P15337 (CREB1_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Cyclic AMP-responsive element-binding protein 1
Short name=CREB-1
Short name=cAMP-responsive element-binding protein 1

Gene names

Name:	Creb1
Synonyms:	Creb-1

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	341 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Phosphorylation-dependent transcription factor that stimulates transcription upon binding to the DNA cAMP response element (CRE), a sequence present in many viral and cellular promoters. Transcription activation is enhanced by the TORC coactivators which act independently of Ser-117 phosphorylation. Involved in different cellular processes including the synchronization of circadian rhythmicity and the differentiation of adipose cells By similarity.
Subunit structure	Interacts with PPRC1. Binds DNA as a dimer. Interacts, through the bZIP domain, with the coactivators TORC1/CRTC1, TORC2/CRTC2 and TORC3/CRTC3 By similarity. When phosphorylated on Ser-133, binds CREBBP. Interacts with ARRB1. Interacts (phosphorylated form) with TOX3. Binds to HIPK2 By similarity. Interacts with SGK1 By similarity. Interacts with CREBL2; regulates CREB1 phosphorylation, stability and transcriptional activity By similarity.
Subcellular location	Nucleus.
Post-translational modification	Phosphorylation of Ser-133 allows CREBBP binding. Stimulated by phosphorylation. Phosphorylation of both Ser-142 and Ser-133 in the SCN regulates the activity of CREB and participate in circadian rhythm generation By similarity. Phosphorylated upon calcium influx by CaMK4 and CaMK2 on Ser-133. CaMK4 is much more potent than CaMK2 in activating CREB. Phosphorylated by CaMK2 on Ser-142. Phosphorylation of Ser-142 blocks CREB-mediated transcription even when Ser-133 is phosphorylated. Phosphorylated by CaMK1. Phosphorylation of Ser-271 by HIPK2 in response to genotoxic stress promotes CREB1 activity, facilitating the recruitment of the coactivator CBP. Phosphorylated at Ser-133 by RPS6KA3, RPS6KA4 and RPS6KA5 in response to mitogenic or stress stimuli By similarity. CREBL2 positively regulates phosphorylation at Ser-133 thereby stimulating CREB1 transcriptional activity By similarity. Ref.3 Ref.4 Ref.5 Sumoylated with SUMO1. Sumoylation on Lys-304, but not on Lys-285, is required for nuclear localization of this protein. Sumoylation is enhanced under hypoxia, promoting nuclear localization and stabilization By similarity.
Sequence similarities	Belongs to the bZIP family. Contains 1 bZIP (basic-leucine zipper) domain. Contains 1 KID (kinase-inducible) domain.

Ontologies

Keywords
Biological process	Differentiation Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Alternative splicing
Ligand	DNA-binding
Molecular function	Activator
PTM	Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	cell differentiation Inferred from electronic annotation. Source: UniProtKB-KW positive regulation of RNA polymerase II transcriptional preinitiation complex assembly Inferred from mutant phenotype PubMed 16891311. Source: RGD positive regulation of fat cell differentiation Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of lipid biosynthetic process Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of transforming growth factor beta3 production Inferred from mutant phenotype PubMed 16891311. Source: RGD protein stabilization Inferred from sequence or structural similarity. Source: UniProtKB regulation of apoptotic process Inferred from direct assay PubMed 12939230. Source: RGD regulation of circadian rhythm Inferred from mutant phenotype PubMed 12409294. Source: RGD transforming growth factor beta receptor signaling pathway Inferred from mutant phenotype PubMed 16891311. Source: RGD
Cellular_component	mitochondrion Inferred from direct assay PubMed 15663486. Source: RGD nuclear chromatin Inferred from direct assay PubMed 16427017. Source: BHF-UCL transcription factor complex Inferred from direct assay PubMed 15632413. Source: RGD
Molecular_function	RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity Inferred from direct assay PubMed 12409294. Source: RGD double-stranded DNA binding Inferred from direct assay PubMed 12697699. Source: RGD sequence-specific DNA binding Inferred from direct assay PubMed 12697699PubMed 15632413PubMed 16891311PubMed 16959941. Source: RGD
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P15337-1)

