UniProtKB - O14503 (BHE40_HUMAN)
Class E basic helix-loop-helix protein 40
BHLHE40
Functioni
Transcriptional repressor involved in the regulation of the circadian rhythm by negatively regulating the activity of the clock genes and clock-controlled genes (PubMed:12397359, PubMed:18411297).
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) (PubMed:14672706).
Both these loops are interlocked as it represses the expression of PER1/2 and in turn is repressed by PER1/2 and CRY1/2 (PubMed:15193144).
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 (PubMed:15560782).
Negatively regulates its own expression and the expression of DBP and BHLHE41/DEC2 (PubMed:14672706).
Acts as a corepressor of RXR and the RXR-LXR heterodimers and represses the ligand-induced RXRA and NR1H3/LXRA transactivation activity (PubMed:19786558).
May be involved in the regulation of chondrocyte differentiation via the cAMP pathway (PubMed:19786558).
Represses the transcription of NR0B2 and attentuates the transactivation of NR0B2 by the CLOCK-ARNTL/BMAL1 complex (PubMed:28797635).
Drives the circadian rhythm of blood pressure through transcriptional repression of ATP1B1 in the cardiovascular system (PubMed:30012868).
8 PublicationsGO - Molecular functioni
- bHLH transcription factor binding Source: BHF-UCL
- DNA-binding transcription factor activity Source: UniProtKB
- DNA-binding transcription factor activity, RNA polymerase II-specific Source: BHF-UCL
- DNA-binding transcription repressor activity, RNA polymerase II-specific Source: BHF-UCL
- E-box binding Source: UniProtKB
- 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 cis-regulatory region sequence-specific DNA binding Source: GO_Central
- RNA polymerase II-specific DNA-binding transcription factor binding Source: BHF-UCL
- sequence-specific double-stranded DNA binding Source: ARUK-UCL
GO - Biological processi
- anterior/posterior pattern specification Source: GO_Central
- circadian regulation of gene expression Source: BHF-UCL
- circadian rhythm Source: UniProtKB
- entrainment of circadian clock by photoperiod Source: BHF-UCL
- negative regulation of DNA-binding transcription factor activity Source: BHF-UCL
- negative regulation of transcription, DNA-templated Source: UniProtKB
- negative regulation of transcription by RNA polymerase II Source: BHF-UCL
- regulation of circadian rhythm Source: UniProtKB
- regulation of neurogenesis Source: GO_Central
- regulation of transcription, DNA-templated Source: UniProtKB
- regulation of transcription by RNA polymerase II Source: GO_Central
Keywordsi
Molecular function | DNA-binding, Repressor |
Biological process | Biological rhythms, Transcription, Transcription regulation |
Enzyme and pathway databases
PathwayCommonsi | O14503 |
Reactomei | R-HSA-1368108, BMAL1:CLOCK,NPAS2 activates circadian gene expression |
SignaLinki | O14503 |
SIGNORi | O14503 |
Protein family/group databases
MoonDBi | O14503, Predicted |
Names & Taxonomyi
Protein namesi | Recommended name: Class E basic helix-loop-helix protein 40Short name: bHLHe40 Alternative name(s): Class B basic helix-loop-helix protein 2 Short name: bHLHb2 Differentially expressed in chondrocytes protein 12 Publications Short name: DEC12 Publications 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, DEC12 Publications, SHARP2, STRA13 |
Organismi | Homo sapiens (Human) |
Taxonomic identifieri | 9606 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Proteomesi |
|
Organism-specific databases
HGNCi | HGNC:1046, BHLHE40 |
MIMi | 604256, gene |
neXtProti | NX_O14503 |
VEuPathDBi | HostDB:ENSG00000134107 |
Subcellular locationi
Nucleus
- nuclear body Source: HPA
- nucleus Source: UniProtKB
Other locations
Keywords - Cellular componenti
Cytoplasm, NucleusPathology & Biotechi
Mutagenesis
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Mutagenesisi | 56 | P → A: No loss of repressor activity against NR0B2. 1 Publication | 1 | |
Mutagenesisi | 57 | H → 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 | 1 | |
Mutagenesisi | 58 | R → A: Loss of repressor activity against NR0B2. 1 Publication | 1 | |
