BHE40_MOUSE
ID BHE40_MOUSE Reviewed; 411 AA.
AC O35185; P97289;
DT 05-MAR-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1998, sequence version 1.
DT 03-AUG-2022, entry version 178.
DE RecName: Full=Class E basic helix-loop-helix protein 40;
DE Short=bHLHe40;
DE AltName: Full=Class B basic helix-loop-helix protein 2;
DE Short=bHLHb2;
DE AltName: Full=Differentially expressed in chondrocytes protein 1 {ECO:0000303|PubMed:30012868};
DE Short=DEC1 {ECO:0000303|PubMed:30012868};
DE AltName: Full=E47 interaction protein 1;
DE Short=EIP1;
DE AltName: Full=Stimulated by retinoic acid gene 13 protein;
GN Name=Bhlhe40;
GN Synonyms=Bhlhb2, Clast5, Dec1 {ECO:0000303|PubMed:30012868}, Stra13;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND FUNCTION.
RC TISSUE=Embryonic carcinoma;
RX PubMed=9284045; DOI=10.1101/gad.11.16.2052;
RA Boudjelal M., Taneja R., Matsubara S., Bouillet P., Dolle P., Chambon P.;
RT "Overexpression of Stra13, a novel retinoic acid-inducible gene of the
RT basic helix-loop-helix family, inhibits mesodermal and promotes neuronal
RT differentiation of P19 cells.";
RL Genes Dev. 11:2052-2065(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND INTERACTION WITH TCF3/E47.
RC STRAIN=BALB/cJ;
RX PubMed=9050988; DOI=10.1038/sj.onc.1200912;
RA Dear T.N., Hainzl T., Follo M., Nehls M., Wilmore H., Matena K., Boehm T.;
RT "Identification of interaction partners for the basic-helix-loop-helix
RT protein E47.";
RL Oncogene 14:891-898(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=C57BL/6J; TISSUE=Spleen;
RA O-Wang J.;
RT "Isolation of a CD40-activated gene from murine splenic B cells.";
RL Submitted (MAR-2001) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Mammary gland;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP FUNCTION.
RX PubMed=14672706; DOI=10.1016/j.bbrc.2003.11.099;
RA Kawamoto T., Noshiro M., Sato F., Maemura K., Takeda N., Nagai R.,
RA Iwata T., Fujimoto K., Furukawa M., Miyazaki K., Honma S., Honma K.I.,
RA Kato Y.;
RT "A novel autofeedback loop of Dec1 transcription involved in circadian
RT rhythm regulation.";
RL Biochem. Biophys. Res. Commun. 313:117-124(2004).
RN [6]
RP HETERODIMERIZATION WITH BHLHE41/DEC2.
RX PubMed=15560782; DOI=10.1111/j.1432-1033.2004.04379.x;
RA Sato F., Kawamoto T., Fujimoto K., Noshiro M., Honda K.K., Honma S.,
RA Honma K., Kato Y.;
RT "Functional analysis of the basic helix-loop-helix transcription factor
RT DEC1 in circadian regulation. Interaction with BMAL1.";
RL Eur. J. Biochem. 271:4409-4419(2004).
RN [7]
RP FUNCTION.
RX PubMed=18411297; DOI=10.1128/mcb.02168-07;
RA Nakashima A., Kawamoto T., Honda K.K., Ueshima T., Noshiro M., Iwata T.,
RA Fujimoto K., Kubo H., Honma S., Yorioka N., Kohno N., Kato Y.;
RT "DEC1 modulates the circadian phase of clock gene expression.";
RL Mol. Cell. Biol. 28:4080-4092(2008).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic fibroblast;
RX PubMed=19131326; DOI=10.1074/mcp.m800451-mcp200;
RA Sweet S.M., Bailey C.M., Cunningham D.L., Heath J.K., Cooper H.J.;
RT "Large scale localization of protein phosphorylation by use of electron
RT capture dissociation mass spectrometry.";
RL Mol. Cell. Proteomics 8:904-912(2009).
