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O14503

- BHE40_HUMAN

UniProt

O14503 - BHE40_HUMAN

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
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    • History
      Entry version 129 (01 Oct 2014)
      Sequence version 1 (01 Jan 1998)
      Previous versions | rss
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    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 binding Source: UniProtKB
    5. protein domain specific binding Source: BHF-UCL
    6. protein heterodimerization activity Source: BHF-UCL
    7. protein homodimerization activity Source: BHF-UCL
    8. RNA polymerase II activating transcription factor binding Source: BHF-UCL
    9. RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in negative regulation of transcription Source: BHF-UCL
    10. RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity Source: BHF-UCL
    11. RNA polymerase II transcription factor binding transcription factor activity involved in negative regulation of transcription Source: BHF-UCL
    12. sequence-specific DNA binding RNA polymerase II transcription factor activity Source: BHF-UCL
    13. sequence-specific DNA binding transcription factor activity Source: UniProtKB
    14. 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

    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

    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. 2 Publications
    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. 2 Publications
    Mutagenesisi78 – 792LL → AA: Abolishes RXRA repression. 1 Publication
    Mutagenesisi159 – 1591K → R: Partial loss of sumoylation. Complete loss of sumoylation; when associated with R-279. 2 Publications
    Mutagenesisi279 – 2791K → R: Partial loss of sumoylation. Complete loss of sumoylation; when associated with R-159. 2 Publications

    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

    ArrayExpressiO14503.
    BgeeiO14503.
    CleanExiHS_DEC1.
    HS_STRA13.
    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
    TP53P046375EBI-711810,EBI-366083
    UBE2IP632793EBI-711810,EBI-80168

    Protein-protein interaction databases

    BioGridi114123. 24 interactions.
    DIPiDIP-36698N.
    IntActiO14503. 48 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

    MERIPSAQPP PACLPKAPGL EHGDLPGMYP AHMYQVYKSR RGIKRSEDSK    50
    ETYKLPHRLI EKKRRDRINE CIAQLKDLLP EHLKLTTLGH LEKAVVLELT 100
    LKHVKALTNL IDQQQQKIIA LQSGLQAGEL SGRNVETGQE MFCSGFQTCA 150
    REVLQYLAKH ENTRDLKSSQ LVTHLHRVVS ELLQGGTSRK PSDPAPKVMD 200
    FKEKPSSPAK GSEGPGKNCV PVIQRTFAHS SGEQSGSDTD TDSGYGGESE 250
    KGDLRSEQPC FKSDHGRRFT MGERIGAIKQ ESEEPPTKKN RMQLSDDEGH 300
    FTSSDLISSP FLGPHPHQPP FCLPFYLIPP SATAYLPMLE KCWYPTSVPV 350
    LYPGLNASAA ALSSFMNPDK ISAPLLMPQR LPSPLPAHPS VDSSVLLQAL 400
    KPIPPLNLET KD 412
    Length:412
    Mass (Da):45,510
    Last modified:January 1, 1998 - v1
    Checksum:i2D73A3D4980793E5
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    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:
    EMBL
    GenBank
    DDBJ
    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. 24 interactions.
    DIPi DIP-36698N.
    IntActi O14503. 48 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

    ArrayExpressi O14503.
    Bgeei O14503.
    CleanExi HS_DEC1.
    HS_STRA13.
    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

    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 1, 2014
    This is version 129 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