ID BMAL1_MOUSE Reviewed; 632 AA. AC Q9WTL8; O88295; Q921S4; Q9R0U2; Q9WTL9; DT 15-AUG-2003, integrated into UniProtKB/Swiss-Prot. DT 15-AUG-2003, sequence version 2. DT 27-MAR-2024, entry version 201. DE RecName: Full=Basic helix-loop-helix ARNT-like protein 1; DE AltName: Full=Arnt3; DE AltName: Full=Aryl hydrocarbon receptor nuclear translocator-like protein 1; DE AltName: Full=Brain and muscle ARNT-like 1; GN Name=Bmal1; Synonyms=Arntl {ECO:0000312|MGI:MGI:1096381}; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 5). RC TISSUE=Brain; RX PubMed=10403839; DOI=10.1006/bbrc.1999.0970; RA Yu W., Ikeda M., Abe H., Honma S., Ebisawa T., Yamauchi T., Honma K., RA Nomura M.; RT "Characterization of three splice variants and genomic organization of the RT mouse BMAL1 gene."; RL Biochem. Biophys. Res. Commun. 260:760-767(1999). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4). RX PubMed=9704006; DOI=10.1006/bbrc.1998.9012; RA Takahata S., Sogawa K., Kobayashi A., Ema M., Mimura J., Ozaki N., RA Fujii-Kuriyama Y.; RT "Transcriptionally active heterodimer formation of an Arnt-like PAS RT protein, Arnt3, with HIF-1a, HLF, and clock."; RL Biochem. Biophys. Res. Commun. 248:789-794(1998). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 4). 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 INTERACTION WITH CLOCK. RX PubMed=9616112; DOI=10.1126/science.280.5369.1564; RA Gekakis N., Staknis D., Nguyen H.B., Davis F.C., Wilsbacher L.D., RA King D.P., Takahashi J.S., Weitz C.J.; RT "Role of the CLOCK protein in the mammalian circadian mechanism."; RL Science 280:1564-1569(1998). RN [5] RP IDENTIFICATION IN A COMPLEX WITH CLOCK; PER1; PER2; CRY1; CRY2; CSNK1D AND RP CSNK1E, PHOSPHORYLATION, AND SUBCELLULAR LOCATION. RX PubMed=11779462; DOI=10.1016/s0092-8674(01)00610-9; RA Lee C., Etchegaray J.-P., Cagampang F.R.A., Loudon A.S.I., Reppert S.M.; RT "Posttranslational mechanisms regulate the mammalian circadian clock."; RL Cell 107:855-867(2001). RN [6] RP INTERACTION WITH BHLHE40 AND BHLHE41. 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 PHOSPHORYLATION, AND SUBCELLULAR LOCATION. RX PubMed=12897057; DOI=10.1101/gad.1099503; RA Kondratov R.V., Chernov M.V., Kondratova A.A., Gorbacheva V.Y., RA Gudkov A.V., Antoch M.P.; RT "BMAL1-dependent circadian oscillation of nuclear CLOCK: posttranslational RT events induced by dimerization of transcriptional activators of the RT mammalian clock system."; RL Genes Dev. 17:1921-1932(2003). RN [8] 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 [9] RP SUMOYLATION AT LYS-266, AND MUTAGENESIS OF LYS-230; LYS-236; LYS-266 AND RP LYS-279. RX PubMed=16109848; DOI=10.1126/science.1110689; RA Cardone L., Hirayama J., Giordano F., Tamaru T., Palvimo J.J., RA Sassone-Corsi P.; RT "Circadian clock control by SUMOylation of BMAL1."; RL Science 309:1390-1394(2005). RN [10] RP INTERACTION WITH NPAS2. RX PubMed=16628007; DOI=10.4161/cc.5.8.2684; RA Kondratov R.V., Kondratova A.A., Lee C., Gorbacheva V.Y., Chernov M.V., RA Antoch M.P.; RT "Post-translational regulation of circadian transcriptional RT CLOCK(NPAS2)/BMAL1 complex by CRYPTOCHROMES."; RL Cell Cycle 5:890-895(2006). RN [11] RP INTERACTION WITH EZH2; CLOCK; PER1; PER2; CRY1 AND CRY2. RX PubMed=16717091; DOI=10.1074/jbc.m603722200; RA Etchegaray J.P., Yang X., DeBruyne J.P., Peters A.H., Weaver D.R., RA Jenuwein T., Reppert S.M.; RT "The polycomb group protein EZH2 is required for mammalian circadian clock RT function."; RL J. Biol. Chem. 281:21209-21215(2006). RN [12] RP SUBCELLULAR LOCATION, NUCLEAR LOCALIZATION SIGNAL, NUCLEAR EXPORT SIGNAL, RP INTERACTION WITH CLOCK, MUTAGENESIS OF 38-LYS-ARG-39; LEU-154; LEU-157; RP LEU-370 AND LEU-374, UBIQUITINATION, AND PROTEASOMAL DEGRADATION. RX PubMed=16980631; DOI=10.1128/mcb.00337-06; RA Kwon I., Lee J., Chang S.H., Jung N.C., Lee B.J., Son G.H., Kim K., RA Lee K.H.; RT "BMAL1 shuttling controls transactivation and degradation of the RT CLOCK/BMAL1 heterodimer."; RL Mol. Cell. Biol. 26:7318-7330(2006). RN [13] RP TISSUE SPECIFICITY, AND INDUCTION. RX PubMed=16790549; DOI=10.1073/pnas.0604138103; RA Partch C.L., Shields K.F., Thompson C.L., Selby C.P., Sancar A.; RT "Posttranslational regulation of the mammalian circadian clock by RT cryptochrome and protein phosphatase 5."; RL Proc. Natl. Acad. Sci. U.S.A. 103:10467-10472(2006). RN [14] RP ACETYLATION AT LYS-544. RX PubMed=18075593; DOI=10.1038/nature06394; RA Hirayama J., Sahar S., Grimaldi B., Tamaru T., Takamatsu K., Nakahata Y., RA Sassone-Corsi P.; RT "CLOCK-mediated acetylation of BMAL1 controls circadian function."; RL Nature 450:1086-1090(2007). RN [15] RP INTERACTION WITH CRY1; CRY2 AND PER2. RX PubMed=18430226; DOI=10.1186/1471-2199-9-41; RA Langmesser S., Tallone T., Bordon A., Rusconi S., Albrecht U.; RT "Interaction of circadian clock proteins PER2 and CRY with BMAL1 and RT CLOCK."; RL BMC Mol. Biol. 9:41-41(2008). RN [16] RP INTERACTION WITH SIRT1 AND CLOCK. RX PubMed=18662546; DOI=10.1016/j.cell.2008.06.050; RA Asher G., Gatfield D., Stratmann M., Reinke H., Dibner C., Kreppel F., RA Mostoslavsky R., Alt F.W., Schibler U.; RT "SIRT1 regulates circadian clock gene expression