Also known as: Alpha;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P15337-2)

Also known as: Delta;

The sequence of this isoform differs from the canonical sequence as follows:
     88-101: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 341

341

Cyclic AMP-responsive element-binding protein 1

PRO_0000076599

Regions

Domain

101 – 160

60

KID

Domain

283 – 341

59

bZIP

Region

284 – 309

26

Basic motif By similarity

Region

311 – 332

22

Leucine-zipper By similarity

Amino acid modifications

Modified residue

133

1

Phosphoserine; by CaMK1, CaMK2, CaMK4, PKB/AKT1 or PKB/AKT2, RPS6KA3, RPS6KA4, RPS6KA5 and SGK1 Ref.3 Ref.4 Ref.5

Modified residue

142

1

Phosphoserine; by CaMK2 Ref.4

Modified residue

271

1

Phosphoserine; by HIPK2 By similarity

Cross-link

285

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1) By similarity

Cross-link

304

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1) By similarity

Natural variations

Alternative sequence

88 – 101

14

Missing in isoform 2.

VSP_000598

Experimental info

Mutagenesis

133

1

S → A: Loss of activation by CaMK4. Ref.4

Mutagenesis

142

1

S → A: Loss of phosphorylation by CaMK2. Activation by CaMK2. Ref.4

Sequence conflict

135

1

R → K in CAA42619. Ref.2

Sequence conflict

319

1

E → K in CAA42619. Ref.2

Secondary structure

1

.

.

.

.

.

341

Helix Strand Turn

Details...

Helix

120 – 128

9

Helix

133 – 144

12

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (Alpha) [UniParc]. Last modified April 1, 1990. Version 1. Checksum: FC08AC5A335D4C2F	FASTA	341	36,633
	10 20 30 40 50 60 MTMDSGADNQ QSGDAAVTEA ESQQMTVQAQ PQIATLAQVS MPAAHATSSA PTVTLVQLPN 70 80 90 100 110 120 GQTVQVHGVI QAAQPSVIQS PQVQTVQSSC KDLKRLFSGT QISTIAESED SQESVDSVTD 130 140 150 160 170 180 SQKRREILSR RPSYRKILND LSSDAPGVPR IEEEKSEEET SAPAITTVTV PTPIYQTSSG 190 200 210 220 230 240 QYIAITQGGA IQLANNGTDG VQGLQTLTMT NAAATQPGTT ILQYAQTTDG QQILVPSNQV 250 260 270 280 290 300 VVQAASGDVQ TYQIRTAPTS TIAPGVVMAS SPALPTQPAE EAARKREVRL MKNREAAREC 310 320 330 340 RRKKKEYVKC LENRVAVLEN QNKTLIEELK ALKDLYCHKS D
	Isoform 2 (Delta) [UniParc]. Checksum: D6D715DEED679FF2	FASTA	327	35,081
	10 20 30 40 50 60 MTMDSGADNQ QSGDAAVTEA ESQQMTVQAQ PQIATLAQVS MPAAHATSSA PTVTLVQLPN 70 80 90 100 110 120 GQTVQVHGVI QAAQPSVIQS PQVQTVQIST IAESEDSQES VDSVTDSQKR REILSRRPSY 130 140 150 160 170 180 RKILNDLSSD APGVPRIEEE KSEEETSAPA ITTVTVPTPI YQTSSGQYIA ITQGGAIQLA 190 200 210 220 230 240 NNGTDGVQGL QTLTMTNAAA TQPGTTILQY AQTTDGQQIL VPSNQVVVQA ASGDVQTYQI 250 260 270 280 290 300 RTAPTSTIAP GVVMASSPAL PTQPAEEAAR KREVRLMKNR EAARECRRKK KEYVKCLENR 310 320 VAVLENQNKT LIEELKALKD LYCHKSD

