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P18848 (ATF4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 155. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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 names
Name:ATF4
Synonyms:CREB2, TXREB
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length351 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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 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. Ref.7 Ref.9 Ref.10

Subunit structure

Binds DNA as a homo- or heterodimer. 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). Interacts with NEK6, DAPK2 (isoform 2)and ZIPK/DAPK3. Forms a heterodimer with TXLNG in osteoblasts. Interacts with DDIT3/CHOP. Ref.8 Ref.9 Ref.10 Ref.11 Ref.13

Subcellular location

Cytoplasm. Cell membrane. Nucleus. Cytoplasmcytoskeletonmicrotubule organizing centercentrosome. Note: Colocalizes with GABBR1 in hippocampal neuron dendritic membranes By similarity. Co- localizes with NEK6 in the centrosome. Ref.9 Ref.11

Domain

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

Post-translational modification

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. Ref.11

Phosphorylated by NEK6. Ref.11

Sequence similarities

Belongs to the bZIP family.

Contains 1 bZIP (basic-leucine zipper) domain.

Ontologies

Keywords
   Biological processTranscription
Transcription regulation
   Cellular componentCell membrane
Cytoplasm
Cytoskeleton
Membrane
Nucleus
   Coding sequence diversityPolymorphism
   DomainCoiled coil
   LigandDNA-binding
   Molecular functionActivator
   PTMLipoprotein
Phosphoprotein
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processactivation of signaling protein activity involved in unfolded protein response

Traceable author statement. Source: Reactome

cellular amino acid metabolic process

Traceable author statement PubMed 12689582. Source: UniProtKB

cellular protein metabolic process

Traceable author statement. Source: Reactome

endoplasmic reticulum unfolded protein response

Traceable author statement. Source: Reactome

gamma-aminobutyric acid signaling pathway

Inferred from electronic annotation. Source: Ensembl

gluconeogenesis

Inferred from sequence or structural similarity. Source: UniProtKB

intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of potassium ion transport

Inferred from electronic annotation. Source: Ensembl

positive regulation of neuron apoptotic process

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of transcription from RNA polymerase II promoter

Inferred from mutant phenotype PubMed 15788408. Source: UniProtKB

positive regulation of transcription, DNA-templated

Inferred from direct assay Ref.7Ref.10. Source: UniProtKB

regulation of transcription, DNA-templated

Inferred from sequence or structural similarity. Source: UniProtKB

response to endoplasmic reticulum stress

Inferred from direct assay PubMed 19061639. Source: BHF-UCL

transcription from RNA polymerase II promoter

Inferred from sequence or structural similarity. Source: UniProtKB

   Cellular_componentcytoplasm

Inferred from sequence or structural similarity. Source: UniProtKB

dendrite membrane

Inferred from electronic annotation. Source: Ensembl

microtubule organizing center

Inferred from electronic annotation. Source: UniProtKB-SubCell

nucleoplasm

Traceable author statement. Source: Reactome

nucleus

Inferred from sequence or structural similarity. Source: UniProtKB

transcription factor complex

Inferred from electronic annotation. Source: Ensembl

   Molecular_functionDNA binding

Inferred from direct assay PubMed 15788408Ref.10. Source: UniProtKB

sequence-specific DNA binding

Inferred from electronic annotation. Source: InterPro

sequence-specific DNA binding transcription factor activity

Inferred from sequence or structural similarity. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 351351Cyclic AMP-dependent transcription factor ATF-4
PRO_0000076584

Regions

Domain278 – 34164bZIP
Region280 – 30021Basic motif By similarity
Region305 – 34137Interaction with GABBR1 By similarity
Region306 – 33429Leucine-zipper By similarity
Coiled coil280 – 34061
Motif215 – 22410BetaTrCP degron motif