Mutagenesisi | 65 | R → 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 | 1 | |
Mutagenesisi | 78 – 79 | LL → AA: Abolishes RXRA repression. 1 Publication | 2 | |
Mutagenesisi | 159 | K → R: Partial loss of sumoylation. Complete loss of sumoylation; when associated with R-279. 1 Publication | 1 | |
Mutagenesisi | 279 | K → R: Partial loss of sumoylation. Complete loss of sumoylation; when associated with R-159. 1 Publication | 1 |
Organism-specific databases
DisGeNETi | 8553 |
OpenTargetsi | ENSG00000134107 |
PharmGKBi | PA25347 |
Miscellaneous databases
Pharosi | O14503, Tbio |
Genetic variation databases
BioMutai | BHLHE40 |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000127144 | 1 – 412 | Class E basic helix-loop-helix protein 40Add BLAST | 412 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Cross-linki | 159 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1, SUMO2 and SUMO3)1 Publication | ||
Cross-linki | 167 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources | ||
Modified residuei | 235 | PhosphoserineCombined sources | 1 | |
Cross-linki | 279 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1); alternateCombined sources | ||
Cross-linki | 279 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1, SUMO2 and SUMO3); alternate | ||
Cross-linki | 279 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2); alternateCombined sources | ||
Cross-linki | 288 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources | ||
Modified residuei | 383 | PhosphoserineBy similarity | 1 |
Post-translational modificationi
Keywords - PTMi
Isopeptide bond, Phosphoprotein, Ubl conjugationProteomic databases
EPDi | O14503 |
jPOSTi | O14503 |
MassIVEi | O14503 |
PaxDbi | O14503 |
PeptideAtlasi | O14503 |
PRIDEi | O14503 |
ProteomicsDBi | 48045 |
PTM databases
iPTMneti | O14503 |
PhosphoSitePlusi | O14503 |
Expressioni
Tissue specificityi
Gene expression databases
Bgeei | ENSG00000134107, Expressed in ectocervix and 245 other tissues |
ExpressionAtlasi | O14503, baseline and differential |
Genevisiblei | O14503, HS |
Organism-specific databases
HPAi | ENSG00000134107, Low tissue specificity |
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 PublicationsBinary interactionsi
O14503
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-specific DNA-binding transcription factor binding Source: BHF-UCL
Protein-protein interaction databases
BioGRIDi | 114123, 105 interactors |
DIPi | DIP-36698N |
IntActi | O14503, 120 interactors |
MINTi | O14503 |
STRINGi | 9606.ENSP00000256495 |
Miscellaneous databases
RNActi | O14503, protein |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 52 – 107 | bHLHPROSITE-ProRule annotationAdd BLAST | 56 | |
Domaini | 142 – 175 | OrangePROSITE-ProRule annotationAdd BLAST | 34 |
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 1 – 139 | Essential for interaction with ARNTL/BMAL1, E-box binding and repressor activity against the CLOCK-ARNTL/BMAL1 heterodimerAdd BLAST | 139 | |
Regioni | 75 – 79 | Necessary for interaction with RXRA and repressor activity against RXRA1 Publication | 5 | |
Regioni | 182 – 303 | DisorderedSequence analysisAdd BLAST | 122 |
Compositional bias
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Compositional biasi | 224 – 243 | Polar residuesSequence analysisAdd BLAST | 20 | |
Compositional biasi | 244 – 298 | Basic and acidic residuesSequence analysisAdd BLAST | 55 |
Phylogenomic databases
eggNOGi | KOG4304, Eukaryota |
GeneTreei | ENSGT00940000158384 |
HOGENOMi | CLU_049895_0_1_1 |
InParanoidi | O14503 |
OMAi | EGHAKNC |
OrthoDBi | 629563at2759 |
PhylomeDBi | O14503 |
TreeFami | TF330859 |
Family and domain databases
Gene3Di | 4.10.280.10, 1 hit |
InterProi | View protein in InterPro IPR011598, bHLH_dom IPR036638, HLH_DNA-bd_sf IPR003650, Orange_dom |
Pfami | View protein in Pfam PF07527, Hairy_orange, 1 hit PF00010, HLH, 1 hit |
SMARTi | View protein in SMART SM00353, HLH, 1 hit SM00511, ORANGE, 1 hit |
SUPFAMi | SSF47459, SSF47459, 1 hit |
PROSITEi | View protein in PROSITE PS50888, BHLH, 1 hit PS51054, ORANGE, 1 hit |
i Sequence
Sequence statusi: Complete.
