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Protein

Cyclic AMP-responsive element-binding protein 3

Gene

CREB3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Endoplasmic reticulum (ER)-bound sequence-specific transcription factor that directly binds DNA and activates transcription (PubMed:9271389, PubMed:19779205, PubMed:10984507, PubMed:15845366, PubMed:16940180). Plays a role in the unfolded protein response (UPR), promoting cell survival versus ER stress-induced apoptotic cell death (PubMed:15845366, PubMed:16940180). Also involved in cell proliferation, migration and differentiation, tumor suppression and inflammatory gene expression. Acts as a positive regulator of LKN-1/CCL15-induced chemotaxis signaling of leukocyte cell migration (PubMed:19779205, PubMed:15001559, PubMed:17296613). Associates with chromatin to the HERPUD1 promoter (PubMed:16940180). Also induces transcriptional activation of chemokine receptors (PubMed:18587271, PubMed:17296613).8 Publications
Processed cyclic AMP-responsive element-binding protein 3: This is the transcriptionally active form that translocates to the nucleus and activates unfolded protein response (UPR) target genes during endoplasmic reticulum (ER) stress response. Binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AG][AG]-3') and C/EBP sequences present in many promoters to activate transcription of the genes. Binds to the unfolded protein response element (UPRE) consensus sequences sites. Binds DNA to the 5'-CCAC[GA]-3'half of ERSE II (5'-ATTGG-N-CCACG-3').1 Publication
Isoform 2: Functions as a negative transcriptional regulator in ligand-induced transcriptional activation of the glucocorticoid receptor NR3C1 by recruiting and activating histone deacetylases (HDAC1, HDAC2 and HDAC6). Also decreases the acetylation level of histone H4. Does not promote the chemotactic activity of leukocyte cells.1 Publication
(Microbial infection) Plays a role in human immunodeficiency virus type 1 (HIV-1) virus protein expression.1 Publication
(Microbial infection) Isoform 1: Plays a role in herpes simplex virus-1 (HSV-1) latent infection and reactivation from latency. Represses the VP16-mediated transactivation of immediate early genes of the HSV-1 virus by sequestering host cell factor-1 HCFC1 in the ER membrane of sensory neurons, thereby preventing the initiation of the replicative cascade leading to latent infection.2 Publications
(Microbial infection) Isoform 1: May play a role as a cellular tumor suppressor that is targeted by the hepatitis C virus (HCV) core protein.1 Publication
(Microbial infection) Processed cyclic AMP-responsive element-binding protein 3: Activates transcription of genes required for reactivation of the latent HSV-1 virus. It's transcriptional activity is inhibited by CREBZF in a HCFC1-dependent manner, by the viral transactivator protein VP16. Binds DNA to the cAMP response element (CRE) (consensus: 5'-GTGACGT[AG][AG]-3') and C/EBP sequences present in many viral promoters.1 Publication
(Microbial infection) Processed cyclic AMP-responsive element-binding protein 3: It's transcriptional activity is inhibited by CREBZF in a HCFC1-dependent manner, by the viral transactivator HCV core protein.1 Publication

Caution

All experiments concerning the proteolytic cleavage are done with isoform 1.Curated

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionActivator, DNA-binding, Repressor
Biological processChemotaxis, Host-virus interaction, Transcription, Transcription regulation, Unfolded protein response

Enzyme and pathway databases

ReactomeiR-HSA-8874211 CREB3 factors activate genes
SIGNORiO43889

Names & Taxonomyi

Protein namesi
Recommended name:
Cyclic AMP-responsive element-binding protein 3
Short name:
CREB-3
Short name:
cAMP-responsive element-binding protein 3
Alternative name(s):
Leucine zipper protein
Luman
Transcription factor LZIP-alpha
Cleaved into the following chain:
Processed cyclic AMP-responsive element-binding protein 3
Short name:
N-terminal Luman
Short name:
Transcriptionally active form
Gene namesi
Name:CREB3
Synonyms:LZIP
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 9

Organism-specific databases

EuPathDBiHostDB:ENSG00000107175.10
HGNCiHGNC:2347 CREB3
MIMi606443 gene
neXtProtiNX_O43889

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 230Cytoplasmic1 PublicationAdd BLAST230
Transmembranei231 – 247Helical; Signal-anchor for type II membrane proteinSequence analysisAdd BLAST17
Topological domaini248 – 371Lumenal1 PublicationAdd BLAST124

