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)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › 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. It binds to a Tax-responsive enhancer element in the long terminal repeat of HTLV-I. Ref.8
Subunit structure	Interaction with SATB2 results in enhanced DNA binding and transactivation by these transcription factors By similarity. Interacts with the C-terminal region of GABBR1 via the leucine zipper of its C-terminal bZIP domain. Interacts with the C-terminal region of GABBR2 By similarity. Binds DNA as a homo- or heterodimer. Interacts with the N-terminal region of CEP290. Forms a heterodimer with TXLNG in osteoblasts. Interacts with NEK6. Interacts with isoform 2 but not isoform 1 of DAPK2. Interacts with ZIPK/DAPK3. Ref.7 Ref.8 Ref.10 Ref.11
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.8 Ref.10
Post-translational modification	Phosphorylated by NEK6. Ref.9 Ref.10
Sequence similarities	Belongs to the bZIP family. Contains 1 bZIP 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	cellular amino acid metabolic process Traceable author statement. Source: UniProtKB gluconeogenesis Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of transcription from RNA polymerase II promoter Inferred from mutant phenotype. Source: UniProtKB response to endoplasmic reticulum stress Inferred from direct assay. Source: BHF-UCL transcription from RNA polymerase II promoter Inferred from sequence or structural similarity. Source: UniProtKB
Cellular component	microtubule organizing center Inferred from electronic annotation. Source: UniProtKB-SubCell plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	protein dimerization activity Inferred from electronic annotation. Source: InterPro sequence-specific DNA binding Inferred from electronic annotation. Source: InterPro sequence-specific DNA binding transcription factor activity Traceable author statement. 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

306 – 334

29

Leucine-zipper

DNA binding

280 – 300

21

Basic motif

Region

305 – 341

37

Interaction with GABBR1 By similarity

Coiled coil

280 – 340

61

Amino acid modifications

Modified residue

69

1

Phosphoserine Ref.9

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: 1847461] [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: 1534408] [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: 10591208] [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: 15489334] [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: 2516827] [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]	"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: 15911876] [Abstract] Cited for: INTERACTION WITH TXLNG.
[8]	"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: 16682973] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH CEP290.
[9]	"Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach." Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S. Anal. Chem. 81:4493-4501(2009) [PubMed: 19413330] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-69, MASS SPECTROMETRY. Tissue: Embryonic kidney.
[10]	"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: 20873783] [Abstract] Cited for: SUBCELLULAR LOCATION, INTERACTION WITH NEK6, PHOSPHORYLATION.
[11]	"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: 21408167] [Abstract] Cited for: INTERACTION WITH DAPK2 AND ZIPK/DAPK3.
[12]	"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: 11018027] [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.

SMR

P18848. Positions 286-341.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-207N.
DIP-354N.

IntAct

P18848. 22 interactions.

MINT

MINT-146610.

STRING

P18848.

PTM databases

PhosphoSite

P18848.

Polymorphism databases

DMDM

116241262.

Proteomic databases

PRIDE

P18848.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

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

GeneID

468.

KEGG

hsa:468.

UCSC

uc003axz.1. human.

Organism-specific databases

CTD

468.

GeneCards

GC22P039916.

H-InvDB

HIX0016494.

HGNC

HGNC:786. ATF4.

HPA

CAB011596.

MIM

604064. gene.

neXtProt

NX_P18848.

PharmGKB

PA25086.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG04260.

HOGENOM

HBG714302.

HOVERGEN

HBG004301.

InParanoid

P18848.

OMA

YLGSPQH.

OrthoDB

EOG47M1ZB.

PhylomeDB

P18848.

Enzyme and pathway databases

Reactome

REACT_15380. Diabetes pathways.

Gene expression databases

ArrayExpress

P18848.

Bgee

P18848.

CleanEx

HS_ATF4.

Genevestigator

P18848.

GermOnline

ENSG00000128272. Homo sapiens.

Family and domain databases

InterPro

IPR004827. bZIP.
IPR011616. bZIP_1.
[Graphical view]

KO

K04374.

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

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:	January 25, 2012
This is version 134 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.