References

[1]	"A cluster of phosphorylation sites on the cyclic AMP-regulated nuclear factor CREB predicted by its sequence." Gonzalez G.A., Yamamoto K.K., Fischer W.H., Karr D., Menzel P., Biggs W. III, Vale W.W., Montminy M.R. Nature 337:749-752(1989) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PARTIAL PROTEIN SEQUENCE.
[2]	"Nucleotide and derived amino-acid sequences of the CRE-binding proteins from rat C6 glioma and HeLa cells." Short M.L., Manohar C.F., Furtado M.R., Ghadge G.D., Wolinsky S.M., Thimmapaya B., Jungmann R.A. Nucleic Acids Res. 19:4290-4290(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
[3]	"CREB: a Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases." Sheng M., Thompson M.A., Greenberg M.E. Science 252:1427-1430(1991) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-133, PHOSPHORYLATION BY CAMK1 AND CAMK4.
[4]	"Differential activation of CREB by Ca2+/calmodulin-dependent protein kinases type II and type IV involves phosphorylation of a site that negatively regulates activity." Sun P., Enslen H., Myung P.S., Maurer R.A. Genes Dev. 8:2527-2539(1994) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-133 AND SER-142, MUTAGENESIS OF SER-133 AND SER-142.
[5]	"Regulation of activating transcription factor-1 and the cAMP response element-binding protein by Ca2+/calmodulin-dependent protein kinases type I, II, and IV." Sun P., Lou L., Maurer R.A. J. Biol. Chem. 271:3066-3073(1996) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-133, PHOSPHORYLATION BY CAMK1.
[6]	"Structural analyses of CREB-CBP transcriptional activator-coactivator complexes by NMR spectroscopy: implications for mapping the boundaries of structural domains." Radhakrishnan I., Perez-Alvarado G.C., Parker D., Dyson H.J., Montminy M.R., Wright P.E. J. Mol. Biol. 287:859-865(1999) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 119-146 IN COMPLEX WITH CREBBP.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X14788 mRNA. Translation: CAA32890.1.
X60002 mRNA. Translation: CAA42619.1.

IPI

IPI00208239.
IPI00327194.

PIR

A35663.
S03343.
S22299.

RefSeq

NP_112279.1. NM_031017.1.
NP_604392.1. NM_134443.1.

UniGene

Rn.90061.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1KDX	NMR	-	B	119-146	[»]

DisProt

DP00080.

ProteinModelPortal

P15337.

SMR

P15337. Positions 119-146, 285-339.

ModBase

Search...

Protein-protein interaction databases

IntAct

P15337. 1 interaction.

MINT

MINT-1529999.

STRING

10116.ENSRNOP00000018326.

PTM databases

PhosphoSite

P15337.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENSRNOT00000018326; ENSRNOP00000018326; ENSRNOG00000013412.
ENSRNOT00000049654; ENSRNOP00000049369; ENSRNOG00000013412.

GeneID

81646.

KEGG

rno:81646.

UCSC

RGD:620218. rat.

Organism-specific databases

CTD

1385.

RGD

620218. Creb1.

Phylogenomic databases

eggNOG

NOG300199.

GeneTree

ENSGT00390000008655.

HOGENOM

HOG000007365.

HOVERGEN

HBG011077.

InParanoid

P15337.

KO

K05870.

OMA

QXISTIA.

OrthoDB

EOG4TB4C8.

Enzyme and pathway databases

Reactome

REACT_109781. Immune System.
REACT_110573. Disease.
REACT_111984. Signal Transduction.

Gene expression databases

ArrayExpress

P15337.

Genevestigator

P15337.

GermOnline

ENSRNOG00000013412. Rattus norvegicus.

Family and domain databases

InterPro

IPR004827. bZIP.
IPR003102. Coactivator_CBP_pKID.
IPR001630. Leuzip_CREB.
[Graphical view]

Pfam

PF00170. bZIP_1. 1 hit.
PF02173. pKID. 1 hit.
[Graphical view]

PRINTS

PR00041. LEUZIPPRCREB.

SMART

SM00338. BRLZ. 1 hit.
[Graphical view]

PROSITE

PS50217. BZIP. 1 hit.
PS00036. BZIP_BASIC. 1 hit.
PS50953. KID. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

P15337.

NextBio

615164.

Entry information

Entry name

CREB1_RAT

Accession

Primary (citable) accession number: P15337

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 1, 1990
Last sequence update:	April 1, 1990
Last modified:	May 29, 2013
This is version 138 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program