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O35185 (BHE40_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 123. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Class E basic helix-loop-helix protein 40

Short name=bHLHe40
Alternative name(s):
Class B basic helix-loop-helix protein 2
Short name=bHLHb2
E47 interaction protein 1
Short name=EIP1
Stimulated by retinoic acid gene 13 protein
Gene names
Name:Bhlhe40
Synonyms:Bhlhb2, Clast5, Stra13
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length411 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Transcriptional repressor involved in the regulation of the circadian rhythm by negatively regulating the activity of the clock genes and clock-controlled genes. Acts as the negative limb of a novel autoregulatory feedback loop (DEC loop) which differs from the one formed by the PER and CRY transcriptional repressors (PER/CRY loop). Both these loops are interlocked as it represses the expression of PER1/2 and in turn is repressed by PER1/2 and CRY1/2. Represses the activity of the circadian transcriptional activator: CLOCK-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer by competing for the binding to E-box elements (5'-CACGTG-3') found within the promoters of its target genes. Negatively regulates its own expression and the expression of DBP and BHLHE41/DEC2. Acts as a corepressor of RXR and the RXR-LXR heterodimers and represses the ligand-induced RXRA and NR1H3/LXRA transactivation activity. May function as a transcriptional factor for neuronal differentiation. Ref.5 Ref.7 Ref.8

Subunit structure

Homodimer. Heterodimer with BHLHE41/DEC2. Interacts with ubiquitin-conjugating enzyme UBE2I/UBC9. Interacts with HDAC1, SUMO1, RXRA and ARNTL/BMAL1 By similarity. Interacts with TCF3/E47. Ref.2 Ref.6

Subcellular location

Cytoplasm By similarity. Nucleus By similarity. Nucleusnucleolus By similarity. Note: Predominantly localized in the nucleus By similarity.

Developmental stage

Expressed from E9.5 day to E17.5 day in the ventricular layer of the brain and spinal cord, but also in the retinal pigment epithelium, developing eyelids, nasal epithelium, serous gland, vibrissae, epithelium of the mouth cavity and the tooth buds. Highly expressed in the heart, thymus and adrenal glands followed by lung, liver parenchyma, kidney tubules, epithelium of the esophagus and stomach. From E15.5 to E17.5 it is expressed in urinary bladder and urethra. From E17.5, it is expressed in developing muscle.

Induction

Stimulated by retinoic acid (RA). Expressed in a circadian manner in the liver with a peak at ZT10. Ref.8

Post-translational modification

Ubiquitinated; which may lead to proteasomal degradation By similarity.

Sumoylation inhibits its ubiquitination and promotes its negative regulation of the CLOCK-ARNTL/BMAL1 heterodimer transcriptional activator activity By similarity.

Sequence similarities

Contains 1 bHLH (basic helix-loop-helix) domain.

Contains 1 Orange domain.

Ontologies

Keywords
   Biological processBiological rhythms
Transcription
Transcription regulation
   Cellular componentCytoplasm
Nucleus
   LigandDNA-binding
   Molecular functionRepressor
   PTMIsopeptide bond
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcircadian regulation of gene expression

Inferred from mutant phenotype Ref.7. Source: BHF-UCL

circadian rhythm

Inferred from expression pattern. Source: BHF-UCL

entrainment of circadian clock by photoperiod

Inferred from mutant phenotype Ref.7. Source: BHF-UCL

negative regulation of sequence-specific DNA binding transcription factor activity

