ID BHE40_HUMAN Reviewed; 412 AA. AC O14503; Q96TD3; DT 05-MAR-2002, integrated into UniProtKB/Swiss-Prot. DT 01-JAN-1998, sequence version 1. DT 24-JAN-2024, entry version 196. 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:28797635, ECO:0000303|PubMed:30012868}; DE Short=DEC1 {ECO:0000303|PubMed:28797635, ECO:0000303|PubMed:30012868}; DE AltName: Full=Enhancer-of-split and hairy-related protein 2; DE Short=SHARP-2; DE AltName: Full=Stimulated by retinoic acid gene 13 protein; GN Name=BHLHE40; GN Synonyms=BHLHB2, DEC1 {ECO:0000303|PubMed:28797635, GN ECO:0000303|PubMed:30012868}, SHARP2, STRA13; 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]. RC TISSUE=Cartilage; RX PubMed=9240428; DOI=10.1006/bbrc.1997.6960; RA Shen M., Kawamoto T., Yan W., Nakamasu K., Tamagami M., Koyano Y., RA Noshiro M., Kato Y.; RT "Molecular characterization of the novel basic helix-loop-helix protein RT DEC1 expressed in differentiated human embryo chondrocytes."; RL Biochem. Biophys. Res. Commun. 236:294-298(1997). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RC TISSUE=Leukocyte; RX PubMed=11226878; DOI=10.1093/oxfordjournals.jbchem.a002869; RA Teramoto M., Nakamasu K., Noshiro M., Matsuda Y., Gotoh O., Shen M., RA Tsutsumi S., Kawamoto T., Iwamoto Y., Kato Y.; RT "Gene structure and chromosomal location of a human bHLH transcriptional RT factor DEC1 x Stra13 x SHARP-2/BHLHB2."; RL J. Biochem. 129:391-396(2001). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Skin; 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 [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 4-412. RA Ivanov S.V., Lerman M.I.; RT "Exon-intron structure of the human STRA13(DEC1) bHLH transcription factor RT gene."; RL Submitted (FEB-2001) to the EMBL/GenBank/DDBJ databases. RN [5] RP UBIQUITINATION, INTERACTION WITH UBE2I, AND SUBCELLULAR LOCATION. RX PubMed=11278694; DOI=10.1074/jbc.m010516200; RA Ivanova A.V., Ivanov S.V., Danilkovitch-Miagkova A., Lerman M.I.; RT "Regulation of STRA13 by the von Hippel-Lindau tumor suppressor protein, RT hypoxia, and the UBC9/ubiquitin proteasome degradation pathway."; RL J. Biol. Chem. 276:15306-15315(2001). RN [6] RP FUNCTION, AND INTERACTION WITH BMAL1. 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 [7] 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 [8] RP FUNCTION, HETERODIMERIZATION WITH BHLHE41/DEC2, AND INTERACTION WITH BMAL1. 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 [9] RP FUNCTION, INTERACTION WITH BMAL1, AND MUTAGENESIS OF HIS-57 AND ARG-65. 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 [10] 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 [11] RP FUNCTION, INTERACTION WITH RXRA, AND MUTAGENESIS OF 78-LEU-LEU-79. 