through PER2 RT deacetylation."; RL Cell 134:317-328(2008). RN [17] RP ACETYLATION AT LYS-544, DEACETYLATION, AND INTERACTION WITH SIRT1. RX PubMed=18662547; DOI=10.1016/j.cell.2008.07.002; RA Nakahata Y., Kaluzova M., Grimaldi B., Sahar S., Hirayama J., Chen D., RA Guarente L.P., Sassone-Corsi P.; RT "The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin RT remodeling and circadian control."; RL Cell 134:329-340(2008). RN [18] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=18258755; DOI=10.1177/0748730407311254; RA Alvarez J.D., Hansen A., Ord T., Bebas P., Chappell P.E., RA Giebultowicz J.M., Williams C., Moss S., Sehgal A.; RT "The circadian clock protein BMAL1 is necessary for fertility and proper RT testosterone production in mice."; RL J. Biol. Rhythms 23:26-36(2008). RN [19] RP FUNCTION. RX PubMed=18316400; DOI=10.1128/mcb.01931-07; RA Bertolucci C., Cavallari N., Colognesi I., Aguzzi J., Chen Z., Caruso P., RA Foa A., Tosini G., Bernardi F., Pinotti M.; RT "Evidence for an overlapping role of CLOCK and NPAS2 transcription factors RT in liver circadian oscillators."; RL Mol. Cell. Biol. 28:3070-3075(2008). RN [20] RP SUMOYLATION AT LYS-259, SUBCELLULAR LOCATION, INTERACTION WITH SUMO3, RP MUTAGENESIS OF LYS-259, UBIQUITINATION, AND PROTEASOMAL DEGRADATION. RX PubMed=18644859; DOI=10.1128/mcb.00583-08; RA Lee J., Lee Y., Lee M.J., Park E., Kang S.H., Chung C.H., Lee K.H., Kim K.; RT "Dual modification of BMAL1 by SUMO2/3 and ubiquitin promotes circadian RT activation of the CLOCK/BMAL1 complex."; RL Mol. Cell. Biol. 28:6056-6065(2008). RN [21] RP INTERACTION WITH GSK3B AND CLOCK, AND PHOSPHORYLATION. RX PubMed=19946213; DOI=10.4161/cc.8.24.10273; RA Spengler M.L., Kuropatwinski K.K., Schumer M., Antoch M.P.; RT "A serine cluster mediates BMAL1-dependent CLOCK phosphorylation and RT degradation."; RL Cell Cycle 8:4138-4146(2009). RN [22] RP FUNCTION. RX PubMed=19141540; DOI=10.1096/fj.08-117697; RA Nader N., Chrousos G.P., Kino T.; RT "Circadian rhythm transcription factor CLOCK regulates the transcriptional RT activity of the glucocorticoid receptor by acetylating its hinge region RT lysine cluster: potential physiological implications."; RL FASEB J. 23:1572-1583(2009). RN [23] RP FUNCTION, AND INTERACTION WITH PER2. RX PubMed=19605937; DOI=10.1074/jbc.m109.040758; RA Sasaki M., Yoshitane H., Du N.H., Okano T., Fukada Y.; RT "Preferential inhibition of BMAL2-CLOCK activity by PER2 reemphasizes its RT negative role and a positive role of BMAL2 in the circadian RT transcription."; RL J. Biol. Chem. 284:25149-25159(2009). RN [24] RP PHOSPHORYLATION. RX PubMed=19414601; DOI=10.1128/mcb.01864-08; RA Yoshitane H., Takao T., Satomi Y., Du N.H., Okano T., Fukada Y.; RT "Roles of CLOCK phosphorylation in suppression of E-box-dependent RT transcription."; RL Mol. Cell. Biol. 29:3675-3686(2009). RN [25] RP PHOSPHORYLATION AT SER-97, SUBCELLULAR LOCATION, MUTAGENESIS OF SER-97, AND RP INTERACTION WITH CLOCK. RX PubMed=19330005; DOI=10.1038/nsmb.1578; RA Tamaru T., Hirayama J., Isojima Y., Nagai K., Norioka S., Takamatsu K., RA Sassone-Corsi P.; RT "CK2alpha phosphorylates BMAL1 to regulate the mammalian clock."; RL Nat. Struct. Mol. Biol. 16:446-448(2009). RN [26] RP FUNCTION, AND INTERACTION WITH SIRT1. RX PubMed=19299583; DOI=10.1126/science.1171641; RA Ramsey K.M., Yoshino J., Brace C.S., Abrassart D., Kobayashi Y., RA Marcheva B., Hong H.K., Chong J.L., Buhr E.D., Lee C., Takahashi J.S., RA Imai S., Bass J.; RT "Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis."; RL Science 324:651-654(2009). RN [27] RP FUNCTION. RX PubMed=19286518; DOI=10.1126/science.1170803; RA Nakahata Y., Sahar S., Astarita G., Kaluzova M., Sassone-Corsi P.; RT "Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1."; RL Science 324:654-657(2009). RN [28] RP FUNCTION, AND INTERACTION WITH CRY2. RX PubMed=20840750; DOI=10.1186/1471-2199-11-69; RA Ozber N., Baris I., Tatlici G., Gur I., Kilinc S., Unal E.B., Kavakli I.H.; RT "Identification of two amino acids in the C-terminal domain of mouse CRY2 RT essential for PER2 interaction."; RL BMC Mol. Biol. 11:69-69(2010). RN [29] RP FUNCTION. RX PubMed=20153195; DOI=10.1016/j.cub.2009.12.034; RA Shi S., Hida A., McGuinness O.P., Wasserman D.H., Yamazaki S., RA Johnson C.H.; RT "Circadian clock gene Bmal1 is not essential; functional replacement with RT its paralog, Bmal2."; RL Curr. Biol. 20:316-321(2010). RN [30] RP FUNCTION. RX PubMed=20430893; DOI=10.1074/jbc.m110.110361; RA Doi R., Oishi K., Ishida N.; RT "CLOCK regulates circadian rhythms of hepatic glycogen synthesis through RT transcriptional activation of Gys2."; RL J. Biol. Chem. 285:22114-22121(2010). RN [31] RP SUBCELLULAR LOCATION, AND INTERACTION WITH ID1; ID2 AND ID3. RX PubMed=20861012; DOI=10.1074/jbc.m110.175182; RA Ward S.M., Fernando S.J., Hou T.Y., Duffield G.E.; RT "The transcriptional repressor ID2 can interact with the canonical clock RT components CLOCK and BMAL1 and mediate inhibitory effects on mPer1 RT expression."; RL J. Biol. Chem. 285:38987-39000(2010). RN [32] RP FUNCTION, AND INDUCTION. RX PubMed=20385766; DOI=10.1128/mcb.01141-09; RA Guillaumond F., Grechez-Cassiau