P18848 (ATF4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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 names

Name:	ATF4
Synonyms:	CREB2, TXREB

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	351 AA.
Sequence status	Complete.
Protein existence	Evidence 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. 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. Cytoplasm › cytoskeleton › centrosome. Note: Colocalizes with GABBR1 in hippocampal neuron dendritic membranes By similarity. Co-localizes with NEK6 in the centrosome. Ref.9 Ref.11
Post-translational modification	Phosphorylated by NEK6. Ref.11
Sequence similarities	Belongs to the bZIP family. Contains 1 bZIP (basic-leucine zipper) domain.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Cell membrane Cytoplasm Cytoskeleton Membrane Nucleus
Coding sequence diversity	Polymorphism
Domain	Coiled coil
Ligand	DNA-binding
Molecular function	Activator
PTM	Lipoprotein Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	activation 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 gamma-aminobutyric acid signaling pathway Inferred from electronic annotation. Source: Compara 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: Compara 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 transcription from RNA polymerase II promoter Inferred from sequence or structural similarity. Source: UniProtKB
Cellular_component	cytoplasm Inferred from sequence or structural similarity. Source: UniProtKB dendrite membrane Inferred from electronic annotation. Source: Compara microtubule organizing center Inferred from electronic annotation. Source: UniProtKB-SubCell nucleoplasm Traceable author statement. Source: Reactome transcription factor complex Inferred from electronic annotation. Source: Compara
Molecular_function	DNA 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 Traceable author statement PubMed 12689582. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
DISC1	Q9NRI5	3	EBI-492498,EBI-529989
TRIB3	Q96RU7	2	EBI-492498,EBI-492476

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 351

351

Cyclic AMP-dependent transcription factor ATF-4

PRO_0000076584

Regions

Domain

278 – 341

64

bZIP

Region

280 – 300

21

Basic motif By similarity

Region

305 – 341

37

Interaction with GABBR1 By similarity

Region

306 – 334

29

Leucine-zipper By similarity

Coiled coil

280 – 340

61

Natural variations

Natural variant

22

1

Q → P. Ref.1 Ref.2 Ref.4
Corresponds to variant rs4894 [ dbSNP | Ensembl ].

VAR_028253

Natural variant

258

1

P → A.
Corresponds to variant rs1803323 [ dbSNP | Ensembl ].

VAR_029259

Natural variant

322

1

E → D.
Corresponds to variant rs1803324 [ dbSNP | Ensembl ].

VAR_014768

Experimental info

Sequence conflict

284

1

K → R no nucleotide entry Ref.5

Sequence conflict

290

1

T → R no nucleotide entry Ref.5

Sequence conflict

329 – 331

3

KEI → REK no nucleotide entry Ref.5

Sequence conflict

338

1

I → L no nucleotide entry Ref.5

Secondary structure

1

.

.

.

351

Helix Strand Turn

Details...

Helix

288 – 340

53

Sequences

	Sequence		Length	Mass (Da)
	P18848 [UniParc]. Last modified October 17, 2006. Version 3. Checksum: 3BBB7379DC3B0D07	FASTA	351	38,590
	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

References

	« Hide 'large scale' referencesShow '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. , 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. , 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.

IPI

IPI00002503.

PIR

A45377.

RefSeq

NP_001666.2. NM_001675.2.
NP_877962.1. NM_182810.1.

UniGene

Hs.496487.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1CI6	X-ray	2.60	A	280-341	[»]

ProteinModelPortal

P18848.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-207N.
DIP-354N.

IntAct

P18848. 22 interactions.

MINT

MINT-146610.

STRING

9606.ENSP00000336790.

PTM databases

PhosphoSite

P18848.

Polymorphism databases

DMDM

116241262.

Proteomic databases

PaxDb

P18848.

PRIDE

P18848.

Protocols and materials databases

DNASU

468.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000337304; ENSP00000336790; ENSG00000128272.
ENST00000396680; ENSP00000379912; ENSG00000128272.
ENST00000404241; ENSP00000384587; ENSG00000128272.

GeneID

468.

KEGG

hsa:468.

UCSC

uc003axz.3. human.

Organism-specific databases

CTD

468.

GeneCards

GC22P039916.

HGNC

HGNC:786. ATF4.

HPA

CAB011596.

MIM

604064. gene.

neXtProt

NX_P18848.

PharmGKB

PA25086.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG325856.

HOGENOM

HOG000004844.

HOVERGEN

HBG004301.

InParanoid

P18848.

KO

K04374.

OMA

QCIKEED.

OrthoDB

EOG47M1ZB.

PhylomeDB

P18848.

Enzyme and pathway databases

Reactome

REACT_116125. Disease.

Gene expression databases

ArrayExpress

P18848.

Bgee

P18848.

CleanEx

HS_ATF4.

Genevestigator

P18848.

GermOnline

ENSG00000128272. Homo sapiens.

Family and domain databases

InterPro

IPR004827. bZIP.
[Graphical view]

Pfam

PF00170. bZIP_1. 1 hit.
[Graphical view]

SMART

SM00338. BRLZ. 1 hit.
[Graphical view]

PROSITE

PS50217. BZIP. 1 hit.
PS00036. BZIP_BASIC. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

ATF4. human.

EvolutionaryTrace

P18848.

GenomeRNAi

468.

NextBio

1935.

SOURCE

Search...

Entry information

Entry name

ATF4_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 147 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.