Keywords - Cellular componenti

Cytoplasm, Endoplasmic reticulum, Golgi apparatus, Membrane, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi12 – 13LL → AA: Does not inhibit interaction with HCFC1. Reduces transcriptional activation. Inhibits strongly transcriptional activation; when associated with 56-A-A-57 and 78-A--A-81 (isoform 1). 1 Publication2
Mutagenesisi16 – 17LL → AA: Does not affect the transcriptional activation of the glucocorticoid receptor NR3C1; when associated with 57-A-A-58 (isoform 2). 2 Publications2
Mutagenesisi57 – 58LL → AA: Does not affect the transcriptional activation of the glucocorticoid receptor NR3C1; when associated with 16-A-A-17 (isoform 2). 1 Publication2
Mutagenesisi57 – 58LL → AA: Does not inhibit interaction with HCFC1. Reduces transcriptional activation. Inhibits strongly transcriptional activation; when associated with 12-A-A-13 and 78-A--A-81 (isoform 1). 1 Publication2
Mutagenesisi78 – 81DHTY → AAAA: Inhibits interaction with HCFC1. Reduces transcriptional activation. Inhibits strongly transcriptional activation; when associated with 12-A-A-13 and 56-A-A-57. Colocalizes with HCFC1 in the nucleus (isoform 1). 2 Publications4
Mutagenesisi81Y → A: Does not retain HCFC1 in the cytoplasm, does not interact with HCFC1, does not activate promoter and fail to protect cells from a productive infection by HSV-1. 1 Publication1
Mutagenesisi160N → G: Does not bind to DNA but retains its ability to interact with HCFC1. Reduces transcriptional activation of unfolded protein response elements (UPRE)-containing promoter. Colocalizes with HCFC1 in the ER membrane. 1 Publication1
Mutagenesisi252R → A: Does not inhibit proteolytic cleavage and transcriptional activation. 1 Publication1
Mutagenesisi264R → G: Inhibits proteolytic cleavage and transcriptional activation. 1 Publication1
Mutagenesisi267R → G: Inhibits proteolytic cleavage and transcriptional activation. 1 Publication1

Organism-specific databases

DisGeNETi10488
OpenTargetsiENSG00000107175
PharmGKBiPA26865

Polymorphism and mutation databases

BioMutaiCREB3

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000766021 – 371Cyclic AMP-responsive element-binding protein 3Add BLAST371
ChainiPRO_00002962041 – ?Processed cyclic AMP-responsive element-binding protein 3

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi307N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi348N-linked (GlcNAc...) asparagineSequence analysis1

Post-translational modificationi

First proteolytically cleaved by site-1 protease (S1P) that generates membrane-associated N-terminus and a luminal C-terminus forms. The membrane-associated N-terminus form is further proteolytically processed probably by the site-2 protease (S2P) through a regulated intramembrane proteolysis (RIP), releasing the transcriptional active processed cyclic AMP-responsive element-binding protein 3 form, which is transported to the nucleus. The proteolytic cleavage is strongly induced during dendritic cell (DC) maturation and inhibited by DCSTAMP. That form is rapidly degraded.5 Publications
N-glycosylated.2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei263 – 264Cleavage; by PS11 Publication2
Sitei266 – 267Cleavage; by PS11 Publication2

Keywords - PTMi

Glycoprotein

Proteomic databases

PeptideAtlasiO43889
PRIDEiO43889
ProteomicsDBi49216
49217 [O43889-2]
49218 [O43889-3]

PTM databases

iPTMnetiO43889
PhosphoSitePlusiO43889

Expressioni

Tissue specificityi

Ubiquitously expressed (PubMed:9271389, PubMed:19779205). Expressed in dendritic cells (DC). Weakly expressed in monocytes (at protein level) (PubMed:20546900).3 Publications

Inductioni

Up-regulated upon differentiation of monocytes towards immature dendritic cells (DC). Down-regulated upon DC maturation. Up-regulated by endoplasmic reticulum stress triggered by thapsigargin (Tg) or tunicamycin (Tm). Up-regulated by CCR1-dependent chemokines in an immediate early response and biphasic manner and by NF-kappa-B.5 Publications

Gene expression databases

BgeeiENSG00000107175 Expressed in 219 organ(s), highest expression level in adenohypophysis
CleanExiHS_CREB3
GenevisibleiO43889 HS