RN [9]
RP FUNCTION, AND INDUCTION.
RX PubMed=19786558; DOI=10.1124/mol.109.057000;
RA Cho Y., Noshiro M., Choi M., Morita K., Kawamoto T., Fujimoto K., Kato Y.,
RA Makishima M.;
RT "The basic helix-loop-helix proteins differentiated embryo chondrocyte
RT (DEC) 1 and DEC2 function as corepressors of retinoid X receptors.";
RL Mol. Pharmacol. 76:1360-1369(2009).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-383, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Kidney;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [11]
RP FUNCTION.
RX PubMed=30012868; DOI=10.1161/hypertensionaha.118.11075;
RA Nakashima A., Kawamoto T., Noshiro M., Ueno T., Doi S., Honda K.,
RA Maruhashi T., Noma K., Honma S., Masaki T., Higashi Y., Kato Y.;
RT "Dec1 and CLOCK regulate Na+/K+-ATPase beta1 subunit expression and blood
RT pressure.";
RL Hypertension 72:746-754(2018).
CC -!- FUNCTION: Transcriptional repressor involved in the regulation of the
CC circadian rhythm by negatively regulating the activity of the clock
CC genes and clock-controlled genes (PubMed:18411297). Acts as the
CC negative limb of a novel autoregulatory feedback loop (DEC loop) which
CC differs from the one formed by the PER and CRY transcriptional
CC repressors (PER/CRY loop) (PubMed:14672706). Both these loops are
CC interlocked as it represses the expression of PER1/2 and in turn is
CC repressed by PER1/2 and CRY1/2 (By similarity). Represses the activity
CC of the circadian transcriptional activator: CLOCK-
CC ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer by competing for the binding to E-
CC box elements (5'-CACGTG-3') found within the promoters of its target
CC genes (By similarity). Negatively regulates its own expression and the
CC expression of DBP and BHLHE41/DEC2 (PubMed:14672706). Acts as a
CC corepressor of RXR and the RXR-LXR heterodimers and represses the
CC ligand-induced RXRA and NR1H3/LXRA transactivation activity
CC (PubMed:19786558). May function as a transcriptional factor for
CC neuronal differentiation (PubMed:9284045). Represses the transcription
CC of NR0B2 and attentuates the transactivation of NR0B2 by the CLOCK-
CC ARNTL/BMAL1 complex (By similarity). Drives the circadian rhythm of
CC blood pressure through transcriptional repression of ATP1B1 in the
CC cardiovascular system (PubMed:30012868). {ECO:0000250|UniProtKB:O14503,
CC ECO:0000269|PubMed:14672706, ECO:0000269|PubMed:18411297,
CC ECO:0000269|PubMed:19786558, ECO:0000269|PubMed:30012868,
CC ECO:0000269|PubMed:9284045}.
CC -!- SUBUNIT: Homodimer. Heterodimer with BHLHE41/DEC2. Interacts with
CC ubiquitin-conjugating enzyme UBE2I/UBC9. Interacts with HDAC1, SUMO1,
CC RXRA and ARNTL/BMAL1 (By similarity). Interacts with TCF3/E47.
CC {ECO:0000250, ECO:0000269|PubMed:9050988}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:O14503}. Nucleus
CC {ECO:0000250|UniProtKB:O14503}. Note=Predominantly localized in the
CC nucleus (By similarity). {ECO:0000250|UniProtKB:O14503}.
CC -!- DEVELOPMENTAL STAGE: Expressed from 9.5 dpc to 17.5 dpc in the
CC ventricular layer of the brain and spinal cord, but also in the retinal
CC pigment epithelium, developing eyelids, nasal epithelium, serous gland,
CC vibrissae, epithelium of the mouth cavity and the tooth buds. Highly
CC expressed in the heart, thymus and adrenal glands followed by lung,
CC liver parenchyma, kidney tubules, epithelium of the esophagus and
CC stomach. From 15.5 dpc to 17.5 dpc it is expressed in urinary bladder
CC and urethra. From 17.5 dpc, it is expressed in developing muscle.