Amino acid modifications

Modified residue2131Phosphothreonine By similarity
Modified residue2191Phosphoserine By similarity
Modified residue2241Phosphoserine By similarity
Modified residue2311Phosphoserine By similarity
Modified residue2351Phosphoserine By similarity
Modified residue2481Phosphoserine By similarity

Natural variations

Natural variant221Q → P. Ref.1 Ref.2 Ref.4
Corresponds to variant rs4894 [ dbSNP | Ensembl ].
VAR_028253
Natural variant2581P → A.
Corresponds to variant rs1803323 [ dbSNP | Ensembl ].
VAR_029259
Natural variant3221E → D.
Corresponds to variant rs1803324 [ dbSNP | Ensembl ].
VAR_014768

Experimental info

Sequence conflict2841K → R no nucleotide entry Ref.5
Sequence conflict2901T → R no nucleotide entry Ref.5
Sequence conflict329 – 3313KEI → REK no nucleotide entry Ref.5
Sequence conflict3381I → L no nucleotide entry Ref.5

Secondary structure

... 351
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P18848 [UniParc].

Last modified October 17, 2006. Version 3.
Checksum: 3BBB7379DC3B0D07

FASTA35138,590
        10         20         30         40         50         60 
MTEMSFLSSE VLVGDLMSPF DQSGLGAEES LGLLDDYLEV AKHFKPHGFS SDKAKAGSSE 

        70         80         90        100        110        120 
WLAVDGLVSP SNNSKEDAFS GTDWMLEKMD LKEFDLDALL GIDDLETMPD DLLTTLDDTC 

       130        140        150        160        170        180 
DLFAPLVQET NKQPPQTVNP IGHLPESLTK PDQVAPFTFL QPLPLSPGVL SSTPDHSFSL 

       190        200        210        220        230        240 
ELGSEVDITE GDRKPDYTAY VAMIPQCIKE EDTPSDNDSG ICMSPESYLG SPQHSPSTRG 

       250        260        270        280        290        300 
SPNRSLPSPG VLCGSARPKP YDPPGEKMVA AKVKGEKLDK KLKKMEQNKT AATRYRQKKR 