Inferred from electronic annotation. Source: Ensembl

negative regulation of transcription, DNA-templated

Inferred from direct assay PubMed 12297495. Source: MGI

response to light stimulus

Inferred from expression pattern PubMed 15038852. Source: BHF-UCL

   Cellular_componentGolgi apparatus

Inferred from electronic annotation. Source: Ensembl

nucleolus

Inferred from electronic annotation. Source: Ensembl

nucleoplasm

Traceable author statement. Source: Reactome

nucleus

Inferred from direct assay PubMed 12297495. Source: MGI

   Molecular_functionDNA binding

Inferred from direct assay PubMed 12297495. Source: MGI

E-box binding

Inferred from direct assay. Source: BHF-UCL

MRF binding

Inferred from direct assay PubMed 17487425. Source: BHF-UCL

RNA polymerase II activating transcription factor binding

Inferred from direct assay PubMed 17487425. Source: BHF-UCL

RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in negative regulation of transcription

Inferred from direct assay PubMed 15147242PubMed 17487425. Source: BHF-UCL

RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity

Inferred from direct assay PubMed 15147242. Source: BHF-UCL

RNA polymerase II transcription factor binding transcription factor activity involved in negative regulation of transcription

Inferred from electronic annotation. Source: Ensembl

protein binding

Inferred from physical interaction PubMed 12297495. Source: MGI

protein heterodimerization activity

Inferred from direct assay PubMed 17487425. Source: BHF-UCL

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 411411Class E basic helix-loop-helix protein 40
PRO_0000127145

Regions

Domain52 – 10756bHLH
Domain142 – 17534Orange
Region1 – 139139Essential for its interaction with ARNTL/BMAL1, E-box binding and repressor activity against the CLOCK-ARNTL/BMAL1 heterodimer By similarity
Region75 – 795Necessary for its interaction with RXRA and repressor activity against RXRA By similarity

Amino acid modifications

Cross-link159Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1, SUMO2 and SUMO3) By similarity
Cross-link279Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1, SUMO2 and SUMO3) By similarity

Experimental info

Sequence conflict2881K → T in CAA69169. Ref.2

Sequences

Sequence LengthMass (Da)Tools
O35185 [UniParc].

Last modified January 1, 1998. Version 1.
Checksum: B392893CD49292BC

FASTA41145,361
        10         20         30         40         50         60 
MERIPSAQPP PTCLPKAPGL EHGDLSGMDF AHMYQVYKSR RGIKRSEDSK ETYKLPHRLI 

        70         80         90        100        110        120 
EKKRRDRINE CIAQLKDLLP EHLKLTTLGH LEKAVVLELT LKHVKALTNL IDQQQQKIIA 

       130        140        150        160        170        180 
LQSGLQAGDL SGRNLEAGQE MFCSGFQTCA REVLQYLAKH ENTRDLKSSQ LVTHLHRVVS 

       190        200        210        220        230        240 
ELLQGGASRK PLDSAPKAVD LKEKPSFLAK GSEGPGKNCV PVIQRTFAPS GGEQSGSDTD 

       250        260        270        280        290        300 
TDSGYGGELE KGDLRSEQPY FKSDHGRRFA VGERVSTIKQ ESEEPPTKKS RMQLSEEEGH 

       310        320        330        340        350        360 
FAGSDLMGSP FLGPHPHQPP FCLPFYLIPP SATAYLPMLE KCWYPTSVPV LYPGLNTSAA 

