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Protein

Cyclic AMP-responsive element-binding protein 3-like protein 1

Gene

CREB3L1

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

Functioni

Transcription factor involved in unfolded protein response (UPR). Binds the DNA consensus sequence 5'-GTGXGCXGC-3' (PubMed:21767813). In the absence of endoplasmic reticulum (ER) stress, inserted into ER membranes, with N-terminal DNA-binding and transcription activation domains oriented toward the cytosolic face of the membrane. In response to ER stress, transported to the Golgi, where it is cleaved in a site-specific manner by resident proteases S1P/MBTPS1 and S2P/MBTPS2. The released N-terminal cytosolic domain is translocated to the nucleus to effect transcription of specific target genes. Plays a critical role in bone formation through the transcription of COL1A1, and possibly COL1A2, and the secretion of bone matrix proteins. Directly binds to the UPR element (UPRE)-like sequence in an osteoblast-specific COL1A1 promoter region and induces its transcription. Does not regulate COL1A1 in other tissues, such as skin (By similarity). Required to protect astrocytes from ER stress-induced cell death. In astrocytes, binds to the cAMP response element (CRE) of the BiP/HSPA5 promoter and participate in its transcriptional activation (By similarity). Required for TGFB1 to activate genes involved in the assembly of collagen extracellular matrix (PubMed:25310401).By similarity3 Publications
(Microbial infection) May play a role in limiting virus spread by inhibiting proliferation of virus-infected cells. Upon infection with diverse DNA and RNA viruses, inhibits cell-cycle progression by binding to promoters and activating transcription of genes encoding cell-cycle inhibitors, such as p21/CDKN1A (PubMed:21767813).1 Publication

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionActivator, Developmental protein, DNA-binding
Biological processTranscription, Transcription regulation, Unfolded protein response

Enzyme and pathway databases

ReactomeiR-HSA-8874211 CREB3 factors activate genes
SIGNORiQ96BA8

Names & Taxonomyi

Protein namesi
Recommended name:
Cyclic AMP-responsive element-binding protein 3-like protein 1
Short name:
cAMP-responsive element-binding protein 3-like protein 1
Alternative name(s):
Old astrocyte specifically-induced substance
Short name:
OASIS
Cleaved into the following chain:
Gene namesi
Name:CREB3L1
Synonyms:OASIS
ORF Names:PSEC0238
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 11

Organism-specific databases

EuPathDBiHostDB:ENSG00000157613.10
HGNCiHGNC:18856 CREB3L1
MIMi616215 gene
neXtProtiNX_Q96BA8

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 – 374CytoplasmicSequence analysisAdd BLAST374
Transmembranei375 – 395Helical; Signal-anchor for type II membrane proteinSequence analysisAdd BLAST21
Topological domaini396 – 519LumenalSequence analysisAdd BLAST124

Keywords - Cellular componenti

Endoplasmic reticulum, Membrane, Nucleus

Pathology & Biotechi

Involvement in diseasei

Osteogenesis imperfecta 16 (OI16)1 Publication
The disease may be caused by mutations affecting the gene represented in this entry. OI16 affected patients show a genomic deletion encompassing CREB3L1 and the first exon of DGKZ. The absence of this exon does not affect all DGKZ isoforms, some are still produced at normal level. It cannot be ruled out that DGKZ could contribute to the phenotype, but in view of its role in bone formation, CREB3L1 is a strong OI16-causing candidate (PubMed:24079343). This hypothesis is corroborated by the observation of CREB3L1 knockout mice which exhibit features reminiscent of severe human osteogenesis imperfecta.1 Publication
Disease descriptionAn autosomal recessive form of osteogenesis imperfecta, a connective tissue disorder characterized by low bone mass, bone fragility and susceptibility to fractures after minimal trauma. Disease severity ranges from very mild forms without fractures to intrauterine fractures and perinatal lethality. Extraskeletal manifestations, which affect a variable number of patients, are dentinogenesis imperfecta, hearing loss, and blue sclerae. OI16 is a severe form.
See also OMIM:616229