       310        320        330        340        350 
AEQEALTGEC KELEKKNEAL KERADSLAKE IQYLKDLIEE VRKARGKKRV P 

« Hide

References

« Hide 'large scale' references
[1]"Isolation of cDNAs for DNA-binding proteins which specifically bind to a tax-responsive enhancer element in the long terminal repeat of human T-cell leukemia virus type I."
Tsujimoto A., Nyunoya H., Morita T., Sato T., Shimotohno K.
J. Virol. 65:1420-1426(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT PRO-22.
Tissue: Fibroblast.
[2]"Molecular cloning of human CREB-2: an ATF/CREB transcription factor that can negatively regulate transcription from the cAMP response element."
Karpinski B.A., Morle G.D., Huggenvik J., Uhler M.D., Leiden J.M.
Proc. Natl. Acad. Sci. U.S.A. 89:4820-4824(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT PRO-22.
Tissue: Leukemic T-cell.
[3]"The DNA sequence of human chromosome 22."
Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M., Clamp M., Smink L.J., Ainscough R., Almeida J.P., Babbage A.K., Bagguley C., Bailey J., Barlow K.F., Bates K.N., Beasley O.P., Bird C.P., Blakey S.E., Bridgeman A.M. expand/collapse author list , Buck D., Burgess J., Burrill W.D., Burton J., Carder C., Carter N.P., Chen Y., Clark G., Clegg S.M., Cobley V.E., Cole C.G., Collier R.E., Connor R., Conroy D., Corby N.R., Coville G.J., Cox A.V., Davis J., Dawson E., Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M., Ellington A.G., Evans K.L., Fey J.M., Fleming K., French L., Garner A.A., Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C., Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S., Hunt S.E., Jones M.C., Kershaw J., Kimberley A.M., King A., Laird G.K., Langford C.F., Leversha M.A., Lloyd C., Lloyd D.M., Martyn I.D., Mashreghi-Mohammadi M., Matthews L.H., Mccann O.T., Mcclay J., Mclaren S., McMurray A.A., Milne S.A., Mortimore B.J., Odell C.N., Pavitt R., Pearce A.V., Pearson D., Phillimore B.J.C.T., Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y., Rogers L., Ross M.T., Scott C.E., Sehra H.K., Skuce C.D., Smalley S., Smith M.L., Soderlund C., Spragon L., Steward C.A., Sulston J.E., Swann R.M., Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L., Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L., Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N., Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J., Shintani A., Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S., Roe B.A., Chen F., Chu L., Crabtree J., Deschamps S., Do A., Do T., Dorman A., Fang F., Fu Y., Hu P., Hua A., Kenton S., Lai H., Lao H.I., Lewis J., Lewis S., Lin S.-P., Loh P., Malaj E., Nguyen T., Pan H., Phan S., Qi S., Qian Y., Ray L., Ren Q., Shaull S., Sloan D., Song L., Wang Q., Wang Y., Wang Z., White J., Willingham D., Wu H., Yao Z., Zhan M., Zhang G., Chissoe S., Murray J., Miller N., Minx P., Fulton R., Johnson D., Bemis G., Bentley D., Bradshaw H., Bourne S., Cordes M., Du Z., Fulton L., Goela D., Graves T., Hawkins J., Hinds K., Kemp K., Latreille P., Layman D., Ozersky P., Rohlfing T., Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K., Nelson J., Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R., Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S., Budarf M.L., McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E., Edelmann L., Kim U.J., Shizuya H., Simon M.I., Dumanski J.P., Peyrard M., Kedra D., Seroussi E., Fransson I., Tapia I., Bruder C.E., O'Brien K.P., Wilkinson P., Bodenteich A., Hartman K., Hu X., Khan A.S., Lane L., Tilahun Y., Wright H.
Nature 402:489-495(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT PRO-22.
Tissue: Lung and Placenta.
[5]"Transcription factor ATF cDNA clones: an extensive family of leucine zipper proteins able to selectively form DNA-binding heterodimers."
Hai T., Liu F., Coukos W.J., Green M.R.
Genes Dev. 3:2083-2090(1989) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 274-341.
[6]Erratum
Hai T., Liu F., Coukos W.J., Green M.R.
Genes Dev. 4:682-682(1990)
[7]"TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death."
Ohoka N., Yoshii S., Hattori T., Onozaki K., Hayashi H.
EMBO J. 24:1243-1255(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[8]"FIAT represses ATF4-mediated transcription to regulate bone mass in transgenic mice."
Yu V.W., Ambartsoumian G., Verlinden L., Moir J.M., Prud'homme J., Gauthier C., Roughley P.J., St-Arnaud R.
J. Cell Biol. 169:591-601(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TXLNG.
[9]"The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4."
Sayer J.A., Otto E.A., O'toole J.F., Nurnberg G., Kennedy M.A., Becker C., Hennies H.C., Helou J., Attanasio M., Fausett B.V., Utsch B., Khanna H., Liu Y., Drummond I., Kawakami I., Kusakabe T., Tsuda M., Ma L. expand/collapse author list , Lee H., Larson R.G., Allen S.J., Wilkinson C.J., Nigg E.A., Shou C., Lillo C., Williams D.S., Hoppe B., Kemper M.J., Neuhaus T., Parisi M.A., Glass I.A., Petry M., Kispert A., Gloy J., Ganner A., Walz G., Zhu X., Goldman D., Nurnberg P., Swaroop A., Leroux M.R., Hildebrandt F.
Nat. Genet. 38:674-681(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH CEP290.
[10]"C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene."
Su N., Kilberg M.S.
J. Biol. Chem. 283:35106-35117(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH DDIT3.
[11]"Characterization of hNek6 interactome reveals an important role for its short N-terminal domain and colocalization with proteins at the centrosome."
Vaz Meirelles G., Ferreira Lanza D.C., da Silva J.C., Santana Bernachi J., Paes Leme A.F., Kobarg J.
J. Proteome Res. 9:6298-6316(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, INTERACTION WITH NEK6, PHOSPHORYLATION.
[12]"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis."
Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.
Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[13]"New modularity of DAP-kinases: alternative splicing of the DRP-1 gene produces a ZIPk-like isoform."
Shoval Y., Berissi H., Kimchi A., Pietrokovski S.
PLoS ONE 6:E17344-E17344(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH DAPK2 AND ZIPK/DAPK3.
[14]"Crystal structure of the CCAAT box/enhancer-binding protein beta activating transcription factor-4 basic leucine zipper heterodimer in the absence of DNA."
Podust L.M., Krezel A.M., Kim Y.
J. Biol. Chem. 276:505-513(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 279-341 IN COMPLEX WITH MOUSE CEBPB.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
D90209 mRNA. Translation: BAA14234.1.
M86842 mRNA. Translation: AAA52071.1.
AL022312 Genomic DNA. Translation: CAB45284.1.
BC008090 mRNA. Translation: AAH08090.1.
BC011994 mRNA. Translation: AAH11994.1.
BC024775 mRNA. Translation: AAH24775.1.
BC073990 mRNA. Translation: AAH73990.1.
PIRA45377.
RefSeqNP_001666.2. NM_001675.4.
NP_877962.1. NM_182810.2.
UniGeneHs.496487.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1CI6X-ray2.60A280-341[»]
ProteinModelPortalP18848.
SMRP18848. Positions 286-341.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid106958. 66 interactions.
DIPDIP-207N.
DIP-354N.
IntActP18848. 23 interactions.
MINTMINT-146610.
STRING9606.ENSP00000336790.

