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Protein

Class E basic helix-loop-helix protein 40

Gene

BHLHE40

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

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

Protein family/group databases

MoonDBiO14503 Predicted

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
MIMi604256 gene
neXtProtiNX_O14503

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

EPDiO14503
PaxDbiO14503
PeptideAtlasiO14503
PRIDEiO14503
ProteomicsDBi48045

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 Expressed in 233 organ(s), highest expression level in ectocervix
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

GO - Molecular functioni

Protein-protein interaction databases

BioGridi114123, 58 interactors
DIPiDIP-36698N
IntActiO14503, 115 interactors
MINTiO14503
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

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
CCDSiCCDS2565.1
PIRiJC5547
RefSeqiNP_003661.1, NM_003670.2
UniGeneiHs.744856

3D structure databases

ProteinModelPortaliO14503
SMRiO14503
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi114123, 58 interactors
DIPiDIP-36698N
IntActiO14503, 115 interactors
MINTiO14503
STRINGi9606.ENSP00000256495

Protein family/group databases

MoonDBiO14503 Predicted

PTM databases

iPTMnetiO14503
PhosphoSitePlusiO14503

Polymorphism and mutation databases

BioMutaiBHLHE40

Proteomic databases

EPDiO14503
PaxDbiO14503
PeptideAtlasiO14503
PRIDEiO14503
ProteomicsDBi48045

Protocols and materials databases

DNASUi8553
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000256495; ENSP00000256495; ENSG00000134107
GeneIDi8553
KEGGihsa:8553

Organism-specific databases

CTDi8553
DisGeNETi8553
EuPathDBiHostDB:ENSG00000134107.4
GeneCardsiBHLHE40
HGNCiHGNC:1046 BHLHE40
HPAiHPA028922
MIMi604256 gene
neXtProtiNX_O14503
OpenTargetsiENSG00000134107
PharmGKBiPA25347
GenAtlasiSearch...

Phylogenomic databases

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

Enzyme and pathway databases

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

Miscellaneous databases

ChiTaRSiBHLHE40 human
GeneWikiiBHLHB2
GenomeRNAii8553
PROiPR:O14503
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000134107 Expressed in 233 organ(s), highest expression level in ectocervix
CleanExiHS_DEC1
HS_STRA13
ExpressionAtlasiO14503 baseline and differential
GenevisibleiO14503 HS

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
ProtoNetiSearch...

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: November 7, 2018
This is version 166 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
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Main funding by: National Institutes of Health

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