BHE40_RAT
ID BHE40_RAT Reviewed; 411 AA.
AC O35780;
DT 05-MAR-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1998, sequence version 1.
DT 25-MAY-2022, entry version 141.
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=Enhancer-of-split and hairy-related protein 2;
DE Short=SHARP-2;
GN Name=Bhlhe40; Synonyms=Bhlhb2, Sharp2;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Sprague-Dawley; TISSUE=Hippocampus;
RX PubMed=9532582; DOI=10.1006/mcne.1997.0640;
RA Rossner M.J., Doerr J., Gass P., Schwab M.H., Nave K.-A.;
RT "SHARPs: mammalian enhancer-of-split- and hairy-related proteins coupled to
RT neuronal stimulation.";
RL Mol. Cell. Neurosci. 10:460-475(1997).
RN [2]
RP INDUCTION, AND TISSUE SPECIFICITY.
RX PubMed=12397359; DOI=10.1038/nature01123;
RA Honma S., Kawamoto T., Takagi Y., Fujimoto K., Sato F., Noshiro M.,
RA Kato Y., Honma K.I.;
RT "Dec1 and Dec2 are regulators of the mammalian molecular clock.";
RL Nature 419:841-844(2002).
RN [3]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-383, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
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. Acts as the negative limb of a novel
CC autoregulatory feedback loop (DEC loop) which differs from the one
CC formed by the PER and CRY transcriptional repressors (PER/CRY loop).
CC Both these loops are interlocked as it represses the expression of
CC PER1/2 and in turn is repressed by PER1/2 and CRY1/2. Represses the
CC activity 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. Negatively regulates its own expression and the expression of
CC DBP and BHLHE41/DEC2. Acts as a corepressor of RXR and the RXR-LXR
CC heterodimers and represses the ligand-induced RXRA and NR1H3/LXRA
CC transactivation activity. May be involved in the regulation of
CC chondrocyte differentiation via the cAMP pathway (By similarity).
CC Represses the transcription of NR0B2 and attentuates the
CC transactivation of NR0B2 by the CLOCK-ARNTL/BMAL1 complex (By
CC similarity). Drives the circadian rhythm of blood pressure through
CC transcriptional repression of ATP1B1 in the cardiovascular system (By
CC similarity). {ECO:0000250|UniProtKB:O14503,
CC ECO:0000250|UniProtKB:O35185}.
CC -!- SUBUNIT: Homodimer. Heterodimer with BHLHE41/DEC2. Interacts with
CC TCF3/E47. Interacts with ubiquitin-conjugating enzyme UBE2I/UBC9.
CC Interacts with HDAC1, SUMO1, RXRA and ARNTL/BMAL1 (By similarity).
CC {ECO:0000250}.
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 -!- TISSUE SPECIFICITY: Expressed in heart, spleen, lung, liver, muscle,
CC kidney, uterus and gut. Highly expressed in the cerebral cortex,
CC especially in the fifth layer, thalamus, superior colliculus, olfactory
CC bulb, piriform cortex, hippocampus and hypothalamic nuclei.
CC {ECO:0000269|PubMed:12397359}.
CC -!- INDUCTION: Expressed in a circadian manner in the suprachiasmatic
CC nucleus (SCN) of the brain. {ECO:0000269|PubMed:12397359}.
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; AF009330; AAB63587.1; -; mRNA.
DR RefSeq; NP_445780.1; NM_053328.1.
DR AlphaFoldDB; O35780; -.
DR SMR; O35780; -.
DR STRING; 10116.ENSRNOP00000009564; -.
DR iPTMnet; O35780; -.
DR PhosphoSitePlus; O35780; -.
DR PaxDb; O35780; -.
DR PRIDE; O35780; -.
DR GeneID; 79431; -.
DR KEGG; rno:79431; -.
DR UCSC; RGD:68439; rat.
DR CTD; 8553; -.
DR RGD; 68439; Bhlhe40.
DR eggNOG; KOG4304; Eukaryota.
DR InParanoid; O35780; -.
DR OrthoDB; 629563at2759; -.
DR PhylomeDB; O35780; -.
DR PRO; PR:O35780; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IDA:RGD.
DR GO; GO:0043425; F:bHLH transcription factor binding; ISO:RGD.
DR GO; GO:0003677; F:DNA binding; ISO:RGD.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISO:RGD.
DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; ISS:UniProtKB.
DR GO; GO:0070888; F:E-box binding; ISS:UniProtKB.
DR GO; GO:0043426; F:MRF binding; ISO:RGD.
DR GO; GO:0019904; F:protein domain specific binding; ISO:RGD.
DR GO; GO:0046982; F:protein heterodimerization activity; ISO:RGD.
DR GO; GO:0042803; F:protein homodimerization activity; ISO:RGD.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; ISO:RGD.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; ISO:RGD.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:RGD.
DR GO; GO:0009952; P:anterior/posterior pattern specification; IBA:GO_Central.
DR GO; GO:0032922; P:circadian regulation of gene expression; ISS:UniProtKB.
DR GO; GO:0007623; P:circadian rhythm; IEP:UniProtKB.
DR GO; GO:0043153; P:entrainment of circadian clock by photoperiod; ISO:RGD.
DR GO; GO:0043433; P:negative regulation of DNA-binding transcription factor activity; ISO:RGD.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:RGD.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0007399; P:nervous system development; NAS:RGD.
DR GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB.
DR GO; GO:0050767; P:regulation of neurogenesis; IBA:GO_Central.
DR GO; GO:0048168; P:regulation of neuronal synaptic plasticity; IEP:RGD.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0009416; P:response to light stimulus; IDA:UniProtKB.
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_0000127146"
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..21
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 186..293
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..293
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:22673903"
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"
SQ SEQUENCE 411 AA; 45529 MW; E56BD468D08824AD CRC64;
MERIPSAQPP PTCLPKTPGL EHGDLSGMDF AHMYQVYKSR RGIKRSEDSK ETYKLPHRLI
EKKRRDRINE CIAQLKDLLP EHLKLTTLGH LEKAVVLELT LKHVKALTNL IDQQQQKIMA
LQSGLQAGDL SGKNIEAGQE MFCSGFQTCA REVLQYLAKH ENTRDLKSSQ LVTHLHRVVS
ELLQGSASRK PLDSAPKPVD FKEKPSFLAK GSEGPGKNCV PVIQRTFAPS GGEQSGSDTD
TDSGYGGELE KGDLRSEQPY FKSDHGRRFT VGERVSTIKQ ESEEPPTKKS RMQLSDEEGH
FVGSDLMGSP FLGPHPHQPP FCLPFYLIPP SATAYLPMLE KCWYPTSVPL LYPGLNTSAA
ALSSFMNPDK IPTPLLLPQR LPSPLAHSSL DSSALLQALK QIPPLNLETK D