CC -!- INDUCTION: Stimulated by retinoic acid (RA). Expressed in a circadian
CC manner in the liver with a peak at ZT10. {ECO:0000269|PubMed:19786558}.
CC -!- PTM: Ubiquitinated; which may lead to proteasomal degradation.
CC {ECO:0000250}.
CC -!- PTM: Sumoylation inhibits its ubiquitination and promotes its negative
CC regulation of the CLOCK-ARNTL/BMAL1 heterodimer transcriptional
CC activator activity. {ECO:0000250}.
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DR EMBL; AF010305; AAB64228.1; -; mRNA.
DR EMBL; Y07836; CAA69169.1; -; mRNA.
DR EMBL; AF364051; AAK50859.1; -; mRNA.
DR EMBL; BC010720; AAH10720.1; -; mRNA.
DR CCDS; CCDS20400.1; -.
DR RefSeq; NP_035628.1; NM_011498.4.
DR AlphaFoldDB; O35185; -.
DR BioGRID; 203554; 5.
DR IntAct; O35185; 1.
DR STRING; 10090.ENSMUSP00000032194; -.
DR iPTMnet; O35185; -.
DR PhosphoSitePlus; O35185; -.
DR EPD; O35185; -.
DR PaxDb; O35185; -.
DR PRIDE; O35185; -.
DR ProteomicsDB; 273453; -.
DR Antibodypedia; 10051; 349 antibodies from 33 providers.
DR DNASU; 20893; -.
DR Ensembl; ENSMUST00000032194; ENSMUSP00000032194; ENSMUSG00000030103.
DR GeneID; 20893; -.
DR KEGG; mmu:20893; -.
DR UCSC; uc009ddn.1; mouse.
DR CTD; 8553; -.
DR MGI; MGI:1097714; Bhlhe40.
DR VEuPathDB; HostDB:ENSMUSG00000030103; -.
DR eggNOG; KOG4304; Eukaryota.
DR GeneTree; ENSGT00940000158384; -.
DR HOGENOM; CLU_049895_0_1_1; -.
DR InParanoid; O35185; -.
DR OMA; QQYFKKD; -.
DR OrthoDB; 629563at2759; -.
DR PhylomeDB; O35185; -.
DR TreeFam; TF330859; -.
DR BioGRID-ORCS; 20893; 9 hits in 76 CRISPR screens.
DR ChiTaRS; Bhlhe40; mouse.
DR PRO; PR:O35185; -.
DR Proteomes; UP000000589; Chromosome 6.
DR RNAct; O35185; protein.
DR Bgee; ENSMUSG00000030103; Expressed in tarsal region and 219 other tissues.
DR ExpressionAtlas; O35185; baseline and differential.
DR Genevisible; O35185; MM.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0016604; C:nuclear body; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0043425; F:bHLH transcription factor binding; ISO:MGI.
DR GO; GO:0003677; F:DNA binding; IDA:MGI.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IDA:BHF-UCL.
DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IDA:BHF-UCL.
DR GO; GO:0070888; F:E-box binding; IDA:UniProtKB.
DR GO; GO:0043426; F:MRF binding; IDA:BHF-UCL.
DR GO; GO:0019904; F:protein domain specific binding; ISO:MGI.
DR GO; GO:0046982; F:protein heterodimerization activity; ISO:MGI.
DR GO; GO:0042803; F:protein homodimerization activity; ISO:MGI.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:BHF-UCL.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IDA:BHF-UCL.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:MGI.
DR GO; GO:0009952; P:anterior/posterior pattern specification; IBA:GO_Central.
DR GO; GO:0032922; P:circadian regulation of gene expression; IMP:UniProtKB.
DR GO; GO:0007623; P:circadian rhythm; IEP:UniProtKB.
