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Protein

Class E basic helix-loop-helix protein 40

Gene

BHLHE40

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: 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

GO - Biological processi

  • circadian regulation of gene expression Source: BHF-UCL
  • entrainment of circadian clock by photoperiod Source: BHF-UCL
  • negative regulation of sequence-specific DNA binding transcription factor activity Source: BHF-UCL
  • negative regulation of transcription, DNA-templated Source: UniProtKB
  • negative regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
  • regulation of transcription, DNA-templated Source: UniProtKB
  • transcription, DNA-templated Source: UniProtKB-KW

Keywordsi

Molecular functionDNA-binding, Repressor
Biological processBiological rhythms, Transcription, Transcription regulation

Enzyme and pathway databases

ReactomeiR-HSA-1368108. BMAL1:CLOCK,NPAS2 activates circadian gene expression.
SignaLinkiO14503.
SIGNORiO14503.

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
Proteomesi
  • UP000005640 Componenti: Chromosome 3

Organism-specific databases

EuPathDBiHostDB:ENSG00000134107.4.
HGNCiHGNC:1046. BHLHE40.

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

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi57H → 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 Publication1
Mutagenesisi65R → A: Loss of interaction with ARNTL/BMAL1 and E-box binding. Significant reduction in its repressor activity against the CLOCK-ARNTL/BMAL1 heterodimer. 1 Publication1
Mutagenesisi78 – 79LL → AA: Abolishes RXRA repression. 1 Publication2
Mutagenesisi159K → R: Partial loss of sumoylation. Complete loss of sumoylation; when associated with R-279. 1 Publication1
Mutagenesisi279K → R: Partial loss of sumoylation. Complete loss of sumoylation; when associated with R-159. 1 Publication1

Organism-specific databases

DisGeNETi8553.
OpenTargetsiENSG00000134107.
PharmGKBiPA25347.

Polymorphism and mutation databases

BioMutaiBHLHE40.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001271441 – 412Class E basic helix-loop-helix protein 40Add BLAST412

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Cross-linki159Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1, SUMO2 and SUMO3)1 Publication
Cross-linki167Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
Modified residuei235PhosphoserineCombined sources1
Cross-linki279Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1); alternateCombined sources
Cross-linki279Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1, SUMO2 and SUMO3); alternate
Cross-linki279Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2); alternateCombined sources
Cross-linki288Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
Modified residuei383PhosphoserineBy similarity1

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, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiO14503.
PeptideAtlasiO14503.
PRIDEiO14503.

PTM databases

iPTMnetiO14503.
PhosphoSitePlusiO14503.

Expressioni

Tissue specificityi

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

Gene expression databases

BgeeiENSG00000134107.
CleanExiHS_DEC1.
HS_STRA13.
ExpressionAtlasiO14503. baseline and differential.
GenevisibleiO14503. HS.

Organism-specific databases

HPAiHPA028922.

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

Show more details

GO - Molecular functioni

  • bHLH transcription factor binding Source: BHF-UCL
  • MRF binding Source: BHF-UCL
  • protein domain specific binding Source: BHF-UCL
  • protein heterodimerization activity Source: BHF-UCL
  • protein homodimerization activity Source: BHF-UCL
  • RNA polymerase II activating transcription factor binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi114123. 57 interactors.
DIPiDIP-36698N.
IntActiO14503. 108 interactors.
MINTiMINT-1374397.
STRINGi9606.ENSP00000256495.

Structurei

3D structure databases

ProteinModelPortaliO14503.
SMRiO14503.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini52 – 107bHLHPROSITE-ProRule annotationAdd BLAST56
Domaini142 – 175OrangePROSITE-ProRule annotationAdd BLAST34

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 139Essential for interaction with ARNTL/BMAL1, E-box binding and repressor activity against the CLOCK-ARNTL/BMAL1 heterodimerAdd BLAST139
Regioni75 – 79Necessary for interaction with RXRA and repressor activity against RXRA1 Publication5

Phylogenomic databases

eggNOGiKOG4304. Eukaryota.
ENOG4111F0X. LUCA.
GeneTreeiENSGT00510000046898.
HOGENOMiHOG000234381.
InParanoidiO14503.
KOiK03729.
OMAiAGQEMFC.
OrthoDBiEOG091G0D3I.
PhylomeDBiO14503.
TreeFamiTF330859.

Family and domain databases

CDDicd00083. HLH. 1 hit.
Gene3Di4.10.280.10. 1 hit.
InterProiView protein in InterPro
IPR011598. bHLH_dom.
IPR036638. HLH_DNA-bd_sf.
IPR003650. Orange_dom.
PfamiView protein in Pfam
PF07527. Hairy_orange. 1 hit.
PF00010. HLH. 1 hit.
SMARTiView protein in SMART
SM00353. HLH. 1 hit.
SM00511. ORANGE. 1 hit.
SUPFAMiSSF47459. SSF47459. 1 hit.
PROSITEiView protein in PROSITE
PS50888. BHLH. 1 hit.
PS51054. ORANGE. 1 hit.

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.

Similar proteinsi

Entry informationi

Entry nameiBHE40_HUMAN
AccessioniPrimary (citable) accession number: O14503
Secondary accession number(s): Q96TD3
Entry historyiIntegrated into UniProtKB/Swiss-Prot: March 5, 2002
Last sequence update: January 1, 1998
Last modified: October 25, 2017
This is version 157 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 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