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi392P → A: Abolishes proteolytic cleavage by S2P; when associated with A-395. 1 Publication1
Mutagenesisi392P → L: Abolishes proteolytic cleavage by S2P. 1 Publication1
Mutagenesisi395P → A: Abolishes proteolytic cleavage by S2P; when associated with A-392. 1 Publication1
Mutagenesisi423R → A: Abolishes proteolytic cleavage by S1P. 2 Publications1
Mutagenesisi426L → V: Abolishes proteolytic cleavage by S1P. 1 Publication1

Keywords - Diseasei

Osteogenesis imperfecta

Organism-specific databases

DisGeNETi90993
MalaCardsiCREB3L1
MIMi616229 phenotype
OpenTargetsiENSG00000157613
Orphaneti79105 Myxofibrosarcoma
216812 Osteogenesis imperfecta type 3
PharmGKBiPA134960108

Polymorphism and mutation databases

DMDMi74751763

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002880641 – 519Cyclic AMP-responsive element-binding protein 3-like protein 1Add BLAST519
ChainiPRO_00002962061 – ?Processed cyclic AMP-responsive element-binding protein 3-like protein 1

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Cross-linki184Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
Glycosylationi492N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi513N-linked (GlcNAc...) asparagineSequence analysis1

Post-translational modificationi

Upon ER stress, translocated to the Golgi apparatus, where it is processed by regulated intramembrane proteolysis (RIP) to release the cytosol-facing N-terminal transcription factor domain. The cleavage is performed sequentially by site-1 and site-2 proteases (S1P/MBTPS1 and S2P/MBTPS2). RIP is induced by TGFB1 and ceramide (PubMed:25310401, PubMed:27499293).4 Publications
N-glycosylated.By similarity
Ubiquitinated by HRD1/SYVN1; undergoes 'Lys-48'-linked ubiquitination, followed by rapid proteasomal degradation under normal conditions. Upon ER stress, SYVN1 E3 ubiquitin-protein ligase dissociates from its substrate, ubiquitination does not occur and CREB3L1 is stabilized.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei426 – 427Cleavage; by S1PBy similarity2

Keywords - PTMi

Glycoprotein, Isopeptide bond, Ubl conjugation

Proteomic databases

EPDiQ96BA8
MaxQBiQ96BA8
PaxDbiQ96BA8
PeptideAtlasiQ96BA8
PRIDEiQ96BA8

PTM databases

iPTMnetiQ96BA8
PhosphoSitePlusiQ96BA8

Expressioni

Tissue specificityi

Expressed in several tissues, with highest levels in pancreas and prostate. Expressed at relatively lower levels in brain.1 Publication

Gene expression databases

BgeeiENSG00000157613
CleanExiHS_CREB3L1
ExpressionAtlasiQ96BA8 baseline and differential
GenevisibleiQ96BA8 HS

Organism-specific databases

HPAiCAB026151
HPA024069

Interactioni

Subunit structurei

Interacts with SMAD4, the interaction takes place upon TGFB1 induction and SMAD4 acts as CREB3L1 coactivator to induce the expression of genes involved in assembly of collagen extracellular matrix.1 Publication

Binary interactionsi

Show more details

GO - Molecular functioni

  • SMAD binding Source: UniProtKB

Protein-protein interaction databases

BioGridi124786, 31 interactors
IntActiQ96BA8, 152 interactors
MINTiQ96BA8
STRINGi9606.ENSP00000434939

Structurei

3D structure databases

ProteinModelPortaliQ96BA8
SMRiQ96BA8
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini290 – 353bZIPPROSITE-ProRule annotationAdd BLAST64

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 60Required for transcriptional activationAdd BLAST60
Regioni292 – 321Basic motifPROSITE-ProRule annotationAdd BLAST30
Regioni332 – 353Leucine-zipperPROSITE-ProRule annotationAdd BLAST22

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi392 – 395S2P recognition1 Publication4
Motifi423 – 426S1P recognition1 Publication4