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 [12] RP SUMOYLATION AT LYS-159 AND LYS-279, INTERACTION WITH HDAC1 AND SUMO1, RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-159 AND LYS-279. RX PubMed=21829689; DOI=10.1371/journal.pone.0023046; RA Hong Y., Xing X., Li S., Bi H., Yang C., Zhao F., Liu Y., Ao X., RA Chang A.K., Wu H.; RT "SUMOylation of DEC1 protein regulates its transcriptional activity and RT enhances its stability."; RL PLoS ONE 6:E23046-E23046(2011). RN [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-235, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [14] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-279, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25218447; DOI=10.1038/nsmb.2890; RA Hendriks I.A., D'Souza R.C., Yang B., Verlaan-de Vries M., Mann M., RA Vertegaal A.C.; RT "Uncovering global SUMOylation signaling networks in a site-specific RT manner."; RL Nat. Struct. Mol. Biol. 21:927-936(2014). RN [15] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-279, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25114211; DOI=10.1073/pnas.1413825111; RA Impens F., Radoshevich L., Cossart P., Ribet D.; RT "Mapping of SUMO sites and analysis of SUMOylation changes induced by RT external stimuli."; RL Proc. Natl. Acad. Sci. U.S.A. 111:12432-12437(2014). RN [16] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-279, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25772364; DOI=10.1016/j.celrep.2015.02.033; RA Hendriks I.A., Treffers L.W., Verlaan-de Vries M., Olsen J.V., RA Vertegaal A.C.; RT "SUMO-2 orchestrates chromatin modifiers in response to DNA damage."; RL Cell Rep. 10:1778-1791(2015). RN [17] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-279, AND IDENTIFICATION BY MASS RP 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 [18] RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF PRO-56 AND ARG-58. RX PubMed=28797635; DOI=10.1016/j.abb.2017.08.004; RA Marczak M.M., Yan B.; RT "Circadian rhythmicity: A functional connection between differentiated RT embryonic chondrocyte-1 (DEC1) and small heterodimer partner (SHP)."; RL Arch. Biochem. Biophys. 631:11-18(2017). RN [19] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-167; LYS-279 AND LYS-288, AND RP 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 [20] 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:12397359, PubMed:18411297). CC Acts as the negative limb of a novel autoregulatory feedback loop CC (DEC loop) which differs from the one formed by the PER and CRY CC transcriptional repressors (PER/CRY loop) (PubMed:14672706). Both these CC loops are interlocked as it represses the expression of PER1/2 and in CC turn is repressed by PER1/2 and CRY1/2 (PubMed:15193144). Represses the CC activity of the circadian transcriptional activator: CLOCK-BMAL1|BMAL2 CC heterodimer by competing for the binding to E-box elements (5'-CACGTG- CC 3') found within the promoters of its target genes (PubMed:15560782). CC Negatively regulates its own expression and the expression of DBP and CC BHLHE41/DEC2 (PubMed:14672706). Acts as a corepressor of RXR and the CC RXR-LXR heterodimers and represses the ligand-induced RXRA and CC NR1H3/LXRA transactivation activity (PubMed:19786558). May be involved CC in the regulation of chondrocyte differentiation via the cAMP pathway CC (PubMed:19786558). Represses the transcription of NR0B2 and attentuates CC the transactivation of NR0B2 by the CLOCK-BMAL1 complex CC (PubMed:28797635). Drives the circadian rhythm of blood pressure CC through transcriptional repression of ATP1B1 in the cardiovascular CC system (PubMed:30012868). {ECO:0000269|PubMed:12397359, CC ECO:0000269|PubMed:14672706, ECO:0000269|PubMed:15193144, CC ECO:0000269|PubMed:15560782, ECO:0000269|PubMed:18411297, CC ECO:0000269|PubMed:19786558, ECO:0000269|PubMed:28797635, CC ECO:0000269|PubMed:30012868}. 