translation: BAE33662.1.
CH466550 Genomic DNA. Translation: EDL04604.1.
CH466550 Genomic DNA. Translation: EDL04605.1.
BC085169 mRNA. Translation: AAH85169.1.
CCDSiCCDS37145.1.
RefSeqiNP_001274109.1. NM_001287180.1.
NP_033846.2. NM_009716.3.
UniGeneiMm.641.

3D structure databases

ProteinModelPortaliQ06507.
SMRiQ06507. Positions 284-339.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi198235. 11 interactions.
DIPiDIP-30969N.
IntActiQ06507. 6 interactions.
STRINGi10090.ENSMUSP00000105234.

PTM databases

iPTMnetiQ06507.
PhosphoSiteiQ06507.

Proteomic databases

PaxDbiQ06507.
PRIDEiQ06507.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000109605; ENSMUSP00000105234; ENSMUSG00000042406.
GeneIDi11911.
KEGGimmu:11911.
UCSCiuc007wvl.2. mouse.

Organism-specific databases

CTDi468.
MGIiMGI:88096. Atf4.

Phylogenomic databases

eggNOGiKOG4571. Eukaryota.
ENOG4111ZXT. LUCA.
GeneTreeiENSGT00530000063801.
HOVERGENiHBG004301.
InParanoidiQ06507.
KOiK04374.
OMAiAFSGMDW.
OrthoDBiEOG091G0FNW.
TreeFamiTF316136.

Miscellaneous databases

ChiTaRSiAtf4. mouse.
PROiQ06507.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000042406.
CleanExiMM_ATF4.
GenevisibleiQ06507. MM.

Family and domain databases

InterProiIPR029811. ATF4.
IPR004827. bZIP.
[Graphical view]
PANTHERiPTHR13044:SF2. PTHR13044:SF2. 1 hit.
PfamiPF00170. bZIP_1. 1 hit.
[Graphical view]
SMARTiSM00338. BRLZ. 1 hit.
[Graphical view]
PROSITEiPS50217. BZIP. 1 hit.
PS00036. BZIP_BASIC. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiATF4_MOUSE
AccessioniPrimary (citable) accession number: Q06507
Secondary accession number(s): Q5U4B2, Q61906
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 1, 1996
Last sequence update: July 27, 2011
Last modified: September 7, 2016
This is version 128 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. 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.