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi146 – 154Poly-Ala9

Sequence similaritiesi

Belongs to the bZIP family. ATF subfamily.Curated

Keywords - Domaini

Signal-anchor, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG0709 Eukaryota
ENOG410ZZQM LUCA
GeneTreeiENSGT00520000055538
HOGENOMiHOG000060150
HOVERGENiHBG057480
InParanoidiQ96BA8
KOiK09048
OMAiEPPDGWE
OrthoDBiEOG091G081Z
PhylomeDBiQ96BA8
TreeFamiTF316079

Family and domain databases

InterProiView protein in InterPro
IPR004827 bZIP
IPR001630 Leuzip_CREB
IPR029805 OASIS
PANTHERiPTHR22952:SF24 PTHR22952:SF24, 1 hit
PfamiView protein in Pfam
PF00170 bZIP_1, 1 hit
PRINTSiPR00041 LEUZIPPRCREB
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: Q96BA8-1) [UniParc]FASTAAdd to basket

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
MDAVLEPFPA DRLFPGSSFL DLGDLNESDF LNNAHFPEHL DHFTENMEDF
60 70 80 90 100
SNDLFSSFFD DPVLDEKSPL LDMELDSPTP GIQAEHSYSL SGDSAPQSPL
110 120 130 140 150
VPIKMEDTTQ DAEHGAWALG HKLCSIMVKQ EQSPELPVDP LAAPSAMAAA
160 170 180 190 200
AAMATTPLLG LSPLSRLPIP HQAPGEMTQL PVIKAEPLEV NQFLKVTPED
210 220 230 240 250
LVQMPPTPPS SHGSDSDGSQ SPRSLPPSSP VRPMARSSTA ISTSPLLTAP
260 270 280 290 300
HKLQGTSGPL LLTEEEKRTL IAEGYPIPTK LPLTKAEEKA LKRVRRKIKN
310 320 330 340 350
KISAQESRRK KKEYVECLEK KVETFTSENN ELWKKVETLE NANRTLLQQL
360 370 380 390 400
QKLQTLVTNK ISRPYKMAAT QTGTCLMVAA LCFVLVLGSL VPCLPEFSSG
410 420 430 440 450
SQTVKEDPLA ADGVYTASQM PSRSLLFYDD GAGLWEDGRS TLLPMEPPDG
460 470 480 490 500
WEINPGGPAE QRPRDHLQHD HLDSTHETTK YLSEAWPKDG GNGTSPDFSH
510
SKEWFHDRDL GPNTTIKLS
Length:519
Mass (Da):57,005
Last modified:December 1, 2001 - v1
Checksum:iD08133CD8B02A3AC
GO
Isoform 2 (identifier: Q96BA8-2) [UniParc]FASTAAdd to basket
Also known as: OASISv1

The sequence of this isoform differs from the canonical sequence as follows:
     111-198: Missing.

Show »
Length:431
Mass (Da):47,783
Checksum:i7DD049831DE6024C
GO

Sequence cautioni

The sequence BAC11681 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti249A → P in AAH14097 (PubMed:15489334).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_032392411A → T. Corresponds to variant dbSNP:rs35652107Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_025632111 – 198Missing in isoform 2. CuratedAdd BLAST88

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB063321 mRNA Translation: BAC01278.1
BC014097 mRNA Translation: AAH14097.1
BC015781 mRNA Translation: AAH15781.1
AK075538 mRNA Translation: BAC11681.1 Different initiation.
CCDSiCCDS53620.1 [Q96BA8-1]
RefSeqiNP_443086.1, NM_052854.3 [Q96BA8-1]
UniGeneiHs.405961

Genome annotation databases

EnsembliENST00000621158; ENSP00000481956; ENSG00000157613 [Q96BA8-1]
GeneIDi90993
KEGGihsa:90993
UCSCiuc021qik.3 human [Q96BA8-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiCR3L1_HUMAN
AccessioniPrimary (citable) accession number: Q96BA8
Secondary accession number(s): Q8N2D5, Q96CP0
Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 29, 2007
Last sequence update: December 1, 2001
Last modified: May 23, 2018
This is version 146 of the entry and version 1 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 11
    Human chromosome 11: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. SIMILARITY comments
    Index of protein domains and families

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