A., Subramaniam M., Brangolo S., RA Peteri-Brunback B., Staels B., Fievet C., Spelsberg T.C., Delaunay F., RA Teboul M.; RT "Kruppel-like factor KLF10 is a link between the circadian clock and RT metabolism in liver."; RL Mol. Cell. Biol. 30:3059-3070(2010). RN [33] RP INTERACTION WITH KMT2A. RX PubMed=21113167; DOI=10.1038/nsmb.1961; RA Katada S., Sassone-Corsi P.; RT "The histone methyltransferase MLL1 permits the oscillation of circadian RT gene expression."; RL Nat. Struct. Mol. Biol. 17:1414-1421(2010). RN [34] RP FUNCTION. RX PubMed=20562852; DOI=10.1038/nature09253; RA Marcheva B., Ramsey K.M., Buhr E.D., Kobayashi Y., Su H., Ko C.H., RA Ivanova G., Omura C., Mo S., Vitaterna M.H., Lopez J.P., Philipson L.H., RA Bradfield C.A., Crosby S.D., Je Bailey L., Wang X., Takahashi J.S., RA Bass J.; RT "Disruption of the clock components CLOCK and BMAL1 leads to RT hypoinsulinaemia and diabetes."; RL Nature 466:627-631(2010). RN [35] RP PHOSPHORYLATION AT SER-17 AND THR-21, AND INTERACTION WITH GSK3B. RX PubMed=20049328; DOI=10.1371/journal.pone.0008561; RA Sahar S., Zocchi L., Kinoshita C., Borrelli E., Sassone-Corsi P.; RT "Regulation of BMAL1 protein stability and circadian function by GSK3beta- RT mediated phosphorylation."; RL PLoS ONE 5:E8561-E8561(2010). RN [36] RP FUNCTION. RX PubMed=20956306; DOI=10.1073/pnas.1014523107; RA Andrews J.L., Zhang X., McCarthy J.J., McDearmon E.L., Hornberger T.A., RA Russell B., Campbell K.S., Arbogast S., Reid M.B., Walker J.R., RA Hogenesch J.B., Takahashi J.S., Esser K.A.; RT "CLOCK and BMAL1 regulate MyoD and are necessary for maintenance of RT skeletal muscle phenotype and function."; RL Proc. Natl. Acad. Sci. U.S.A. 107:19090-19095(2010). RN [37] RP INTERACTION WITH RACK1 AND PRKCA, SUBCELLULAR LOCATION, AND IDENTIFICATION RP BY MASS SPECTROMETRY. RX PubMed=20093473; DOI=10.1126/science.1180067; RA Robles M.S., Boyault C., Knutti D., Padmanabhan K., Weitz C.J.; RT "Identification of RACK1 and protein kinase Calpha as integral components RT of the mammalian circadian clock."; RL Science 327:463-466(2010). RN [38] RP INTERACTION WITH AHR. RX PubMed=20106950; DOI=10.1093/toxsci/kfq022; RA Xu C.X., Krager S.L., Liao D.F., Tischkau S.A.; RT "Disruption of CLOCK-BMAL1 transcriptional activity is responsible for aryl RT hydrocarbon receptor-mediated regulation of Period1 gene."; RL Toxicol. Sci. 115:98-108(2010). RN [39] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=22101268; DOI=10.4161/cc.10.23.18381; RA Khapre R.V., Kondratova A.A., Susova O., Kondratov R.V.; RT "Circadian clock protein BMAL1 regulates cellular senescence in vivo."; RL Cell Cycle 10:4162-4169(2011). RN [40] RP FUNCTION. RX PubMed=22045262; DOI=10.4161/isl.3.6.18157; RA Lee J., Kim M.S., Li R., Liu V.Y., Fu L., Moore D.D., Ma K., Yechoor V.K.; RT "Loss of Bmal1 leads to uncoupling and impaired glucose-stimulated insulin RT secretion in beta-cells."; RL Islets 3:381-388(2011). RN [41] RP INTERACTION WITH CLOCK; CRY1 AND PER2. RX PubMed=21613214; DOI=10.1074/jbc.m111.254680; RA Ye R., Selby C.P., Ozturk N., Annayev Y., Sancar A.; RT "Biochemical analysis of the canonical model for the mammalian circadian RT clock."; RL J. Biol. Chem. 286:25891-25902(2011). RN [42] RP FUNCTION. RX PubMed=21768648; DOI=10.1074/jbc.m111.258970; RA Koyanagi S., Hamdan A.M., Horiguchi M., Kusunose N., Okamoto A., RA Matsunaga N., Ohdo S.; RT "cAMP-response element (CRE)-mediated transcription by activating RT transcription factor-4 (ATF4) is essential for circadian expression of the RT Period2 gene."; RL J. Biol. Chem. 286:32416-32423(2011). RN [43] RP FUNCTION. RX PubMed=20658528; DOI=10.1002/jcp.22314; RA Somanath P.R., Podrez E.A., Chen J., Ma Y., Marchant K., Antoch M., RA Byzova T.V.; RT "Deficiency in core circadian protein Bmal1 is associated with a RT prothrombotic and vascular phenotype."; RL J. Cell. Physiol. 226:132-140(2011). RN [44] RP INTERACTION WITH MAGEL2, AND SUBCELLULAR LOCATION. RX PubMed=22208286; DOI=10.1186/1740-3391-9-12; RA Devos J., Weselake S.V., Wevrick R.; RT "Magel2, a Prader-Willi syndrome candidate gene, modulates the activities RT of circadian rhythm proteins in cultured cells."; RL J. Circadian. Rhythms. 9:12-12(2011). RN [45] RP FUNCTION. RX PubMed=21966465; DOI=10.1371/journal.pone.0025231; RA Shimba S., Ogawa T., Hitosugi S., Ichihashi Y., Nakadaira Y., Kobayashi M., RA Tezuka M., Kosuge Y., Ishige K., Ito Y., Komiyama K., Okamatsu-Ogura Y., RA Kimura K., Saito M.; RT "Deficient of a clock gene, brain and muscle Arnt-like protein-1 (BMAL1), RT induces dyslipidemia and ectopic fat formation."; RL PLoS ONE 6:E25231-E25231(2011). RN [46] RP INTERACTION WITH KDM5A. RX PubMed=21960634; DOI=10.1126/science.1206022; RA DiTacchio L., Le H.D., Vollmers C., Hatori M., Witcher M., Secombe J., RA Panda S.; RT "Histone lysine demethylase JARID1a activates CLOCK-BMAL1 and influences RT the circadian clock."; RL Science 333:1881-1885(2011). RN [47] RP INTERACTION WITH RELB. RX PubMed=22894897; DOI=10.4161/cc.21669; RA Bellet M.M., Zocchi L., Sassone-Corsi P.; RT "The RelB subunit of NFkappaB acts as a negative regulator of circadian RT gene expression."; RL Cell