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 BMAL1. CC {ECO:0000269|PubMed:11278694, ECO:0000269|PubMed:12397359, CC ECO:0000269|PubMed:15193144, ECO:0000269|PubMed:15560782, CC ECO:0000269|PubMed:19786558, ECO:0000269|PubMed:21829689}. CC -!- INTERACTION: CC O14503; C9JG97: AAMP; NbExp=3; IntAct=EBI-711810, EBI-10176499; CC O14503; Q16613: AANAT; NbExp=6; IntAct=EBI-711810, EBI-7451846; CC O14503; P54253: ATXN1; NbExp=3; IntAct=EBI-711810, EBI-930964; CC O14503; Q13895: BYSL; NbExp=3; IntAct=EBI-711810, EBI-358049; CC O14503; O75909: CCNK; NbExp=3; IntAct=EBI-711810, EBI-739806; CC O14503; Q6NVV7: CDPF1; NbExp=3; IntAct=EBI-711810, EBI-2802782; CC O14503; P10606: COX5B; NbExp=4; IntAct=EBI-711810, EBI-1053725; CC O14503; Q03060-25: CREM; NbExp=3; IntAct=EBI-711810, EBI-12884642; CC O14503; O75553: DAB1; NbExp=3; IntAct=EBI-711810, EBI-7875264; CC O14503; Q15038: DAZAP2; NbExp=5; IntAct=EBI-711810, EBI-724310; CC O14503; Q92997: DVL3; NbExp=3; IntAct=EBI-711810, EBI-739789; CC O14503; Q08426: EHHADH; NbExp=3; IntAct=EBI-711810, EBI-2339219; CC O14503; Q86UY5: FAM83A; NbExp=6; IntAct=EBI-711810, EBI-1384254; CC O14503; Q8NEA9: GMCL2; NbExp=3; IntAct=EBI-711810, EBI-745707; CC O14503; Q86YR5-3: GPSM1; NbExp=3; IntAct=EBI-711810, EBI-10261098; CC O14503; Q96G42: KLHDC7B; NbExp=3; IntAct=EBI-711810, EBI-9478422; CC O14503; Q8IUG1: KRTAP1-3; NbExp=3; IntAct=EBI-711810, EBI-11749135; CC O14503; Q8IUB9: KRTAP19-1; NbExp=3; IntAct=EBI-711810, EBI-12811111; CC O14503; Q3LI72: KRTAP19-5; NbExp=3; IntAct=EBI-711810, EBI-1048945; CC O14503; Q3SYF9: KRTAP19-7; NbExp=3; IntAct=EBI-711810, EBI-10241353; CC O14503; A1A580: KRTAP23-1; NbExp=3; IntAct=EBI-711810, EBI-10171734; CC O14503; Q3LI64: KRTAP6-1; NbExp=3; IntAct=EBI-711810, EBI-12111050; CC O14503; Q3LI66: KRTAP6-2; NbExp=3; IntAct=EBI-711810, EBI-11962084; CC O14503; Q8IUC2: KRTAP8-1; NbExp=3; IntAct=EBI-711810, EBI-10261141; CC O14503; Q71RC2-6: LARP4; NbExp=3; IntAct=EBI-711810, EBI-10255841; CC O14503; Q14847-2: LASP1; NbExp=3; IntAct=EBI-711810, EBI-9088686; CC O14503; Q8TAP4-4: LMO3; NbExp=3; IntAct=EBI-711810, EBI-11742507; CC O14503; Q9Y5V3: MAGED1; NbExp=6; IntAct=EBI-711810, EBI-716006; CC O14503; Q96EZ8: MCRS1; NbExp=3; IntAct=EBI-711810, EBI-348259; CC O14503; Q9GZZ1: NAA50; NbExp=6; IntAct=EBI-711810, EBI-1052523; CC O14503; Q9HC98-4: NEK6; NbExp=3; IntAct=EBI-711810, EBI-11750983; CC O14503; Q9BVI4: NOC4L; NbExp=3; IntAct=EBI-711810, EBI-395927; CC O14503; P18545: PDE6G; NbExp=3; IntAct=EBI-711810, EBI-2622029; CC O14503; Q99471: PFDN5; NbExp=3; IntAct=EBI-711810, EBI-357275; CC O14503; O43189: PHF1; NbExp=3; IntAct=EBI-711810, EBI-530034; CC O14503; Q96CS7: PLEKHB2; NbExp=3; IntAct=EBI-711810, EBI-373552; CC O14503; P78424: POU6F2; NbExp=3; IntAct=EBI-711810, EBI-12029004; CC O14503; Q13131: PRKAA1; NbExp=3; IntAct=EBI-711810, EBI-1181405; CC O14503; P86480: PRR20D; NbExp=3; IntAct=EBI-711810, EBI-12754095; CC O14503; Q9Y4B4: RAD54L2; NbExp=3; IntAct=EBI-711810, EBI-948156; CC O14503; Q9NWB1-5: RBFOX1; NbExp=3; IntAct=EBI-711810, EBI-12123390; CC O14503; Q86U06: RBM23; NbExp=3; IntAct=EBI-711810, EBI-780319; CC O14503; Q86U06-2: RBM23; NbExp=3; IntAct=EBI-711810, EBI-10258579; CC O14503; Q93062: RBPMS; NbExp=3; IntAct=EBI-711810, EBI-740322; CC O14503; Q6ZRY4: RBPMS2; NbExp=3; IntAct=EBI-711810, EBI-11987469; CC O14503; O94955: RHOBTB3; NbExp=7; IntAct=EBI-711810, EBI-2367123; CC O14503; Q9H4E5: RHOJ; NbExp=3; IntAct=EBI-711810, EBI-6285694; CC O14503; Q01974: ROR2; NbExp=3; IntAct=EBI-711810, EBI-6422642; CC O14503; P19793: RXRA; NbExp=4; IntAct=EBI-711810, EBI-78598; CC O14503; Q8WU79: SMAP2; NbExp=3; IntAct=EBI-711810, EBI-2822515; CC O14503; Q8NB12: SMYD1; NbExp=8; IntAct=EBI-711810, EBI-8463848; CC O14503; O94964-4: SOGA1; NbExp=3; IntAct=EBI-711810, EBI-14083835; CC O14503; O60248: SOX15; NbExp=3; IntAct=EBI-711810, EBI-5452954; CC O14503; B7ZLI8: STK19; NbExp=6; IntAct=EBI-711810, EBI-10176124; CC O14503; Q96A09: TENT5B; NbExp=3; IntAct=EBI-711810, EBI-752030; CC O14503; Q08117: TLE5; NbExp=3; IntAct=EBI-711810, EBI-717810; CC O14503; Q08117-2: TLE5; NbExp=3; IntAct=EBI-711810, EBI-11741437; CC O14503; Q14106: TOB2; NbExp=3; IntAct=EBI-711810, EBI-2562000; CC O14503; P04637: TP53; NbExp=11; IntAct=EBI-711810, EBI-366083; CC O14503; Q5W5X9: TTC23; NbExp=3; IntAct=EBI-711810, EBI-6447954; CC O14503; Q9NX01: TXNL4B; NbExp=3; IntAct=EBI-711810, EBI-10309345; CC O14503; P63279: UBE2I; NbExp=3; IntAct=EBI-711810, EBI-80168; CC O14503; Q70EL1-9: USP54; NbExp=3; IntAct=EBI-711810, EBI-11975223; CC O14503; Q08AM6: VAC14; NbExp=6; IntAct=EBI-711810, EBI-2107455; CC O14503; O95231: VENTX; NbExp=3; IntAct=EBI-711810, EBI-10191303; CC O14503; P19544-6: WT1; NbExp=3; IntAct=EBI-711810, EBI-11745701; CC O14503; Q15911-2: ZFHX3; NbExp=3; IntAct=EBI-711810, EBI-10237226; CC O14503; P0C206; Xeno; NbExp=3; IntAct=EBI-711810, EBI-9675596; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21829689}. Nucleus CC {ECO:0000269|PubMed:11278694, ECO:0000269|PubMed:21829689, CC ECO:0000269|PubMed:28797635}. Note=Predominantly localized in the CC nucleus (PubMed:11278694). {ECO:0000269|PubMed:11278694}. CC -!- TISSUE SPECIFICITY: Expressed in cartilage, spleen, intestine, lung, CC and to a lesser extent in heart, brain, liver, muscle and stomach. CC -!- PTM: Ubiquitinated; which may lead to proteasomal degradation. CC {ECO:0000269|PubMed:11278694}. CC -!- PTM: Sumoylation inhibits its ubiquitination and promotes its negative CC regulation of the CLOCK-BMAL1 heterodimer transcriptional activator CC activity. {ECO:0000269|PubMed:11278694, ECO:0000269|PubMed:21829689}. 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; AB004066; BAA21720.1; -; mRNA. DR EMBL; AB043885; BAB18565.1; -; Genomic_DNA. DR EMBL; BC082238; AAH82238.1; -; mRNA. DR EMBL; AH010709; AAK49525.1; -; Genomic_DNA. DR CCDS; CCDS2565.1; -. DR PIR; JC5547; JC5547. DR RefSeq; NP_003661.1; NM_003670.2. DR AlphaFoldDB; O14503; -. DR SMR; O14503; -. DR BioGRID; 114123; 117. DR DIP; DIP-36698N; -. DR IntAct; O14503; 122. DR MINT; O14503; -. DR STRING; 9606.ENSP00000256495; -. DR MoonDB; O14503; Predicted. DR iPTMnet; O14503; -. DR PhosphoSitePlus; O14503; -. DR BioMuta; BHLHE40; -. DR EPD; O14503; -. DR jPOST; O14503; -. DR MassIVE; O14503; -. DR PaxDb; 9606-ENSP00000256495; -. DR PeptideAtlas; O14503; -. DR ProteomicsDB; 48045; -. DR Pumba; O14503; -. DR Antibodypedia; 10051; 391 antibodies from 33 providers. DR DNASU; 8553; -. DR Ensembl; ENST00000256495.4; ENSP00000256495.3; ENSG00000134107.5. DR GeneID; 8553; -. DR KEGG; hsa:8553; -. DR MANE-Select; ENST00000256495.4; ENSP00000256495.3; NM_003670.3; NP_003661.1. DR AGR; HGNC:1046; -. DR CTD; 8553; -. DR DisGeNET; 8553; -. DR GeneCards; BHLHE40; -. DR HGNC; HGNC:1046; BHLHE40. DR HPA; ENSG00000134107; Low tissue specificity. DR MIM; 604256; gene. DR neXtProt; NX_O14503; -. DR OpenTargets; ENSG00000134107; -. DR PharmGKB; PA25347; -. DR VEuPathDB; HostDB:ENSG00000134107; -. DR eggNOG; KOG4304; Eukaryota. DR GeneTree; ENSGT00940000158384; -. DR HOGENOM; CLU_049895_0_1_1; -. DR InParanoid; O14503; -. DR OMA; GMPLLYP; -. DR OrthoDB; 2968390at2759; -. DR PhylomeDB; O14503; -. DR TreeFam; TF330859; -. DR PathwayCommons; O14503; -. DR Reactome; R-HSA-1368108; BMAL1:CLOCK,NPAS2 activates circadian gene expression. DR SignaLink; O14503; -. DR SIGNOR; O14503; -. DR BioGRID-ORCS; 8553; 22 hits in 1189 CRISPR screens. DR ChiTaRS; BHLHE40; human. DR GeneWiki; BHLHB2; -. DR GenomeRNAi; 8553; -. DR Pharos; O14503; Tbio. DR PRO; PR:O14503; -. DR Proteomes; UP000005640; Chromosome 3. DR RNAct; O14503; Protein. DR Bgee; ENSG00000134107; Expressed in saphenous vein and 206 other cell types or tissues. DR ExpressionAtlas; O14503; baseline and differential. DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB. DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell. DR GO; GO:0016604; C:nuclear body; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0043425; F:bHLH transcription factor binding; IPI:BHF-UCL. DR GO; GO:0003700; F:DNA-binding transcription factor activity; NAS:UniProtKB. 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; ISS:BHF-UCL. DR GO; GO:0019904; F:protein domain specific binding; IPI:BHF-UCL. DR GO; GO:0046982; F:protein heterodimerization activity; IPI:BHF-UCL. DR GO; GO:0042803; F:protein homodimerization activity; IDA:BHF-UCL. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central. 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; IDA:BHF-UCL. DR GO; GO:0007623; P:circadian rhythm; IDA:UniProtKB. DR GO; GO:0043153; P:entrainment of circadian clock by photoperiod; ISS:BHF-UCL. DR GO; GO:0043433; P:negative regulation of DNA-binding transcription factor activity; IDA:BHF-UCL. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:BHF-UCL. DR GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB. DR GO; GO:0006355; P:regulation of DNA-templated transcription; NAS: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 CDD; cd19749; bHLH-O_DEC1; 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:SF3; CLASS E BASIC HELIX-LOOP-HELIX PROTEIN 40; 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; O14503; HS. 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..412 FT /note="Class E basic helix-loop-helix protein 40" FT /id="PRO_0000127144" 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 BMAL1, E-box binding FT and repressor activity against the CLOCK-BMAL1 heterodimer" FT REGION 75..79 FT /note="Necessary for interaction with RXRA and repressor FT activity against RXRA" FT /evidence="ECO:0000269|PubMed:19786558" FT REGION 182..303 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 224..243 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 244..298 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 235 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 383 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O35185" FT CROSSLNK 159 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO1, SUMO2 and SUMO3)" FT /evidence="ECO:0000269|PubMed:21829689" FT CROSSLNK 167 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT CROSSLNK 279 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO1); alternate" FT /evidence="ECO:0007744|PubMed:25114211" FT CROSSLNK 279 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO1, SUMO2 and SUMO3); alternate" FT CROSSLNK 279 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2); alternate" FT /evidence="ECO:0007744|PubMed:25218447, FT ECO:0007744|PubMed:25755297, ECO:0007744|PubMed:25772364, FT ECO:0007744|PubMed:28112733" FT CROSSLNK 288 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT MUTAGEN 56 FT /note="P->A: No loss of repressor activity against NR0B2." FT /evidence="ECO:0000269|PubMed:28797635" FT MUTAGEN 57 FT /note="H->A: No effect on its interaction with BMAL1 or its FT repressor activity against the CLOCK-BMAL1 heterodimer. FT Significant reduction in E-box binding." FT /evidence="ECO:0000269|PubMed:15560782" FT MUTAGEN 58 FT /note="R->A: Loss of repressor activity against NR0B2." FT /evidence="ECO:0000269|PubMed:28797635" FT MUTAGEN 65 FT /note="R->A: Loss of interaction with BMAL1 and E-box FT binding. Significant reduction in its repressor activity FT against the CLOCK-BMAL1 heterodimer." FT /evidence="ECO:0000269|PubMed:15560782" FT MUTAGEN 78..79 FT /note="LL->AA: Abolishes RXRA repression." FT /evidence="ECO:0000269|PubMed:19786558" FT MUTAGEN 159 FT /note="K->R: Partial loss of sumoylation. Complete loss of FT sumoylation; when associated with R-279." FT /evidence="ECO:0000269|PubMed:21829689" FT MUTAGEN 279 FT /note="K->R: Partial loss of sumoylation. Complete loss of FT sumoylation; when associated with R-159." FT /evidence="ECO:0000269|PubMed:21829689" SQ SEQUENCE 412 AA; 45510 MW; 2D73A3D4980793E5 CRC64; MERIPSAQPP PACLPKAPGL EHGDLPGMYP AHMYQVYKSR RGIKRSEDSK ETYKLPHRLI EKKRRDRINE CIAQLKDLLP EHLKLTTLGH LEKAVVLELT LKHVKALTNL IDQQQQKIIA LQSGLQAGEL SGRNVETGQE MFCSGFQTCA REVLQYLAKH ENTRDLKSSQ LVTHLHRVVS ELLQGGTSRK PSDPAPKVMD FKEKPSSPAK GSEGPGKNCV PVIQRTFAHS SGEQSGSDTD TDSGYGGESE KGDLRSEQPC FKSDHGRRFT MGERIGAIKQ ESEEPPTKKN RMQLSDDEGH FTSSDLISSP FLGPHPHQPP FCLPFYLIPP SATAYLPMLE KCWYPTSVPV LYPGLNASAA ALSSFMNPDK ISAPLLMPQR LPSPLPAHPS VDSSVLLQAL KPIPPLNLET KD //