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 24-JAN-2024, entry version 182. 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-BMAL1 heterodimer by competing for the CC binding to E-box elements (5'-CACGTG-3') found within the promoters of CC its target genes (PubMed:25083013). Negatively regulates its own CC expression and the expression of DBP and BHLHE41/DEC2. Acts as a CC 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 BMAL1 (By similarity). CC Interacts with RXRA (PubMed:19786558). Interacts with NR0B2 and HNF1A CC (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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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; 9606-ENSP00000242728; -. DR PeptideAtlas; Q9C0J9; -. DR ProteomicsDB; 80065; -. DR TopDownProteomics; Q9C0J9; -. DR Antibodypedia; 24289; 529 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 AGR; HGNC:16617; -. 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; KKPKMNW; -. DR OrthoDB; 2968390at2759; -. 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; 25 hits in 1169 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 195 other cell types or tissues. DR ExpressionAtlas; Q9C0J9; baseline and differential. DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB. DR GO; GO:0005634; C:nucleus; IBA:GO_Central. 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:0045892; P:negative regulation of DNA-templated transcription; ISS:UniProtKB. 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:0050767; P:regulation of neurogenesis; IBA:GO_Central. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central. DR CDD; cd19750; bHLH-O_DEC2; 1. DR Gene3D; 6.10.250.980; -; 1. DR Gene3D; 4.10.280.10; Helix-loop-helix DNA-binding domain; 1. DR InterPro; IPR011598; bHLH_dom. DR InterPro; IPR036638; HLH_DNA-bd_sf. DR InterPro; IPR003650; Orange_dom. DR PANTHER; PTHR10985; BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTOR, HES-RELATED; 1. DR PANTHER; PTHR10985:SF76; CLASS E BASIC HELIX-LOOP-HELIX PROTEIN 41; 1. DR Pfam; PF07527; Hairy_orange; 1. DR Pfam; PF00010; HLH; 1. DR SMART; SM00353; HLH; 1. DR SMART; SM00511; ORANGE; 1. DR SUPFAM; SSF47459; HLH, helix-loop-helix DNA-binding domain; 1. DR SUPFAM; SSF158457; Orange domain-like; 1. DR PROSITE; PS50888; BHLH; 1. DR PROSITE; PS51054; ORANGE; 1. DR Genevisible; Q9C0J9; HS. 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 (affects sleep duration; abolishes inhibition FT of CLOCK-BMAL1 and NPAS2/BMAL1 transactivation activities; FT dbSNP:rs1591838266)" FT /evidence="ECO:0000269|PubMed:25083013" FT /id="VAR_082585" FT VARIANT 384 FT /note="P -> Q (affects sleep duration; increases inhibition FT of CLOCK-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 (affects sleep duration; abolishes inhibition FT of CLOCK-BMAL1 and NPAS2/BMAL1 transactivation activities; FT 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 //