Cycle 11:3304-3311(2012). RN [48] RP FUNCTION. RX PubMed=22611086; DOI=10.1096/fj.12-205781; RA Guo B., Chatterjee S., Li L., Kim J.M., Lee J., Yechoor V.K., Minze L.J., RA Hsueh W., Ma K.; RT "The clock gene, brain and muscle Arnt-like 1, regulates adipogenesis via RT Wnt signaling pathway."; RL FASEB J. 26:3453-3463(2012). RN [49] RP FUNCTION. RX PubMed=22981862; DOI=10.1016/j.molcel.2012.08.012; RA Stratmann M., Suter D.M., Molina N., Naef F., Schibler U.; RT "Circadian Dbp transcription relies on highly dynamic BMAL1-CLOCK RT interaction with E boxes and requires the proteasome."; RL Mol. Cell 48:277-287(2012). RN [50] RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND INTERACTION WITH RP DDX4. RX PubMed=22900038; DOI=10.1371/journal.pone.0042695; RA Peruquetti R.L., de Mateo S., Sassone-Corsi P.; RT "Circadian proteins CLOCK and BMAL1 in the chromatoid body, a RNA RT processing granule of male germ cells."; RL PLoS ONE 7:E42695-E42695(2012). RN [51] RP INTERACTION WITH PRKCG, UBIQUITINATION, AND PROTEASOMAL DEGRADATION. RX PubMed=23185022; DOI=10.1073/pnas.1218699110; RA Zhang L., Abraham D., Lin S.T., Oster H., Eichele G., Fu Y.H., Ptacek L.J.; RT "PKCgamma participates in food entrainment by regulating BMAL1."; RL Proc. Natl. Acad. Sci. U.S.A. 109:20679-20684(2012). RN [52] RP INTERACTION WITH PER1, AND TISSUE SPECIFICITY. RX PubMed=24154698; DOI=10.1152/ajprenal.00472.2013; RA Richards J., Cheng K.Y., All S., Skopis G., Jeffers L., Lynch I.J., RA Wingo C.S., Gumz M.L.; RT "A role for the circadian clock protein Per1 in the regulation of RT aldosterone levels and renal Na+ retention."; RL Am. J. Physiol. 305:F1697-F1704(2013). RN [53] RP TISSUE SPECIFICITY, AND INDUCTION. RX PubMed=23531614; DOI=10.1152/ajpendo.00512.2012; RA Barclay J.L., Shostak A., Leliavski A., Tsang A.H., Johren O., RA Muller-Fielitz H., Landgraf D., Naujokat N., van der Horst G.T., Oster H.; RT "High-fat diet-induced hyperinsulinemia and tissue-specific insulin RT resistance in Cry-deficient mice."; RL Am. J. Physiol. 304:E1053-E1063(2013). RN [54] RP REVIEW. RX PubMed=23576606; DOI=10.1152/ajpregu.00066.2013; RA Richards J., Gumz M.L.; RT "Mechanism of the circadian clock in physiology."; RL Am. J. Physiol. 304:R1053-R1064(2013). RN [55] RP FUNCTION. RX PubMed=23955654; DOI=10.1007/s00403-013-1403-0; RA Watabe Y., Tomioka M., Watabe A., Aihara M., Shimba S., Inoue H.; RT "The clock gene brain and muscle Arnt-like protein-1 (BMAL1) is involved in RT hair growth."; RL Arch. Dermatol. Res. 305:755-761(2013). RN [56] RP FUNCTION. RX PubMed=23291174; DOI=10.1016/j.bbrc.2012.12.098; RA Oishi K., Koyanagi S., Ohkura N.; RT "The molecular clock regulates circadian transcription of tissue factor RT gene."; RL Biochem. Biophys. Res. Commun. 431:332-335(2013). RN [57] RP GLYCOSYLATION, AND INTERACTION WITH OGT. RX PubMed=23337503; DOI=10.1016/j.bbrc.2013.01.043; RA Ma Y.T., Luo H., Guan W.J., Zhang H., Chen C., Wang Z., Li J.D.; RT "O-GlcNAcylation of BMAL1 regulates circadian rhythms in NIH3T3 RT fibroblasts."; RL Biochem. Biophys. Res. Commun. 431:382-387(2013). RN [58] RP DNA-BINDING. RX PubMed=23831463; DOI=10.1016/j.bbrc.2013.06.086; RA Yoshii K., Ishijima S., Sagami I.; RT "Effects of NAD(P)H and its derivatives on the DNA-binding activity of RT NPAS2, a mammalian circadian transcription factor."; RL Biochem. Biophys. Res. Commun. 437:386-391(2013). RN [59] RP GLYCOSYLATION, UBIQUITINATION, AND MUTAGENESIS OF SER-418. RX PubMed=23395176; DOI=10.1016/j.cmet.2012.12.015; RA Li M.D., Ruan H.B., Hughes M.E., Lee J.S., Singh J.P., Jones S.P., RA Nitabach M.N., Yang X.; RT "O-GlcNAc signaling entrains the circadian clock by inhibiting BMAL1/CLOCK RT ubiquitination."; RL Cell Metab. 17:303-310(2013). RN [60] RP FUNCTION. RX PubMed=24268780; DOI=10.1016/j.celrep.2013.10.037; RA Bouchard-Cannon P., Mendoza-Viveros L., Yuen A., Kaern M., Cheng H.Y.; RT "The circadian molecular clock regulates adult hippocampal neurogenesis by RT controlling the timing of cell-cycle entry and exit."; RL Cell Rep. 5:961-973(2013). RN [61] RP FUNCTION. RX PubMed=23525013; DOI=10.1242/jcs.120519; RA Chatterjee S., Nam D., Guo B., Kim J.M., Winnier G.E., Lee J., Berdeaux R., RA Yechoor V.K., Ma K.; RT "Brain and muscle Arnt-like 1 is a key regulator of myogenesis."; RL J. Cell Sci. 126:2213-2224(2013). RN [62] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=24270424; DOI=10.1172/jci70317; RA Musiek E.S., Lim M.M., Yang G., Bauer A.Q., Qi L., Lee Y., Roh J.H., RA Ortiz-Gonzalez X., Dearborn J.T., Culver J.P., Herzog E.D., Hogenesch J.B., RA Wozniak D.F., Dikranian K., Giasson B.I., Weaver D.R., Holtzman D.M., RA Fitzgerald G.A.; RT "Circadian clock proteins regulate neuronal redox homeostasis and RT neurodegeneration."; RL J. Clin. Invest. 123:5389-5400(2013). RN [63] RP FUNCTION. RX PubMed=24048828; DOI=10.1523/jneurosci.2039-13.2013; RA Hwang C.K., Chaurasia S.S., Jackson C.R., Chan G.C., Storm D.R., RA Iuvone P.M.; RT "Circadian rhythm of contrast sensitivity is regulated by a dopamine- RT neuronal PAS-domain protein 2-adenylyl cyclase 1 signaling pathway in RT retinal ganglion cells."; RL J. Neurosci. 33:14989-14997(2013). RN [64] RP FUNCTION. RX PubMed=23547261; DOI=10.1128/mcb.01421-12; RA Lee J., Moulik M., Fang Z., Saha P., Zou F., Xu Y., Nelson D.L., Ma K., RA Moore D.D., Yechoor V.K.; RT "Bmal1 and beta-cell clock are required for adaptation to circadian RT disruption, and their loss of function leads to oxidative stress-induced RT beta-cell failure in mice."; RL Mol. Cell. Biol. 33:2327-2338(2013). RN [65] RP FUNCTION, AND INTERACTION WITH MTA1. RX PubMed=24089055; DOI=10.1038/ncomms3545; RA Li D.Q., Pakala S.B., Reddy S.D., Peng S., Balasenthil S., Deng C.X., RA Lee C.C., Rea M.A., Kumar R.; RT "Metastasis-associated protein 1 is an integral component of the circadian RT molecular machinery."; RL Nat. Commun. 4:2545-2545(2013). RN [66] RP FUNCTION. RX PubMed=23750248; DOI=10.1371/journal.pone.0065255; RA Kennaway D.J., Varcoe T.J., Voultsios A., Boden M.J.; RT "Global loss of Bmal1 expression alters adipose tissue hormones, gene RT expression and glucose metabolism."; RL PLoS ONE 8:E65255-E65255(2013). RN [67] RP REVIEW. RX PubMed=23303907; DOI=10.1152/physrev.00016.2012; RA Eckel-Mahan K., Sassone-Corsi P.; RT "Metabolism and the circadian clock converge."; RL Physiol. Rev. 93:107-135(2013). RN [68] RP INTERACTION WITH THRAP3. RX PubMed=24043798; DOI=10.1073/pnas.1305980110; RA Lande-Diner L., Boyault C., Kim J.Y., Weitz C.J.; RT "A positive feedback loop links circadian clock factor CLOCK-BMAL1 to the RT basic transcriptional machinery."; RL Proc. Natl. Acad. Sci. U.S.A. 110:16021-16026(2013). RN [69] RP FUNCTION, AND INTERACTION WITH CLOCK; EED; EZH2 AND SUZ12. RX PubMed=23970558; DOI=10.1126/science.1240636; RA Nguyen K.D., Fentress S.J., Qiu Y., Yun K., Cox J.S., Chawla A.; RT "Circadian gene Bmal1 regulates diurnal oscillations of Ly6C(hi) RT inflammatory monocytes."; RL Science 341:1483-1488(2013). RN [70] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=24481314; DOI=10.18632/aging.100633; RA Khapre R.V., Kondratova A.A., Patel S., Dubrovsky Y., Wrobel M., RA Antoch M.P., Kondratov R.V.; RT "BMAL1-dependent regulation of the mTOR signaling pathway delays aging."; RL Aging (Albany NY) 6:48-57(2014). RN [71] RP INTERACTION WITH NCOA2. RX PubMed=24529706; DOI=10.1016/j.celrep.2014.01.027; RA Stashi E., Lanz R.B., Mao J., Michailidis G., Zhu B., Kettner N.M., RA Putluri N., Reineke E.L., Reineke L.C., Dasgupta S., Dean A., RA Stevenson C.R., Sivasubramanian N., Sreekumar A., Demayo F., York B., RA Fu L., O'Malley B.W.; RT "SRC-2 is an essential coactivator for orchestrating metabolism and RT circadian rhythm."; RL Cell Rep. 6:633-645(2014). RN [72] RP INDUCTION, AND TISSUE SPECIFICITY. RX PubMed=24603368; DOI=10.1038/emm.2013.153; RA Noh J.Y., Han D.H., Kim M.H., Ko I.G., Kim S.E., Park N., Kyoung Choe H., RA Kim K.H., Kim K., Kim C.J., Cho S.; RT "Presence of multiple peripheral circadian oscillators in the tissues RT controlling voiding function in mice."; RL Exp. Mol. Med. 46:E81-E81(2014). RN [73] RP FUNCTION. RX PubMed=24395244; DOI=10.1101/gad.228536.113; RA Menet J.S., Pescatore S., Rosbash M.; RT "CLOCK:BMAL1 is a pioneer-like transcription factor."; RL Genes Dev. 28:8-13(2014). RN [74] RP FUNCTION. RX PubMed=24442997; DOI=10.1002/hep.26992; RA Zhou B., Zhang Y., Zhang F., Xia Y., Liu J., Huang R., Wang Y., Hu Y., RA Wu J., Dai C., Wang H., Tu Y., Peng X., Wang Y., Zhai Q.; RT "CLOCK/BMAL1 regulates circadian change of mouse hepatic insulin RT sensitivity via SIRT1."; RL Hepatology 59:2196-2206(2014). RN [75] RP FUNCTION, AND INTERACTION WITH CIART. RX PubMed=24385426; DOI=10.1074/jbc.m113.534651; RA Annayev Y., Adar S., Chiou Y.Y., Lieb J., Sancar A., Ye R.; RT "Gene model 129 (Gm129) encodes a novel transcriptional repressor that RT modulates circadian gene expression."; RL J. Biol. Chem. 289:5013-5024(2014). RN [76] RP FUNCTION IN GR REPRESSION. RX PubMed=24378737; DOI=10.1016/j.mce.2013.12.013; RA Han D.H., Lee Y.J., Kim K., Kim C.J., Cho S.; RT "Modulation of glucocorticoid receptor induction properties by core RT circadian clock proteins."; RL Mol. Cell. Endocrinol. 383:170-180(2014). RN [77] RP FUNCTION, AND INTERACTION WITH CIART. RX PubMed=24736997; DOI=10.1371/journal.pbio.1001839; RA Goriki A., Hatanaka F., Myung J., Kim J.K., Yoritaka T., Tanoue S., Abe T., RA Kiyonari H., Fujimoto K., Kato Y., Todo T., Matsubara A., Forger D., RA Takumi T.; RT "A novel protein, CHRONO, functions as a core component of the mammalian RT circadian clock."; RL PLoS Biol. 12:E1001839-E1001839(2014). RN [78] RP REVIEW. RX PubMed=23916625; DOI=10.1016/j.tcb.2013.07.002; RA Partch C.L., Green C.B., Takahashi J.S.; RT "Molecular architecture of the mammalian circadian clock."; RL Trends Cell Biol. 24:90-99(2014). RN [79] RP SUBCELLULAR LOCATION, INTERACTION WITH HDAC3 AND CRY1, AND UBIQUITINATION RP AND PROTEASOMAL DEGRADATION. RX PubMed=26776516; DOI=10.1016/j.celrep.2015.12.076; RA Shi G., Xie P., Qu Z., Zhang Z., Dong Z., An Y., Xing L., Liu Z., Dong Y., RA Xu G., Yang L., Liu Y., Xu Y.; RT "Distinct roles of HDAC3 in the core circadian negative feedback loop are RT critical for clock function."; RL Cell Rep. 14:823-834(2016). RN [80] RP FUNCTION. RX PubMed=28985504; DOI=10.1016/j.molcel.2017.09.008; RA Lin R., Mo Y., Zha H., Qu Z., Xie P., Zhu Z.J., Xu Y., Xiong Y., Guan K.L.; RT "CLOCK acetylates ASS1 to drive circadian rhythm of ureagenesis."; RL Mol. Cell 68:198-209(2017). RN [81] RP INTERACTION WITH PIWIL2, AND TISSUE SPECIFICITY. RX PubMed=28903391; DOI=10.18632/oncotarget.18973; RA Lu Y., Zheng X., Hu W., Bian S., Zhang Z., Tao D., Liu Y., Ma Y.; RT "Cancer/testis antigen PIWIL2 suppresses circadian rhythms by regulating RT the stability and activity of BMAL1 and CLOCK."; RL Oncotarget 8:54913-54924(2017). RN [82] RP DEUBIQUITINATION BY USP9X, AND INTERACTION WITH USP9X. RX PubMed=29626158; DOI=10.1042/bcj20180005; RA Zhang Y., Duan C., Yang J., Chen S., Liu Q., Zhou L., Huang Z., Xu Y., RA Xu G.; RT "Deubiquitinating enzyme USP9X regulates cellular clock function by RT modulating the ubiquitination and degradation of a core circadian protein RT BMAL1."; RL Biochem. J. 475:1507-1522(2018). RN [83] RP LYSOSOME-MEDIATED DEGRADATION. RX PubMed=29937374; DOI=10.1016/j.cmet.2018.05.023; RA Toledo M., Batista-Gonzalez A., Merheb E., Aoun M.L., Tarabra E., Feng D., RA Sarparanta J., Merlo P., Botre F., Schwartz G.J., Pessin J.E., Singh R.; RT "Autophagy regulates the liver clock and glucose metabolism by degrading RT CRY1."; RL Cell Metab. 28:268-281(2018). RN [84] RP FUNCTION, DISRUPTION PHENOTYPE, AND MUTAGENESIS OF ILE-323. RX PubMed=29996098; DOI=10.1016/j.celrep.2018.06.026; RA Deng W., Zhu S., Zeng L., Liu J., Kang R., Yang M., Cao L., Wang H., RA Billiar T.R., Jiang J., Xie M., Tang D.; RT "The circadian clock controls immune checkpoint pathway in sepsis."; RL Cell Rep. 24:366-378(2018). RN [85] RP TISSUE SPECIFICITY. RX PubMed=29138967; DOI=10.1007/s12031-017-0996-8; RA Riedel C.S., Georg B., Joergensen H.L., Hannibal J., Fahrenkrug J.; RT "Mice lacking EGR1 have impaired clock gene (BMAL1) oscillation, locomotor RT activity, and body temperature."; RL J. Mol. Neurosci. 64:9-19(2018). RN [86] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=30096135; DOI=10.1371/journal.pbio.2005886; RA Dyar K.A., Hubert M.J., Mir A.A., Ciciliot S., Lutter D., Greulich F., RA Quagliarini F., Kleinert M., Fischer K., Eichmann T.O., Wright L.E., RA Pena Paz M.I., Casarin A., Pertegato V., Romanello V., Albiero M., RA Mazzucco S., Rizzuto R., Salviati L., Biolo G., Blaauw B., Schiaffino S., RA Uhlenhaut N.H.; RT "Transcriptional programming of lipid and amino acid metabolism by the RT skeletal muscle circadian clock."; RL PLoS Biol. 16:E2005886-E2005886(2018). RN [87] RP ACETYLATION AT LYS-544, AND MUTAGENESIS OF LYS-544. RX PubMed=31294688; DOI=10.7554/elife.43235; RA Petkau N., Budak H., Zhou X., Oster H., Eichele G.; RT "Acetylation of BMAL1 by TIP60 controls BRD4-P-TEFb recruitment to RT circadian promoters."; RL Elife 8:0-0(2019). RN [88] RP X-RAY CRYSTALLOGRAPHY (2.27 ANGSTROMS) OF 69-453 IN COMPLEX WITH CLOCK, RP FUNCTION, INTERACTION WITH CLOCK, AND MUTAGENESIS OF LEU-102; LEU-122 AND RP ILE-323. RX PubMed=22653727; DOI=10.1126/science.1222804; RA Huang N., Chelliah Y., Shan Y., Taylor C.A., Yoo S.H., Partch C., RA Green C.B., Zhang H., Takahashi J.S.; RT "Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional RT activator complex."; RL Science 337:189-194(2012). CC -!- FUNCTION: Transcriptional activator which forms a core component of the CC circadian clock. The circadian clock, an internal time-keeping system, CC regulates various physiological processes through the generation of CC approximately 24 hour circadian rhythms in gene expression, which are CC translated into rhythms in metabolism and behavior. It is derived from CC the Latin roots 'circa' (about) and 'diem' (day) and acts as an CC important regulator of a wide array of physiological functions CC including metabolism, sleep, body temperature, blood pressure, CC endocrine, immune, cardiovascular, and renal function. Consists of two CC major components: the central clock, residing in the suprachiasmatic CC nucleus (SCN) of the brain, and the peripheral clocks that are present CC in nearly every tissue and organ system. Both the central and CC peripheral clocks can be reset by environmental cues, also known as CC Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the CC central clock is light, which is sensed by retina and signals directly CC to the SCN. The central clock entrains the peripheral clocks through CC neuronal and hormonal signals, body temperature and feeding-related CC cues, aligning all clocks with the external light/dark cycle. Circadian CC rhythms allow an organism to achieve temporal homeostasis with its CC environment at the molecular level by regulating gene expression to CC create a peak of protein expression once every 24 hours to control when CC a particular physiological process is most active with respect to the CC solar day. Transcription and translation of core clock components CC (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a CC critical role in rhythm generation, whereas delays imposed by post- CC translational modifications (PTMs) are important for determining the CC period (tau) of the rhythms (tau refers to the period of a rhythm and CC is the length, in time, of one complete cycle). A diurnal rhythm is CC synchronized with the day/night cycle, while the ultradian and CC infradian rhythms have a period shorter and longer than 24 hours, CC respectively. Disruptions in the circadian rhythms contribute to the CC pathology of cardiovascular diseases, cancer, metabolic syndromes and CC aging. A transcription/translation feedback loop (TTFL) forms the core CC of the molecular circadian clock mechanism. Transcription factors, CC CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the CC feedback loop, act in the form of a heterodimer and activate the CC transcription of core clock genes and clock-controlled genes (involved CC in key metabolic processes), harboring E-box elements (5'-CACGTG-3') CC within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which CC are transcriptional repressors form the negative limb of the feedback CC loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer CC inhibiting its activity and thereby negatively regulating their own CC expression. This heterodimer also activates nuclear receptors NR1D1/2 CC and RORA/B/G, which form a second feedback loop and which activate and CC repress BMAL1 transcription, respectively. BMAL1 positively regulates CC myogenesis and negatively regulates adipogenesis via the CC transcriptional control of the genes of the canonical Wnt signaling CC pathway. Plays a role in normal pancreatic beta-cell function; CC regulates glucose-stimulated insulin secretion via the regulation of CC antioxidant genes NFE2L2/NRF2 and its targets SESN2, PRDX3, CCLC and CC CCLM. Negatively regulates the mTORC1 signaling pathway; regulates the CC expression of MTOR and DEPTOR. Controls diurnal oscillations of Ly6C CC inflammatory monocytes; rhythmic recruitment of the PRC2 complex CC imparts diurnal variation to chemokine expression that is necessary to CC sustain Ly6C monocyte rhythms. Regulates the expression of HSD3B2, CC STAR, PTGS2, CYP11A1, CYP19A1 and LHCGR in the ovary and also the genes CC involved in hair growth. Plays an important role in adult hippocampal CC neurogenesis by regulating the timely entry of neural stem/progenitor CC cells (NSPCs) into the cell cycle and the number of cell divisions that CC take place prior to cell-cycle exit. Regulates the circadian expression CC of CIART and KLF11. The CLOCK-BMAL1 heterodimer regulates the circadian CC expression of SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, CC PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4, CC MTA1, KLF10 and also genes implicated in glucose and lipid metabolism. CC Promotes rhythmic chromatin opening, regulating the DNA accessibility CC of other transcription factors. May play a role in spermatogenesis; CC contributes to the chromatoid body assembly and physiology. The NPAS2- CC BMAL1 heterodimer positively regulates the expression of MAOA, F7 and CC LDHA and modulates the circadian rhythm of daytime contrast sensitivity CC by regulating the rhythmic expression of adenylate cyclase type 1 CC (ADCY1) in the retina. The preferred binding motif for the CLOCK-BMAL1 CC heterodimer is 5'-CACGTGA-3', which contains a flanking adenine CC nucleotide at the 3-prime end of the canonical 6-nucleotide E-box CC sequence (By similarity). CLOCK specifically binds to the half-site 5'- CC CAC-3', while BMAL1 binds to the half-site 5'-GTGA-3' (By similarity). CC The CLOCK-BMAL1 heterodimer also recognizes the non-canonical E-box CC motifs 5'-AACGTGA-3' and 5'-CATGTGA-3' (By similarity). Essential for CC the rhythmic interaction of CLOCK with ASS1 and plays a critical role CC in positively regulating CLOCK-mediated acetylation of ASS1 CC (PubMed:28985504). Plays a role in protecting against lethal sepsis by CC limiting the expression of immune checkpoint protein CD274 in CC macrophages in a PKM2-dependent manner (PubMed:29996098). Regulates the CC diurnal rhythms of skeletal muscle metabolism via transcriptional CC activation of genes promoting triglyceride synthesis (DGAT2) and CC metabolic efficiency (COQ10B) (PubMed:30096135). CC {ECO:0000250|UniProtKB:O00327, ECO:0000269|PubMed:14672706, CC ECO:0000269|PubMed:18258755, ECO:0000269|PubMed:18316400, CC ECO:0000269|PubMed:19141540, ECO:0000269|PubMed:19286518, CC ECO:0000269|PubMed:19299583, ECO:0000269|PubMed:19605937, CC ECO:0000269|PubMed:20153195, ECO:0000269|PubMed:20385766, CC ECO:0000269|PubMed:20430893, ECO:0000269|PubMed:20562852, CC ECO:0000269|PubMed:20658528, ECO:0000269|PubMed:20840750, CC ECO:0000269|PubMed:20956306, ECO:0000269|PubMed:21768648, CC ECO:0000269|PubMed:21966465, ECO:0000269|PubMed:22045262, CC ECO:0000269|PubMed:22101268, ECO:0000269|PubMed:22611086, CC ECO:0000269|PubMed:22653727, ECO:0000269|PubMed:22900038, CC ECO:0000269|PubMed:22981862, ECO:0000269|PubMed:23291174, CC ECO:0000269|PubMed:23525013, ECO:0000269|PubMed:23547261, CC ECO:0000269|PubMed:23750248, ECO:0000269|PubMed:23955654, CC ECO:0000269|PubMed:23970558, ECO:0000269|PubMed:24048828, CC ECO:0000269|PubMed:24089055, ECO:0000269|PubMed:24268780, CC ECO:0000269|PubMed:24270424, ECO:0000269|PubMed:24378737, CC ECO:0000269|PubMed:24385426, ECO:0000269|PubMed:24395244, CC ECO:0000269|PubMed:24442997, ECO:0000269|PubMed:24481314, CC ECO:0000269|PubMed:24736997, ECO:0000269|PubMed:28985504, CC ECO:0000269|PubMed:29996098, ECO:0000269|PubMed:30096135}. CC -!