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
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 |
Genome annotation databases
Ensembli | ENST00000256495; ENSP00000256495; ENSG00000134107 |
GeneIDi | 8553 |
KEGGi | hsa:8553 |
MANE-Selecti | ENST00000256495.4; ENSP00000256495.3; NM_003670.3; NP_003661.1 |
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 |
CCDSi | CCDS2565.1 |
PIRi | JC5547 |
RefSeqi | NP_003661.1, NM_003670.2 |
3D structure databases
SMRi | O14503 |
ModBasei | Search... |
Protein-protein interaction databases
BioGRIDi | 114123, 105 interactors |
DIPi | DIP-36698N |
IntActi | O14503, 120 interactors |
MINTi | O14503 |
STRINGi | 9606.ENSP00000256495 |
Protein family/group databases
MoonDBi | O14503, Predicted |
PTM databases
iPTMneti | O14503 |
PhosphoSitePlusi | O14503 |
Genetic variation databases
BioMutai | BHLHE40 |
Proteomic databases
EPDi | O14503 |
jPOSTi | O14503 |
MassIVEi | O14503 |
PaxDbi | O14503 |
PeptideAtlasi | O14503 |
PRIDEi | O14503 |
ProteomicsDBi | 48045 |
Protocols and materials databases
Antibodypediai | 10051, 331 antibodies from 33 providers |
DNASUi | 8553 |
Genome annotation databases
Ensembli | ENST00000256495; ENSP00000256495; ENSG00000134107 |
GeneIDi | 8553 |
KEGGi | hsa:8553 |
MANE-Selecti | ENST00000256495.4; ENSP00000256495.3; NM_003670.3; NP_003661.1 |
Organism-specific databases
CTDi | 8553 |
DisGeNETi | 8553 |
GeneCardsi | BHLHE40 |
HGNCi | HGNC:1046, BHLHE40 |
HPAi | ENSG00000134107, Low tissue specificity |
MIMi | 604256, gene |
neXtProti | NX_O14503 |
OpenTargetsi | ENSG00000134107 |
PharmGKBi | PA25347 |
VEuPathDBi | HostDB:ENSG00000134107 |
GenAtlasi | Search... |
Phylogenomic databases
eggNOGi | KOG4304, Eukaryota |
GeneTreei | ENSGT00940000158384 |
HOGENOMi | CLU_049895_0_1_1 |
InParanoidi | O14503 |
OMAi | EGHAKNC |
OrthoDBi | 629563at2759 |
PhylomeDBi | O14503 |
TreeFami | TF330859 |
Enzyme and pathway databases
PathwayCommonsi | O14503 |
Reactomei | R-HSA-1368108, BMAL1:CLOCK,NPAS2 activates circadian gene expression |
SignaLinki | O14503 |
SIGNORi | O14503 |
Miscellaneous databases
BioGRID-ORCSi | 8553, 16 hits in 1073 CRISPR screens |
ChiTaRSi | BHLHE40, human |
GeneWikii | BHLHB2 |
GenomeRNAii | 8553 |
Pharosi | O14503, Tbio |
PROi | PR:O14503 |
RNActi | O14503, protein |
SOURCEi | Search... |
Gene expression databases
Bgeei | ENSG00000134107, Expressed in ectocervix and 245 other tissues |
ExpressionAtlasi | O14503, baseline and differential |
Genevisiblei | O14503, HS |
Family and domain databases
Gene3Di | 4.10.280.10, 1 hit |
InterProi | View protein in InterPro IPR011598, bHLH_dom IPR036638, HLH_DNA-bd_sf IPR003650, Orange_dom |
Pfami | View protein in Pfam PF07527, Hairy_orange, 1 hit PF00010, HLH, 1 hit |
SMARTi | View protein in SMART SM00353, HLH, 1 hit SM00511, ORANGE, 1 hit |
SUPFAMi | SSF47459, SSF47459, 1 hit |
PROSITEi | View protein in PROSITE PS50888, BHLH, 1 hit PS51054, ORANGE, 1 hit |
MobiDBi | Search... |
Entry informationi
Entry namei | BHE40_HUMAN | |
Accessioni | O14503Primary (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: | February 23, 2022 | |
This is version 187 of the entry and version 1 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program | |
Disclaimer | Any 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
Reference proteomeDocuments
- Human chromosome 3
Human chromosome 3: entries, gene names and cross-references to MIM - MIM cross-references
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot