BHE40_HUMAN
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 03-AUG-2022, entry version 189.
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 ARNTL.
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 ARNTL.
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 ARNTL, 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 (DEC
CC 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-
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 (PubMed:15560782). Negatively regulates its own expression and
CC the 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 be involved in the regulation of chondrocyte
CC differentiation via the cAMP pathway (PubMed:19786558). Represses the
CC transcription of NR0B2 and attentuates the transactivation of NR0B2 by
CC the CLOCK-ARNTL/BMAL1 complex (PubMed:28797635). Drives the circadian
CC rhythm of blood pressure through transcriptional repression of ATP1B1
CC in the cardiovascular system (PubMed:30012868).
CC {ECO:0000269|PubMed:12397359, 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:28797635, 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 ARNTL/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-ARNTL/BMAL1 heterodimer transcriptional
CC activator activity. {ECO:0000269|PubMed:11278694,
CC ECO:0000269|PubMed:21829689}.
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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; 105.
DR DIP; DIP-36698N; -.
DR IntAct; O14503; 121.
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; O14503; -.
DR PeptideAtlas; O14503; -.
DR PRIDE; O14503; -.
DR ProteomicsDB; 48045; -.
DR Antibodypedia; 10051; 349 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 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; 629563at2759; -.
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; 18 hits in 1110 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 204 other tissues.
DR ExpressionAtlas; O14503; baseline and differential.
DR Genevisible; O14503; HS.
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:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:BHF-UCL.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB.
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:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; NAS: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..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 ARNTL/BMAL1, E-box
FT binding and repressor activity against the CLOCK-
FT ARNTL/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 ARNTL/BMAL1
FT or its repressor activity against the CLOCK-ARNTL/BMAL1
FT heterodimer. 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 ARNTL/BMAL1 and E-box
FT binding. Significant reduction in its repressor activity
FT against the CLOCK-ARNTL/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
