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O14503

- BHE40_HUMAN

UniProt

O14503 - BHE40_HUMAN

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Protein

Class E basic helix-loop-helix protein 40

Gene

BHLHE40

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

Functioni

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.6 Publications

GO - Molecular functioni

  1. bHLH transcription factor binding Source: BHF-UCL
  2. E-box binding Source: BHF-UCL
  3. MRF binding Source: BHF-UCL
  4. protein domain specific binding Source: BHF-UCL
  5. protein heterodimerization activity Source: BHF-UCL
  6. protein homodimerization activity Source: BHF-UCL
  7. RNA polymerase II activating transcription factor binding Source: BHF-UCL
  8. RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in negative regulation of transcription Source: BHF-UCL
  9. RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity Source: BHF-UCL
  10. RNA polymerase II transcription factor binding transcription factor activity involved in negative regulation of transcription Source: BHF-UCL
  11. sequence-specific DNA binding RNA polymerase II transcription factor activity Source: BHF-UCL
  12. sequence-specific DNA binding transcription factor activity Source: UniProtKB
  13. transcription corepressor activity Source: UniProtKB

GO - Biological processi

  1. circadian regulation of gene expression Source: BHF-UCL
  2. entrainment of circadian clock by photoperiod Source: BHF-UCL
  3. negative regulation of sequence-specific DNA binding transcription factor activity Source: BHF-UCL
  4. negative regulation of transcription, DNA-templated Source: UniProtKB
  5. negative regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
  6. regulation of transcription, DNA-templated Source: UniProtKB
  7. transcription from RNA polymerase II promoter Source: GOC
Complete GO annotation...

Keywords - Molecular functioni

Repressor

Keywords - Biological processi

Biological rhythms, Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding

Enzyme and pathway databases

ReactomeiREACT_111118. BMAL1:CLOCK,NPAS2 activates circadian gene expression.
SignaLinkiO14503.

Names & Taxonomyi

Protein namesi
Recommended 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 namesi
Name:BHLHE40
Synonyms:BHLHB2, DEC1, SHARP2, STRA13
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 3

Organism-specific databases

HGNCiHGNC:1046. BHLHE40.

Subcellular locationi

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

GO - Cellular componenti

  1. Golgi apparatus Source: HPA
  2. nucleolus Source: HPA
  3. nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi57 – 571H → 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. 1 Publication
Mutagenesisi65 – 651R → A: Loss of interaction with ARNTL/BMAL1 and E-box binding. Significant reduction in its repressor activity against the CLOCK-ARNTL/BMAL1 heterodimer. 1 Publication
Mutagenesisi78 – 792LL → AA: Abolishes RXRA repression. 1 Publication
Mutagenesisi159 – 1591K → R: Partial loss of sumoylation. Complete loss of sumoylation; when associated with R-279. 1 Publication
Mutagenesisi279 – 2791K → R: Partial loss of sumoylation. Complete loss of sumoylation; when associated with R-159. 1 Publication

Organism-specific databases

PharmGKBiPA25347.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 412412Class E basic helix-loop-helix protein 40PRO_0000127144Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Cross-linki159 – 159Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1, SUMO2 and SUMO3)
Cross-linki279 – 279Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1, SUMO2 and SUMO3)

Post-translational modificationi

Ubiquitinated; which may lead to proteasomal degradation.1 Publication
Sumoylation inhibits its ubiquitination and promotes its negative regulation of the CLOCK-ARNTL/BMAL1 heterodimer transcriptional activator activity.2 Publications

Keywords - PTMi

Isopeptide bond, Ubl conjugation

Proteomic databases

MaxQBiO14503.
PaxDbiO14503.
PRIDEiO14503.

PTM databases

PhosphoSiteiO14503.

Expressioni

Tissue specificityi

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

Gene expression databases

BgeeiO14503.
CleanExiHS_DEC1.
HS_STRA13.
ExpressionAtlasiO14503. baseline and differential.
GenevestigatoriO14503.

Organism-specific databases

HPAiHPA028921.
HPA028922.

Interactioni

Subunit structurei

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

Binary interactionsi

WithEntry#Exp.IntActNotes
P0C2063EBI-711810,EBI-9675596From a different organism.
TP53P046375EBI-711810,EBI-366083
UBE2IP632793EBI-711810,EBI-80168

Protein-protein interaction databases

BioGridi114123. 25 interactions.
DIPiDIP-36698N.
IntActiO14503. 50 interactions.
MINTiMINT-1374397.
STRINGi9606.ENSP00000256495.

Structurei

3D structure databases

ProteinModelPortaliO14503.
SMRiO14503. Positions 49-109.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini52 – 10756bHLHPROSITE-ProRule annotationAdd
BLAST
Domaini142 – 17534OrangePROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni1 – 139139Essential for its interaction with ARNTL/BMAL1, E-box binding and repressor activity against the CLOCK-ARNTL/BMAL1 heterodimerAdd
BLAST
Regioni75 – 795Necessary for its interaction with RXRA and repressor activity against RXRA

Sequence similaritiesi

Contains 1 bHLH (basic helix-loop-helix) domain.PROSITE-ProRule annotation
Contains 1 Orange domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiNOG281955.
HOGENOMiHOG000234381.
InParanoidiO14503.
KOiK03729.
OMAiEQPYFKS.
OrthoDBiEOG712TWC.
PhylomeDBiO14503.
TreeFamiTF330859.

Family and domain databases

Gene3Di4.10.280.10. 1 hit.
InterProiIPR011598. bHLH_dom.
IPR003650. Orange.
IPR018352. Orange_subgr.
[Graphical view]
PfamiPF07527. Hairy_orange. 1 hit.
PF00010. HLH. 1 hit.
[Graphical view]
SMARTiSM00353. HLH. 1 hit.
SM00511. ORANGE. 1 hit.
[Graphical view]
SUPFAMiSSF47459. SSF47459. 1 hit.
PROSITEiPS50888. BHLH. 1 hit.
PS51054. ORANGE. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

O14503-1 [UniParc]FASTAAdd to Basket

« Hide

        10         20         30         40         50
MERIPSAQPP PACLPKAPGL EHGDLPGMYP AHMYQVYKSR RGIKRSEDSK
60 70 80 90 100
ETYKLPHRLI EKKRRDRINE CIAQLKDLLP EHLKLTTLGH LEKAVVLELT
110 120 130 140 150
LKHVKALTNL IDQQQQKIIA LQSGLQAGEL SGRNVETGQE MFCSGFQTCA
160 170 180 190 200
REVLQYLAKH ENTRDLKSSQ LVTHLHRVVS ELLQGGTSRK PSDPAPKVMD
210 220 230 240 250
FKEKPSSPAK GSEGPGKNCV PVIQRTFAHS SGEQSGSDTD TDSGYGGESE
260 270 280 290 300
KGDLRSEQPC FKSDHGRRFT MGERIGAIKQ ESEEPPTKKN RMQLSDDEGH
310 320 330 340 350
FTSSDLISSP FLGPHPHQPP FCLPFYLIPP SATAYLPMLE KCWYPTSVPV
360 370 380 390 400
LYPGLNASAA ALSSFMNPDK ISAPLLMPQR LPSPLPAHPS VDSSVLLQAL
410
KPIPPLNLET KD
Length:412
Mass (Da):45,510
Last modified:January 1, 1998 - v1
Checksum:i2D73A3D4980793E5
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB004066 mRNA. Translation: BAA21720.1.
AB043885 Genomic DNA. Translation: BAB18565.1.
BC082238 mRNA. Translation: AAH82238.1.
AH010709 Genomic DNA. Translation: AAK49525.1.
CCDSiCCDS2565.1.
PIRiJC5547.
RefSeqiNP_003661.1. NM_003670.2.
UniGeneiHs.744856.

Genome annotation databases

EnsembliENST00000256495; ENSP00000256495; ENSG00000134107.
GeneIDi8553.
KEGGihsa:8553.
UCSCiuc003bqf.3. human.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB004066 mRNA. Translation: BAA21720.1 .
AB043885 Genomic DNA. Translation: BAB18565.1 .
BC082238 mRNA. Translation: AAH82238.1 .
AH010709 Genomic DNA. Translation: AAK49525.1 .
CCDSi CCDS2565.1.
PIRi JC5547.
RefSeqi NP_003661.1. NM_003670.2.
UniGenei Hs.744856.

3D structure databases

ProteinModelPortali O14503.
SMRi O14503. Positions 49-109.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 114123. 25 interactions.
DIPi DIP-36698N.
IntActi O14503. 50 interactions.
MINTi MINT-1374397.
STRINGi 9606.ENSP00000256495.

PTM databases

PhosphoSitei O14503.

Proteomic databases

MaxQBi O14503.
PaxDbi O14503.
PRIDEi O14503.

Protocols and materials databases

DNASUi 8553.
Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000256495 ; ENSP00000256495 ; ENSG00000134107 .
GeneIDi 8553.
KEGGi hsa:8553.
UCSCi uc003bqf.3. human.

Organism-specific databases

CTDi 8553.
GeneCardsi GC03P004997.
HGNCi HGNC:1046. BHLHE40.
HPAi HPA028921.
HPA028922.
MIMi 604256. gene.
neXtProti NX_O14503.
PharmGKBi PA25347.
GenAtlasi Search...

Phylogenomic databases

eggNOGi NOG281955.
HOGENOMi HOG000234381.
InParanoidi O14503.
KOi K03729.
OMAi EQPYFKS.
OrthoDBi EOG712TWC.
PhylomeDBi O14503.
TreeFami TF330859.

Enzyme and pathway databases

Reactomei REACT_111118. BMAL1:CLOCK,NPAS2 activates circadian gene expression.
SignaLinki O14503.

Miscellaneous databases

ChiTaRSi BHLHE40. human.
GeneWikii BHLHB2.
GenomeRNAii 8553.
NextBioi 32049.
PROi O14503.
SOURCEi Search...

Gene expression databases

Bgeei O14503.
CleanExi HS_DEC1.
HS_STRA13.
ExpressionAtlasi O14503. baseline and differential.
Genevestigatori O14503.

Family and domain databases

Gene3Di 4.10.280.10. 1 hit.
InterProi IPR011598. bHLH_dom.
IPR003650. Orange.
IPR018352. Orange_subgr.
[Graphical view ]
Pfami PF07527. Hairy_orange. 1 hit.
PF00010. HLH. 1 hit.
[Graphical view ]
SMARTi SM00353. HLH. 1 hit.
SM00511. ORANGE. 1 hit.
[Graphical view ]
SUPFAMi SSF47459. SSF47459. 1 hit.
PROSITEi PS50888. BHLH. 1 hit.
PS51054. ORANGE. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  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. 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. 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.

Entry informationi

Entry nameiBHE40_HUMAN
AccessioniPrimary (citable) accession number: O14503
Secondary accession number(s): Q96TD3
Entry historyi
Integrated into UniProtKB/Swiss-Prot: March 5, 2002
Last sequence update: January 1, 1998
Last modified: October 29, 2014
This is version 130 of the entry and version 1 of the sequence. [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 3
    Human chromosome 3: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3