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O14503 (BHE40_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 127. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·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
Differentially expressed in chondrocytes protein 1
Short name=DEC1
Enhancer-of-split and hairy-related protein 2
Short name=SHARP-2
Stimulated by retinoic acid gene 13 protein
Gene names
Name:BHLHE40
Synonyms:BHLHB2, DEC1, SHARP2, STRA13
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length412 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 be involved in the regulation of chondrocyte differentiation via the cAMP pathway. Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11

Subunit structure

Homodimer. Heterodimer with BHLHE41/DEC2. Interacts with TCF3/E47. Interacts with ubiquitin-conjugating enzyme UBE2I/UBC9. Interacts with HDAC1, SUMO1, RXRA and ARNTL/BMAL1. Ref.5 Ref.6 Ref.8 Ref.9 Ref.11 Ref.12

Subcellular location

Cytoplasm. Nucleus. Nucleusnucleolus. Note: Predominantly localized in the nucleus. Ref.5 Ref.12

Tissue specificity

Expressed in cartilage, spleen, intestine, lung, and to a lesser extent in heart, brain, liver, muscle and stomach.

Post-translational modification

Ubiquitinated; which may lead to proteasomal degradation. Ref.5

Sumoylation inhibits its ubiquitination and promotes its negative regulation of the CLOCK-ARNTL/BMAL1 heterodimer transcriptional activator activity. Ref.12

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 direct assay Ref.10. Source: BHF-UCL

entrainment of circadian clock by photoperiod

Inferred from sequence or structural similarity Ref.10. Source: BHF-UCL

negative regulation of sequence-specific DNA binding transcription factor activity

Inferred from direct assay Ref.10. Source: BHF-UCL

negative regulation of transcription from RNA polymerase II promoter

Inferred from direct assay Ref.6PubMed 12624110Ref.7Ref.8. Source: BHF-UCL

regulation of transcription, DNA-templated

Non-traceable author statement Ref.1. Source: UniProtKB

transcription from RNA polymerase II promoter

Inferred from direct assay Ref.6. Source: GOC

   Cellular_componentGolgi apparatus

Inferred from direct assay. Source: HPA

nucleolus

Inferred from direct assay. Source: HPA

nucleus

Non-traceable author statement Ref.1. Source: UniProtKB

   Molecular_functionE-box binding

Inferred from direct assay Ref.6PubMed 12624110Ref.7Ref.8Ref.9Ref.10. Source: BHF-UCL

MRF binding

Inferred from sequence or structural similarity. Source: BHF-UCL

RNA polymerase II activating transcription factor binding

Inferred from sequence or structural similarity. 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 12624110Ref.8Ref.10. Source: BHF-UCL

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

Inferred from sequence or structural similarity. Source: BHF-UCL

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

Inferred from direct assay Ref.6Ref.10. Source: BHF-UCL

bHLH transcription factor binding

Inferred from physical interaction Ref.6Ref.8. Source: BHF-UCL

protein binding

Inferred from physical interaction. Source: IntAct

protein domain specific binding

Inferred from physical interaction Ref.9. Source: BHF-UCL

protein heterodimerization activity

Inferred from physical interaction Ref.6Ref.8Ref.9. Source: BHF-UCL

protein homodimerization activity

Inferred from direct assay Ref.9. Source: BHF-UCL

sequence-specific DNA binding RNA polymerase II transcription factor activity

Inferred from direct assay Ref.6. Source: BHF-UCL

sequence-specific DNA binding transcription factor activity

Non-traceable author statement Ref.1. Source: UniProtKB

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

TP53P046375EBI-711810,EBI-366083
UBE2IP632793EBI-711810,EBI-80168

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 412412Class E basic helix-loop-helix protein 40
PRO_0000127144

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
Region75 – 795Necessary for its interaction with RXRA and repressor activity against RXRA

Amino acid modifications

Cross-link159Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1, SUMO2 and SUMO3) Ref.12
Cross-link279Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1, SUMO2 and SUMO3) Ref.12

Experimental info

Mutagenesis571H → A: No effect on its interaction with ARNTL/BMAL1 or its repressor activity against the CLOCK-ARNTL/BMAL1 heterodimer. Significant reduction in E-box binding. Ref.9 Ref.11
Mutagenesis651R → A: Loss of interaction with ARNTL/BMAL1 and E-box binding. Significant reduction in its repressor activity against the CLOCK-ARNTL/BMAL1 heterodimer. Ref.9 Ref.11
Mutagenesis78 – 792LL → AA: Abolishes RXRA repression. Ref.11
Mutagenesis1591K → R: Partial loss of sumoylation. Complete loss of sumoylation; when associated with R-279. Ref.11 Ref.12
Mutagenesis2791K → R: Partial loss of sumoylation. Complete loss of sumoylation; when associated with R-159. Ref.11 Ref.12

Sequences

Sequence LengthMass (Da)Tools
O14503 [UniParc].