DR GO; GO:0043153; P:entrainment of circadian clock by photoperiod; IMP:BHF-UCL.
DR GO; GO:0043433; P:negative regulation of DNA-binding transcription factor activity; ISO:MGI.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISO:MGI.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:MGI.
DR GO; GO:0042752; P:regulation of circadian rhythm; IMP:UniProtKB.
DR GO; GO:0050767; P:regulation of neurogenesis; IBA:GO_Central.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0009416; P:response to light stimulus; IEP:BHF-UCL.
DR Gene3D; 4.10.280.10; -; 1.
DR InterPro; IPR011598; bHLH_dom.
DR InterPro; IPR036638; HLH_DNA-bd_sf.
DR InterPro; IPR003650; Orange_dom.
DR Pfam; PF07527; Hairy_orange; 1.
DR Pfam; PF00010; HLH; 1.
DR SMART; SM00353; HLH; 1.
DR SMART; SM00511; ORANGE; 1.
DR SUPFAM; SSF47459; SSF47459; 1.
DR PROSITE; PS50888; BHLH; 1.
DR PROSITE; PS51054; ORANGE; 1.
PE 1: Evidence at protein level;
KW Biological rhythms; Cytoplasm; DNA-binding; Isopeptide bond; Nucleus;
KW Phosphoprotein; Reference proteome; Repressor; Transcription;
KW Transcription regulation; Ubl conjugation.
FT CHAIN 1..411
FT /note="Class E basic helix-loop-helix protein 40"
FT /id="PRO_0000127145"
FT DOMAIN 52..107
FT /note="bHLH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981"
FT DOMAIN 142..175
FT /note="Orange"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00380"
FT REGION 1..139
FT /note="Essential for interaction with ARNTL/BMAL1, E-box
FT binding and repressor activity against the CLOCK-
FT ARNTL/BMAL1 heterodimer"
FT /evidence="ECO:0000250"
FT REGION 1..20
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 75..79
FT /note="Necessary for interaction with RXRA and repressor
FT activity against RXRA"
FT /evidence="ECO:0000250"
FT REGION 207..294
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 228..242
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 244..294
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 235
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O14503"
FT MOD_RES 383
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT CROSSLNK 159
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1, SUMO2 and SUMO3)"
FT /evidence="ECO:0000250"
FT CROSSLNK 167
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:O14503"
FT CROSSLNK 279
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1); alternate"
FT /evidence="ECO:0000250|UniProtKB:O14503"
FT CROSSLNK 279
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1, SUMO2 and SUMO3); alternate"
FT /evidence="ECO:0000250"
FT CROSSLNK 279
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2); alternate"
FT /evidence="ECO:0000250|UniProtKB:O14503"
FT CROSSLNK 288
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:O14503"
FT CONFLICT 288
FT /note="K -> T (in Ref. 2; CAA69169)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 411 AA; 45361 MW; B392893CD49292BC CRC64;
MERIPSAQPP PTCLPKAPGL EHGDLSGMDF AHMYQVYKSR RGIKRSEDSK ETYKLPHRLI
EKKRRDRINE CIAQLKDLLP EHLKLTTLGH LEKAVVLELT LKHVKALTNL IDQQQQKIIA
LQSGLQAGDL SGRNLEAGQE MFCSGFQTCA REVLQYLAKH ENTRDLKSSQ LVTHLHRVVS
ELLQGGASRK PLDSAPKAVD LKEKPSFLAK GSEGPGKNCV PVIQRTFAPS GGEQSGSDTD
TDSGYGGELE KGDLRSEQPY FKSDHGRRFA VGERVSTIKQ ESEEPPTKKS RMQLSEEEGH
FAGSDLMGSP FLGPHPHQPP FCLPFYLIPP SATAYLPMLE KCWYPTSVPV LYPGLNTSAA
ALSSFMNPDK IPTPLLLPQR LPSPLAHSSL DSSALLQALK QIPPLNLETK D