Organism-specific databases

HPAiHPA030978

Interactioni

Subunit structurei

Homodimer (PubMed:10675342). Isoform 1 interacts with HCFC1; the interaction is required to stimulate CREB3 transcriptional activity (PubMed:9271389, PubMed:9389645, PubMed:10629049, PubMed:10984507). Isoform 1 interacts with CREBZF; the interaction occurs only in combination with HCFC1 (PubMed:15705566). Isoform 1 interacts (via central part and transmembrane region) with DCSTAMP (via C-terminus cytoplasmic domain) (PubMed:20546900). Isoform 1 interacts with OS9 (PubMed:20546900). Isoform 1 interacts (via leucine-zipper domain) with CREBRF (via leucine-zipper domain); the interaction occurs only after CREB3 activation and promotes CREB3 degradation (PubMed:18391022). Isoform 1 interacts (via C-terminal domain) with CCR1 (PubMed:15001559).9 Publications
(Microbial infection) Interacts with the HCV core protein; homodimerization is prevented by the HCV core protein (PubMed:10675342). Isoform 1 interacts (via leucine-zipper and transmembrane domains) with HIV-1 TMgp41 (via cytoplasmic domain); the interaction reduces CREB3 stability (PubMed:17054986). Processed cyclic AMP-responsive element-binding protein 3 interacts with HIV-1 Tat (PubMed:17054986).2 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi115751, 191 interactors
DIPiDIP-33935N
ELMiO43889
IntActiO43889, 169 interactors
MINTiO43889

Structurei

3D structure databases

ProteinModelPortaliO43889
SMRiO43889
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini150 – 213bZIPPROSITE-ProRule annotationAdd BLAST64

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 92Transcription activation (acidic)1 PublicationAdd BLAST92
Regioni152 – 184Basic motifPROSITE-ProRule annotationAdd BLAST33
Regioni192 – 213Leucine-zipperPROSITE-ProRule annotationAdd BLAST22

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi13 – 17LXXLL motif 15
Motifi54 – 58LXXLL motif 25
Motifi78 – 81HCFC1-binding-motif (HBM)4

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi316 – 361Pro-richAdd BLAST46

Sequence similaritiesi

Belongs to the bZIP family. ATF subfamily.Curated

Keywords - Domaini

Repeat, Signal-anchor, Transmembrane, Transmembrane helix

Phylogenomic databases

GeneTreeiENSGT00520000055538
HOGENOMiHOG000133026
HOVERGENiHBG051114
InParanoidiO43889
KOiK09048
OMAiHVSIDLD
PhylomeDBiO43889
TreeFamiTF316079

Family and domain databases

InterProiView protein in InterPro
IPR004827 bZIP
IPR029808 Luman
PANTHERiPTHR22952:SF100 PTHR22952:SF100, 1 hit
PfamiView protein in Pfam
PF00170 bZIP_1, 1 hit
SMARTiView protein in SMART
SM00338 BRLZ, 1 hit
PROSITEiView protein in PROSITE
PS50217 BZIP, 1 hit
PS00036 BZIP_BASIC, 1 hit

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket
Isoform 1 (identifier: O43889-2) [UniParc]FASTAAdd to basket
Also known as: LZIP

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.

« Hide
        10         20         30         40         50
MELELDAGDQ DLLAFLLEES GDLGTAPDEA VRAPLDWALP LSEVPSDWEV
60 70 80 90 100
DDLLCSLLSP PASLNILSSS NPCLVHHDHT YSLPRETVSM DLESESCRKE
110 120 130 140 150
GTQMTPQHME ELAEQEIARL VLTDEEKSLL EKEGLILPET LPLTKTEEQI
160 170 180 190 200
LKRVRRKIRN KRSAQESRRK KKVYVGGLES RVLKYTAQNM ELQNKVQLLE
210 220 230 240 250
EQNLSLLDQL RKLQAMVIEI SNKTSSSSTC ILVLLVSFCL LLVPAMYSSD
260 270 280 290 300
TRGSLPAEHG VLSRQLRALP SEDPYQLELP ALQSEVPKDS THQWLDGSDC
310 320 330 340 350
VLQAPGNTSC LLHYMPQAPS AEPPLEWPFP DLFSEPLCRG PILPLQANLT
360 370
RKGGWLPTGS PSVILQDRYS G
Length:371
Mass (Da):41,379
Last modified:March 28, 2018 - v2
Checksum:i82152E496B924EEC
GO
Isoform 2 (identifier: O43889-3) [UniParc]FASTAAdd to basket
Also known as: small LZIP, sLZIP

The sequence of this isoform differs from the canonical sequence as follows:
     229-245: Missing.