Last modified January 1, 1998. Version 1.
Checksum: 2D73A3D4980793E5

FASTA41245,510
        10         20         30         40         50         60 
MERIPSAQPP PACLPKAPGL EHGDLPGMYP AHMYQVYKSR RGIKRSEDSK ETYKLPHRLI 

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

       130        140        150        160        170        180 
LQSGLQAGEL SGRNVETGQE MFCSGFQTCA REVLQYLAKH ENTRDLKSSQ LVTHLHRVVS 

       190        200        210        220        230        240 
ELLQGGTSRK PSDPAPKVMD FKEKPSSPAK GSEGPGKNCV PVIQRTFAHS SGEQSGSDTD 

       250        260        270        280        290        300 
TDSGYGGESE KGDLRSEQPC FKSDHGRRFT MGERIGAIKQ ESEEPPTKKN RMQLSDDEGH 

       310        320        330        340        350        360 
FTSSDLISSP FLGPHPHQPP FCLPFYLIPP SATAYLPMLE KCWYPTSVPV LYPGLNASAA 

       370        380        390        400        410 
ALSSFMNPDK ISAPLLMPQR LPSPLPAHPS VDSSVLLQAL KPIPPLNLET KD 

« Hide

References

« Hide 'large scale' references
[1]"Molecular characterization of the novel basic helix-loop-helix protein DEC1 expressed in differentiated human embryo chondrocytes."
Shen M., Kawamoto T., Yan W., Nakamasu K., Tamagami M., Koyano Y., Noshiro M., Kato Y.
Biochem. Biophys. Res. Commun. 236:294-298(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Cartilage.
[2]"Gene structure and chromosomal location of a human bHLH transcriptional factor DEC1 x Stra13 x SHARP-2/BHLHB2."
Teramoto M., Nakamasu K., Noshiro M., Matsuda Y., Gotoh O., Shen M., Tsutsumi S., Kawamoto T., Iwamoto Y., Kato Y.
J. Biochem. 129:391-396(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
Tissue: Leukocyte.
[3]"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: Skin.
[4]"Exon-intron structure of the human STRA13(DEC1) bHLH transcription factor gene."
Ivanov S.V., Lerman M.I.
Submitted (FEB-2001) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 4-412.
[5]"Regulation of STRA13 by the von Hippel-Lindau tumor suppressor protein, hypoxia, and the UBC9/ubiquitin proteasome degradation pathway."
Ivanova A.V., Ivanov S.V., Danilkovitch-Miagkova A., Lerman M.I.
J. Biol. Chem. 276:15306-15315(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION, INTERACTION WITH UBE2I, SUBCELLULAR LOCATION.
[6]"Dec1 and Dec2 are regulators of the mammalian molecular clock."
Honma S., Kawamoto T., Takagi Y., Fujimoto K., Sato F., Noshiro M., Kato Y., Honma K.I.
Nature 419:841-844(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH ARNTL.
[7]"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.
[8]"DNA binding, but not interaction with Bmal1, is responsible for DEC1-mediated transcription regulation of the circadian gene mPer1."
Li Y., Song X., Ma Y., Liu J., Yang D., Yan B.
Biochem. J. 382:895-904(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, HETERODIMERIZATION WITH BHLHE41/DEC2, INTERACTION WITH ARNTL.
[9]"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: FUNCTION, INTERACTION WITH ARNTL, MUTAGENESIS OF HIS-57 AND ARG-65.
[10]"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.
[11]"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, INTERACTION WITH RXRA, MUTAGENESIS OF 78-LEU-LEU-79.
[12]"SUMOylation of DEC1 protein regulates its transcriptional activity and enhances its stability."
Hong Y., Xing X., Li S., Bi H., Yang C., Zhao F., Liu Y., Ao X., Chang A.K., Wu H.
PLoS ONE 6:E23046-E23046(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: SUMOYLATION AT LYS-159 AND LYS-279, INTERACTION WITH HDAC1 AND SUMO1, SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-159 AND LYS-279.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AB004066 mRNA. Translation: BAA21720.1.
AB043885 Genomic DNA. Translation: BAB18565.1.
BC082238 mRNA. Translation: AAH82238.1.
AH010709 Genomic DNA. Translation: AAK49525.1.
CCDSCCDS2565.1.
PIRJC5547.
RefSeqNP_003661.1. NM_003670.2.
UniGeneHs.744856.

3D structure databases

ProteinModelPortalO14503.
SMRO14503. Positions 49-109.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid114123. 24 interactions.
DIPDIP-36698N.
IntActO14503. 48 interactions.
MINTMINT-1374397.
STRING9606.ENSP00000256495.

PTM databases

PhosphoSiteO14503.

Proteomic databases

MaxQBO14503.
PaxDbO14503.
PRIDEO14503.

Protocols and materials databases

DNASU8553.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000256495; ENSP00000256495; ENSG00000134107.
GeneID8553.
KEGGhsa:8553.
UCSCuc003bqf.3. human.

Organism-specific databases

CTD8553.
GeneCardsGC03P004997.
HGNCHGNC:1046. BHLHE40.
HPAHPA028921.
HPA028922.
MIM604256. gene.
neXtProtNX_O14503.
PharmGKBPA25347.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG281955.
HOGENOMHOG000234381.
InParanoidO14503.
KOK03729.
OMAEQPYFKS.
OrthoDBEOG712TWC.
PhylomeDBO14503.
TreeFamTF330859.

Enzyme and pathway databases

ReactomeREACT_24941. Circadian Clock.
SignaLinkO14503.

Gene expression databases

ArrayExpressO14503.
BgeeO14503.
CleanExHS_DEC1.
HS_STRA13.
GenevestigatorO14503.

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

ChiTaRSBHLHE40. human.
GeneWikiBHLHB2.
GenomeRNAi8553.
NextBio32049.
PROO14503.
SOURCESearch...

Entry information

Entry nameBHE40_HUMAN
AccessionPrimary (citable) accession number: O14503
Secondary accession number(s): Q96TD3
Entry history
Integrated into UniProtKB/Swiss-Prot: March 5, 2002
Last sequence update: January 1, 1998
Last modified: July 9, 2014
This is version 127 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome 3

Human chromosome 3: entries, gene names and cross-references to MIM