       370        380        390        400        410 
ALSSFMNPDK IPTPLLLPQR LPSPLAHSSL DSSALLQALK QIPPLNLETK D 

« Hide

References

« Hide 'large scale' references
[1]"Overexpression of Stra13, a novel retinoic acid-inducible gene of the basic helix-loop-helix family, inhibits mesodermal and promotes neuronal differentiation of P19 cells."
Boudjelal M., Taneja R., Matsubara S., Bouillet P., Dolle P., Chambon P.
Genes Dev. 11:2052-2065(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Embryonic carcinoma.
[2]"Identification of interaction partners for the basic-helix-loop-helix protein E47."
Dear T.N., Hainzl T., Follo M., Nehls M., Wilmore H., Matena K., Boehm T.
Oncogene 14:891-898(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], INTERACTION WITH TCF3/E47.
Strain: BALB/c.
[3]"Isolation of a CD40-activated gene from murine splenic B cells."
O-Wang J.
Submitted (MAR-2001) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Strain: C57BL/6.
Tissue: Spleen.
[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].
Tissue: Mammary gland.
[5]"A novel autofeedback loop of Dec1 transcription involved in circadian rhythm regulation."
Kawamoto T., Noshiro M., Sato F., Maemura K., Takeda N., Nagai R., Iwata T., Fujimoto K., Furukawa M., Miyazaki K., Honma S., Honma K.I., Kato Y.
Biochem. Biophys. Res. Commun. 313:117-124(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[6]"Functional analysis of the basic helix-loop-helix transcription factor DEC1 in circadian regulation. Interaction with BMAL1."
Sato F., Kawamoto T., Fujimoto K., Noshiro M., Honda K.K., Honma S., Honma K., Kato Y.
Eur. J. Biochem. 271:4409-4419(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: HETERODIMERIZATION WITH BHLHE41/DEC2.
[7]"DEC1 modulates the circadian phase of clock gene expression."
Nakashima A., Kawamoto T., Honda K.K., Ueshima T., Noshiro M., Iwata T., Fujimoto K., Kubo H., Honma S., Yorioka N., Kohno N., Kato Y.
Mol. Cell. Biol. 28:4080-4092(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[8]"The basic helix-loop-helix proteins differentiated embryo chondrocyte (DEC) 1 and DEC2 function as corepressors of retinoid X receptors."
Cho Y., Noshiro M., Choi M., Morita K., Kawamoto T., Fujimoto K., Kato Y., Makishima M.
Mol. Pharmacol. 76:1360-1369(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INDUCTION.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF010305 mRNA. Translation: AAB64228.1.
Y07836 mRNA. Translation: CAA69169.1.
AF364051 mRNA. Translation: AAK50859.1.
BC010720 mRNA. Translation: AAH10720.1.
CCDSCCDS20400.1.
RefSeqNP_035628.1. NM_011498.4.
UniGeneMm.2436.

3D structure databases

ProteinModelPortalO35185.
SMRO35185. Positions 49-109.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid203554. 4 interactions.
IntActO35185. 1 interaction.

PTM databases

PhosphoSiteO35185.

Proteomic databases

PRIDEO35185.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000032194; ENSMUSP00000032194; ENSMUSG00000030103.
GeneID20893.
KEGGmmu:20893.
UCSCuc009ddn.1. mouse.

Organism-specific databases

CTD8553.
MGIMGI:1097714. Bhlhe40.

Phylogenomic databases

eggNOGNOG281955.
HOGENOMHOG000234381.
InParanoidO35185.
KOK03729.
OMAEQPYFKS.
OrthoDBEOG712TWC.
PhylomeDBO35185.
TreeFamTF330859.

Enzyme and pathway databases

ReactomeREACT_200794. Mus musculus biological processes.

Gene expression databases

ArrayExpressO35185.
BgeeO35185.
CleanExMM_STRA13.
GenevestigatorO35185.

Family and domain databases

Gene3D4.10.280.10. 1 hit.
InterProIPR011598. bHLH_dom.
IPR003650. Orange.
IPR018352. Orange_subgr.
[Graphical view]
PfamPF07527. Hairy_orange. 1 hit.
PF00010. HLH. 1 hit.
[Graphical view]
SMARTSM00353. HLH. 1 hit.
SM00511. ORANGE. 1 hit.
[Graphical view]
SUPFAMSSF47459. SSF47459. 1 hit.
PROSITEPS50888. BHLH. 1 hit.
PS51054. ORANGE. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio299753.
PROO35185.
SOURCESearch...

Entry information

Entry nameBHE40_MOUSE
AccessionPrimary (citable) accession number: O35185
Secondary accession number(s): P97289
Entry history
Integrated into UniProtKB/Swiss-Prot: March 5, 2002
Last sequence update: January 1, 1998
Last modified: July 9, 2014
This is version 123 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot