BHE41_HUMAN
ID BHE41_HUMAN Reviewed; 482 AA.
AC Q9C0J9; A2I2N8;
DT 05-MAR-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2001, sequence version 1.
DT 03-AUG-2022, entry version 174.
DE RecName: Full=Class E basic helix-loop-helix protein 41 {ECO:0000305};
DE Short=bHLHe41;
DE AltName: Full=Class B basic helix-loop-helix protein 3;
DE Short=bHLHb3;
DE AltName: Full=Differentially expressed in chondrocytes protein 2;
DE Short=hDEC2;
DE AltName: Full=Enhancer-of-split and hairy-related protein 1;
DE Short=SHARP-1;
GN Name=BHLHE41 {ECO:0000312|HGNC:HGNC:16617};
GN Synonyms=BHLHB3, DEC2 {ECO:0000303|PubMed:11162494}, SHARP1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=11162494; DOI=10.1006/bbrc.2000.4133;
RA Fujimoto K., Shen M., Noshiro M., Matsubara K., Shingu S., Honda K.,
RA Yoshida E., Suardita K., Matsuda Y., Kato Y.;
RT "Molecular cloning and characterization of DEC2, a new member of basic
RT helix-loop-helix proteins.";
RL Biochem. Biophys. Res. Commun. 280:164-171(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G);
RL Submitted (SEP-2006) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP FUNCTION.
RX PubMed=11278948; DOI=10.1074/jbc.m011619200;
RA Garriga-Canut M., Roopra A., Buckley N.J.;
RT "The basic helix-loop-helix protein, SHARP-1, represses transcription by a
RT histone deacetylase-dependent and histone deacetylase-independent
RT mechanism.";
RL J. Biol. Chem. 276:14821-14828(2001).
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 FUNCTION, AND HETERODIMERIZATION WITH BHLHE40/DEC1.
RX PubMed=15193144; DOI=10.1042/bj20040592;
RA Li Y., Song X., Ma Y., Liu J., Yang D., Yan B.;
RT "DNA binding, but not interaction with Bmal1, is responsible for DEC1-
RT mediated transcription regulation of the circadian gene mPer1.";
RL Biochem. J. 382:895-904(2004).
RN [7]
RP FUNCTION.
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 [8]
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 [9]
RP FUNCTION, INTERACTION WITH RXRA, AND MUTAGENESIS OF 70-LEU-LEU-71.
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 SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-210 AND LYS-266, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25755297; DOI=10.1074/mcp.o114.044792;
RA Xiao Z., Chang J.G., Hendriks I.A., Sigurdsson J.O., Olsen J.V.,
RA Vertegaal A.C.;
RT "System-wide analysis of SUMOylation dynamics in response to replication
RT stress reveals novel small ubiquitin-like modified target proteins and
RT acceptor lysines relevant for genome stability.";
RL Mol. Cell. Proteomics 14:1419-1434(2015).
RN [11]
RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-31; LYS-121; LYS-210 AND LYS-266,
RP AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=28112733; DOI=10.1038/nsmb.3366;
RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C.,
RA Nielsen M.L.;
RT "Site-specific mapping of the human SUMO proteome reveals co-modification
RT with phosphorylation.";
RL Nat. Struct. Mol. Biol. 24:325-336(2017).
RN [12]
RP VARIANT ARG-384, ASSOCIATION OF VARIANT ARG-384 WITH SHORT SLEEP PHENOTYPE,
RP AND POLYMORPHISM.
RX PubMed=19679812; DOI=10.1126/science.1174443;
RA He Y., Jones C.R., Fujiki N., Xu Y., Guo B., Holder J.L. Jr., Rossner M.J.,
RA Nishino S., Fu Y.H.;
RT "The transcriptional repressor DEC2 regulates sleep length in mammals.";
RL Science 325:866-870(2009).
RN [13]
RP VARIANTS HIS-362 AND GLN-384, CHARACTERIZATION OF VARIANTS HIS-362; ARG-384
RP AND GLN-384, FUNCTION, AND POLYMORPHISM.
RX PubMed=25083013; DOI=10.5665/sleep.3924;
RA Pellegrino R., Kavakli I.H., Goel N., Cardinale C.J., Dinges D.F.,
RA Kuna S.T., Maislin G., Van Dongen H.P., Tufik S., Hogenesch J.B.,
RA Hakonarson H., Pack A.I.;
RT "A novel BHLHE41 variant is associated with short sleep and resistance to
RT sleep deprivation in humans.";
RL Sleep 37:1327-1336(2014).
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:11278948, PubMed:14672706,
CC PubMed:15193144, PubMed:15560782, PubMed:18411297, PubMed:19786558,
CC PubMed:25083013). Acts as the negative limb of a novel autoregulatory
CC feedback loop (DEC loop) which differs from the one formed by the PER
CC and CRY transcriptional repressors (PER/CRY loop). Both these loops are
CC interlocked as it represses the expression of PER1 and in turn is
CC repressed by PER1/2 and CRY1/2. Represses the activity of the circadian
CC transcriptional activator: CLOCK-ARNTL/BMAL1 heterodimer by competing
CC for the binding to E-box elements (5'-CACGTG-3') found within the
CC promoters of its target genes (PubMed:25083013). Negatively regulates
CC its own expression and the expression of DBP and BHLHE41/DEC2. Acts as
CC a corepressor of RXR and the RXR-LXR heterodimers and represses the
CC ligand-induced RXRA/B/G, NR1H3/LXRA, NR1H4 and VDR transactivation
CC activity. Inhibits HNF1A-mediated transactivation of CYP1A2, CYP2E1 AND
CC CYP3A11 (By similarity). {ECO:0000250|UniProtKB:Q99PV5,
CC ECO:0000269|PubMed:11278948, ECO:0000269|PubMed:14672706,
CC ECO:0000269|PubMed:15193144, ECO:0000269|PubMed:15560782,
CC ECO:0000269|PubMed:18411297, ECO:0000269|PubMed:19786558,
CC ECO:0000269|PubMed:25083013}.
CC -!- SUBUNIT: Homodimer (By similarity). Heterodimer with BHLHE40/DEC1
CC (PubMed:15193144). Interacts with CIART and ARNTL/BMAL1 (By
CC similarity). Interacts with RXRA (PubMed:19786558). Interacts with
CC NR0B2 and HNF1A (By similarity). {ECO:0000250|UniProtKB:Q99PV5,
CC ECO:0000269|PubMed:15193144, ECO:0000269|PubMed:19786558}.
CC -!- INTERACTION:
CC Q9C0J9; Q16665: HIF1A; NbExp=2; IntAct=EBI-10988877, EBI-447269;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00380,
CC ECO:0000255|PROSITE-ProRule:PRU00981}.
CC -!- TISSUE SPECIFICITY: Highly expressed in skeletal muscle and brain,
CC moderately expressed in pancreas and heart, weakly expressed in
CC placenta, lung, liver and kidney.
CC -!- POLYMORPHISM: Genetic variations in BHLHE41 are associated with the
CC familial natural short sleep 1 (FNSS1) phenotype, an autosomal dominant
CC trait [MIM:612975]. Individuals with this trait require less sleep in
CC any 24-hour period than is typical for their age group.
CC {ECO:0000269|PubMed:19679812, ECO:0000269|PubMed:25083013}.
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DR EMBL; AB044088; BAB21502.1; -; mRNA.
DR EMBL; EF015896; ABM64207.1; -; Genomic_DNA.
DR EMBL; CH471094; EAW96527.1; -; Genomic_DNA.
DR CCDS; CCDS8706.1; -.
DR PIR; JC7583; JC7583.
DR RefSeq; NP_110389.1; NM_030762.2.
DR AlphaFoldDB; Q9C0J9; -.
DR SMR; Q9C0J9; -.
DR BioGRID; 122654; 39.
DR DIP; DIP-59904N; -.
DR IntAct; Q9C0J9; 10.
DR STRING; 9606.ENSP00000242728; -.
DR iPTMnet; Q9C0J9; -.
DR PhosphoSitePlus; Q9C0J9; -.
DR BioMuta; BHLHE41; -.
DR DMDM; 20137459; -.
DR EPD; Q9C0J9; -.
DR jPOST; Q9C0J9; -.
DR MassIVE; Q9C0J9; -.
DR MaxQB; Q9C0J9; -.
DR PaxDb; Q9C0J9; -.
DR PeptideAtlas; Q9C0J9; -.
DR PRIDE; Q9C0J9; -.
DR ProteomicsDB; 80065; -.
DR TopDownProteomics; Q9C0J9; -.
DR Antibodypedia; 24289; 460 antibodies from 32 providers.
DR DNASU; 79365; -.
DR Ensembl; ENST00000242728.5; ENSP00000242728.4; ENSG00000123095.6.
DR GeneID; 79365; -.
DR KEGG; hsa:79365; -.
DR MANE-Select; ENST00000242728.5; ENSP00000242728.4; NM_030762.3; NP_110389.1.
DR UCSC; uc001rhb.4; human.
DR CTD; 79365; -.
DR DisGeNET; 79365; -.
DR GeneCards; BHLHE41; -.
DR HGNC; HGNC:16617; BHLHE41.
DR HPA; ENSG00000123095; Tissue enhanced (retina, skeletal muscle).
DR MalaCards; BHLHE41; -.
DR MIM; 606200; gene.
DR MIM; 612975; phenotype.
DR neXtProt; NX_Q9C0J9; -.
DR OpenTargets; ENSG00000123095; -.
DR PharmGKB; PA164716636; -.
DR VEuPathDB; HostDB:ENSG00000123095; -.
DR eggNOG; KOG4304; Eukaryota.
DR GeneTree; ENSGT00940000161014; -.
DR HOGENOM; CLU_049895_0_0_1; -.
DR InParanoid; Q9C0J9; -.
DR OMA; PLYMCKS; -.
DR OrthoDB; 629563at2759; -.
DR PhylomeDB; Q9C0J9; -.
DR TreeFam; TF330859; -.
DR PathwayCommons; Q9C0J9; -.
DR Reactome; R-HSA-1368108; BMAL1:CLOCK,NPAS2 activates circadian gene expression.
DR Reactome; R-HSA-400253; Circadian Clock.
DR SignaLink; Q9C0J9; -.
DR SIGNOR; Q9C0J9; -.
DR BioGRID-ORCS; 79365; 24 hits in 1093 CRISPR screens.
DR ChiTaRS; BHLHE41; human.
DR GeneWiki; BHLHB3; -.
DR GenomeRNAi; 79365; -.
DR Pharos; Q9C0J9; Tbio.
DR PRO; PR:Q9C0J9; -.
DR Proteomes; UP000005640; Chromosome 12.
DR RNAct; Q9C0J9; protein.
DR Bgee; ENSG00000123095; Expressed in right uterine tube and 193 other tissues.
DR ExpressionAtlas; Q9C0J9; baseline and differential.
DR Genevisible; Q9C0J9; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0043425; F:bHLH transcription factor binding; IPI:BHF-UCL.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISS:BHF-UCL.
DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IDA:GO_Central.
DR GO; GO:0070888; F:E-box binding; IDA:BHF-UCL.
DR GO; GO:0042826; F:histone deacetylase binding; ISS:BHF-UCL.
DR GO; GO:0043426; F:MRF binding; ISS:BHF-UCL.
DR GO; GO:0046982; F:protein heterodimerization activity; IPI:BHF-UCL.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:BHF-UCL.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; ISS:BHF-UCL.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; ISS:BHF-UCL.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL.