PTM databases

PhosphoSiteP18848.

Polymorphism databases

DMDM116241262.

Proteomic databases

PaxDbP18848.
PRIDEP18848.

Protocols and materials databases

DNASU468.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000337304; ENSP00000336790; ENSG00000128272.
ENST00000396680; ENSP00000379912; ENSG00000128272.
ENST00000404241; ENSP00000384587; ENSG00000128272.
GeneID468.
KEGGhsa:468.
UCSCuc003axz.3. human.

Organism-specific databases

CTD468.
GeneCardsGC22P039916.
HGNCHGNC:786. ATF4.
HPACAB011596.
HPA036934.
MIM604064. gene.
neXtProtNX_P18848.
PharmGKBPA25086.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG325856.
HOGENOMHOG000004844.
HOVERGENHBG004301.
InParanoidP18848.
KOK04374.
OMAGECRELE.
OrthoDBEOG72JWGW.
PhylomeDBP18848.
TreeFamTF316136.

Enzyme and pathway databases

ReactomeREACT_17015. Metabolism of proteins.

Gene expression databases

BgeeP18848.
CleanExHS_ATF4.
GenevestigatorP18848.

Family and domain databases

InterProIPR004827. bZIP.
[Graphical view]
PfamPF00170. bZIP_1. 1 hit.
[Graphical view]
SMARTSM00338. BRLZ. 1 hit.
[Graphical view]
PROSITEPS50217. BZIP. 1 hit.
PS00036. BZIP_BASIC. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSATF4. human.
EvolutionaryTraceP18848.
GeneWikiATF4.
GenomeRNAi468.
NextBio1935.
PROP18848.
SOURCESearch...

Entry information

Entry nameATF4_HUMAN
AccessionPrimary (citable) accession number: P18848
Secondary accession number(s): Q9UH31
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1990
Last sequence update: October 17, 2006
Last modified: April 16, 2014
This is version 155 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 22

Human chromosome 22: entries, gene names and cross-references to MIM