Note: Does not contain a helical transmembrane domain.
Show »
Length:354
Mass (Da):39,580
Checksum:iBC8F014103A52111
GO

Sequence cautioni

The sequence AAC04325 differs from that shown. Probable cloning artifact.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti21G → E in AAG43527 (Ref. 6) Curated1
Sequence conflicti230C → G in AAD09210 (PubMed:10675342).Curated1
Sequence conflicti246M → I in AAH09402 (PubMed:15489334).Curated1
Sequence conflicti262L → C in AAD09210 (PubMed:10675342).Curated1
Sequence conflicti333F → S in AAB69652 (PubMed:9271389).Curated1
Sequence conflicti338C → V in AAD09210 (PubMed:10675342).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_059386229 – 245Missing in isoform 2. Add BLAST17

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF009368 mRNA Translation: AAB69652.1
AF029674 mRNA Translation: AAB84166.1
U59629 Genomic DNA Translation: AAD09210.1
FJ263669 mRNA Translation: ACN32251.1
U88528 mRNA Translation: AAC04325.1 Sequence problems.
AF211847 Genomic DNA Translation: AAG43527.1
AF211848 mRNA Translation: AAG43528.1
AL133410 Genomic DNA No translation available.
BC009402 mRNA Translation: AAH09402.1
BC010158 mRNA Translation: AAH10158.1
CCDSiCCDS6588.1 [O43889-2]
RefSeqiNP_006359.3, NM_006368.4 [O43889-2]
UniGeneiHs.522110

Genome annotation databases

EnsembliENST00000353704; ENSP00000342136; ENSG00000107175 [O43889-2]
GeneIDi10488
KEGGihsa:10488
UCSCiuc003zxv.4 human [O43889-2]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF009368 mRNA Translation: AAB69652.1
AF029674 mRNA Translation: AAB84166.1
U59629 Genomic DNA Translation: AAD09210.1
FJ263669 mRNA Translation: ACN32251.1
U88528 mRNA Translation: AAC04325.1 Sequence problems.
AF211847 Genomic DNA Translation: AAG43527.1
AF211848 mRNA Translation: AAG43528.1
AL133410 Genomic DNA No translation available.
BC009402 mRNA Translation: AAH09402.1
BC010158 mRNA Translation: AAH10158.1
CCDSiCCDS6588.1 [O43889-2]
RefSeqiNP_006359.3, NM_006368.4 [O43889-2]
UniGeneiHs.522110

3D structure databases

ProteinModelPortaliO43889
SMRiO43889
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi115751, 191 interactors
DIPiDIP-33935N
ELMiO43889
IntActiO43889, 169 interactors
MINTiO43889

PTM databases

iPTMnetiO43889
PhosphoSitePlusiO43889

Polymorphism and mutation databases

BioMutaiCREB3

Proteomic databases

PeptideAtlasiO43889
PRIDEiO43889
ProteomicsDBi49216
49217 [O43889-2]
49218 [O43889-3]

Protocols and materials databases

DNASUi10488
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000353704; ENSP00000342136; ENSG00000107175 [O43889-2]
GeneIDi10488
KEGGihsa:10488
UCSCiuc003zxv.4 human [O43889-2]

Organism-specific databases

CTDi10488
DisGeNETi10488
EuPathDBiHostDB:ENSG00000107175.10
GeneCardsiCREB3
HGNCiHGNC:2347 CREB3
HPAiHPA030978
MIMi606443 gene
neXtProtiNX_O43889
OpenTargetsiENSG00000107175
PharmGKBiPA26865
GenAtlasiSearch...

Phylogenomic databases

GeneTreeiENSGT00520000055538
HOGENOMiHOG000133026
HOVERGENiHBG051114
InParanoidiO43889
KOiK09048
OMAiHVSIDLD
PhylomeDBiO43889
TreeFamiTF316079

Enzyme and pathway databases

ReactomeiR-HSA-8874211 CREB3 factors activate genes
SIGNORiO43889

Miscellaneous databases

ChiTaRSiCREB3 human
GeneWikiiCREB3
GenomeRNAii10488
PROiPR:O43889
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000107175 Expressed in 219 organ(s), highest expression level in adenohypophysis
CleanExiHS_CREB3
GenevisibleiO43889 HS

Family and domain databases

InterProiView protein in InterPro
IPR004827 bZIP
IPR029808 Luman
PANTHERiPTHR22952:SF100 PTHR22952:SF100, 1 hit
PfamiView protein in Pfam
PF00170 bZIP_1, 1 hit
SMARTiView protein in SMART
SM00338 BRLZ, 1 hit
PROSITEiView protein in PROSITE
PS50217 BZIP, 1 hit
PS00036 BZIP_BASIC, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiCREB3_HUMAN
AccessioniPrimary (citable) accession number: O43889
Secondary accession number(s): D0PTW6
, O14671, O14919, Q5TCV1, Q96GK8, Q9H2W3, Q9UE77
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 9, 2004
Last sequence update: March 28, 2018
Last modified: September 12, 2018
This is version 174 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 9
    Human chromosome 9: entries, gene names and cross-references to MIM
  2. SIMILARITY comments
    Index of protein domains and families
  3. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
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