DR GO; GO:0009952; P:anterior/posterior pattern specification; IBA:GO_Central.
DR GO; GO:0032922; P:circadian regulation of gene expression; IBA:GO_Central.
DR GO; GO:0010832; P:negative regulation of myotube differentiation; ISS:BHF-UCL.
DR GO; GO:0010944; P:negative regulation of transcription by competitive promoter binding; ISS:BHF-UCL.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:BHF-UCL.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISS: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 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; DNA-binding; Isopeptide bond; Nucleus;
KW Reference proteome; Repressor; Transcription; Transcription regulation;
KW Ubl conjugation.
FT CHAIN 1..482
FT /note="Class E basic helix-loop-helix protein 41"
FT /id="PRO_0000127147"
FT DOMAIN 44..99
FT /note="bHLH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981"
FT DOMAIN 131..166
FT /note="Orange"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00380"
FT REGION 67..71
FT /note="Necessary for interaction with RXRA and repressor
FT activity towards RXRA"
FT /evidence="ECO:0000269|PubMed:19786558"
FT REGION 228..298
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 438..482
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 242..259
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CROSSLNK 31
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:28112733"
FT CROSSLNK 121
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:28112733"
FT CROSSLNK 210
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:25755297,
FT ECO:0007744|PubMed:28112733"
FT CROSSLNK 266
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:25755297,
FT ECO:0007744|PubMed:28112733"
FT VARIANT 362
FT /note="Y -> H (associated with short sleep phenotype;
FT abolishes inhibition of CLOCK-ARNTL/BMAL1 and NPAS2/BMAL1
FT transactivation activities; dbSNP:rs1591838266)"
FT /evidence="ECO:0000269|PubMed:25083013"
FT /id="VAR_082585"
FT VARIANT 384
FT /note="P -> Q (associated with short sleep phenotype;
FT heterogeneous phenotype; increases inhibition of CLOCK-
FT ARNTL/BMAL1 and NPAS2/BMAL1 transactivation activities;
FT dbSNP:rs121912617)"
FT /evidence="ECO:0000269|PubMed:25083013"
FT /id="VAR_082586"
FT VARIANT 384
FT /note="P -> R (associated with short sleep phenotype;
FT abolishes inhibition of CLOCK-ARNTL/BMAL1 and NPAS2/BMAL1
FT transactivation activities; dbSNP:rs121912617)"
FT /evidence="ECO:0000269|PubMed:19679812"
FT /id="VAR_063259"
FT MUTAGEN 70..71
FT /note="LL->AA: Abolishes RXRA repression."
FT /evidence="ECO:0000269|PubMed:19786558"
SQ SEQUENCE 482 AA; 50498 MW; 2BECDC2FDEB7CE14 CRC64;
MDEGIPHLQE RQLLEHRDFI GLDYSSLYMC KPKRSMKRDD TKDTYKLPHR LIEKKRRDRI
NECIAQLKDL LPEHLKLTTL GHLEKAVVLE LTLKHLKALT ALTEQQHQKI IALQNGERSL
KSPIQSDLDA FHSGFQTCAK EVLQYLSRFE SWTPREPRCV QLINHLHAVA TQFLPTPQLL
TQQVPLSKGT GAPSAAGSAA APCLERAGQK LEPLAYCVPV IQRTQPSAEL AAENDTDTDS
GYGGEAEARP DREKGKGAGA SRVTIKQEPP GEDSPAPKRM KLDSRGGGSG GGPGGGAAAA
AAALLGPDPA AAAALLRPDA ALLSSLVAFG GGGGAPFPQP AAAAAPFCLP FCFLSPSAAA
AYVQPFLDKS GLEKYLYPAA AAAPFPLLYP GIPAPAAAAA AAAAAAAAAA AFPCLSSVLS
PPPEKAGAAA ATLLPHEVAP LGAPHPQHPH GRTHLPFAGP REPGNPESSA QEDPSQPGKE
AP