- ACTIVITY REGULATION: The redox state of the cell can modulate the CC transcriptional activity of the CLOCK-BMAL1 and NPAS2-BMAL1 CC heterodimers; NADH and NADPH enhance the DNA-binding activity of the CC heterodimers. {ECO:0000250|UniProtKB:O00327}. CC -!- SUBUNIT: Component of the circadian clock oscillator which includes the CC CRY1/2 proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, CC TIMELESS and the PER1/2/3 proteins (PubMed:11779462). Forms a CC heterodimer with CLOCK (PubMed:9616112, PubMed:16717091, CC PubMed:16980631, PubMed:18662546, PubMed:19946213, PubMed:19330005, CC PubMed:21613214, PubMed:23970558, PubMed:22653727). The CLOCK-BMAL1 CC heterodimer is required for E-box-dependent transactivation, for CLOCK CC nuclear translocation and degradation, and, for phosphorylation of both CC CLOCK and BMAL1 (PubMed:11779462). Part of a nuclear complex which also CC includes RACK1 and PRKCA; RACK1 and PRKCA are recruited to the complex CC in a circadian manner (PubMed:20093473). Interacts with NPAS2 CC (PubMed:16628007). Interacts with EZH2 (PubMed:16717091, CC PubMed:23970558). Interacts with SUMO3 (PubMed:18644859). Interacts CC with SIRT1 (PubMed:18662546, PubMed:18662547, PubMed:19299583). CC Interacts with AHR (PubMed:20106950). Interacts with ID1, ID2 and ID3 CC (PubMed:20861012). Interacts with DDX4 (PubMed:22900038). Interacts CC with OGT (PubMed:23337503). Interacts with EED and SUZ12 CC (PubMed:23970558). Interacts with MTA1 (PubMed:24089055). Interacts CC with CIART (PubMed:24385426, PubMed:24736997). Interacts with HSP90 (By CC similarity). Interacts with KAT2B and EP300 (By similarity). Interacts CC with BHLHE40/DEC1 and BHLHE41/DEC2 (PubMed:12397359). Interacts with CC RELB and the interaction is enhanced in the presence of CLOCK CC (PubMed:22894897). Interacts with PER1, PER2, CRY1 and CRY2 and this CC interaction requires a translocation to the nucleus (PubMed:18430226, CC PubMed:19605937, PubMed:20840750, PubMed:21613214, PubMed:24154698). CC Interaction of the CLOCK-BMAL1 heterodimer with PER or CRY inhibits CC transcription activation (PubMed:21613214). Interaction of the CLOCK- CC BMAL1 with CRY1 is independent of DNA but with PER2 is off DNA CC (PubMed:21613214). The CLOCK-BMAL1 heterodimer interacts with GSK3B CC (PubMed:19946213, PubMed:20049328). Interacts with KDM5A CC (PubMed:21960634). Interacts with KMT2A; in a circadian manner CC (PubMed:21113167). Interacts with UBE3A (By similarity). Interacts with CC PRKCG (PubMed:23185022). Interacts with MAGEL2 (PubMed:22208286). CC Interacts with NCOA2 (PubMed:24529706). Interacts with THRAP3 CC (PubMed:24043798). The CLOCK-BMAL1 heterodimer interacts with PASD1 (By CC similarity). Interacts with PASD1 (By similarity). Interacts with USP9X CC (PubMed:29626158). Interacts with PIWIL2 (via PIWI domain) CC (PubMed:28903391). Interacts with HDAC3 (PubMed:26776516). Interacts CC with HNF4A (By similarity). {ECO:0000250|UniProtKB:O00327, CC ECO:0000269|PubMed:12397359, ECO:0000269|PubMed:16628007, CC ECO:0000269|PubMed:16717091, ECO:0000269|PubMed:16980631, CC ECO:0000269|PubMed:18430226, ECO:0000269|PubMed:18644859, CC ECO:0000269|PubMed:18662546, ECO:0000269|PubMed:18662547, CC ECO:0000269|PubMed:19299583, ECO:0000269|PubMed:19330005, CC ECO:0000269|PubMed:19605937, ECO:0000269|PubMed:19946213, CC ECO:0000269|PubMed:20049328, ECO:0000269|PubMed:20093473, CC ECO:0000269|PubMed:20106950, ECO:0000269|PubMed:20840750, CC ECO:0000269|PubMed:20861012, ECO:0000269|PubMed:21113167, CC ECO:0000269|PubMed:21613214, ECO:0000269|PubMed:21960634, CC ECO:0000269|PubMed:22208286, ECO:0000269|PubMed:22653727, CC ECO:0000269|PubMed:22894897, ECO:0000269|PubMed:22900038, CC ECO:0000269|PubMed:23185022, ECO:0000269|PubMed:23337503, CC ECO:0000269|PubMed:23970558, ECO:0000269|PubMed:24043798, CC ECO:0000269|PubMed:24089055, ECO:0000269|PubMed:24154698, CC ECO:0000269|PubMed:24385426, ECO:0000269|PubMed:24529706, CC ECO:0000269|PubMed:24736997, ECO:0000269|PubMed:26776516, CC ECO:0000269|PubMed:28903391, ECO:0000269|PubMed:29626158, CC ECO:0000269|PubMed:9616112}. CC -!- INTERACTION: CC Q9WTL8; Q3TQ03: Ciart; NbExp=3; IntAct=EBI-644534, EBI-16101489; CC Q9WTL8; O08785: Clock; NbExp=39; IntAct=EBI-644534, EBI-79859; CC Q9WTL8; P97784: Cry1; NbExp=23; IntAct=EBI-644534, EBI-1266607; CC Q9WTL8; Q99JJ1: Cry2; NbExp=4; IntAct=EBI-644534, EBI-1794634; CC Q9WTL8; Q9R194: Cry2; NbExp=12; IntAct=EBI-644534, EBI-1266619; CC Q9WTL8; Q60737: Csnk2a1; NbExp=5; IntAct=EBI-644534, EBI-771698; CC Q9WTL8; P67871: Csnk2b; NbExp=8; IntAct=EBI-644534, EBI-348179; CC Q9WTL8; P11103: Parp1; NbExp=7; IntAct=EBI-644534, EBI-642213; CC Q9WTL8; O54943: Per2; NbExp=9; IntAct=EBI-644534, EBI-1266779; CC Q9WTL8; P62137: Ppp1ca; NbExp=2; IntAct=EBI-644534, EBI-357187; CC Q9WTL8; Q8N365: CIART; Xeno; NbExp=6; IntAct=EBI-644534, EBI-10265133; CC Q9WTL8; P67870: CSNK2B; Xeno; NbExp=4; IntAct=EBI-644534, EBI-348169; CC Q9WTL8; Q03164: KMT2A; Xeno; NbExp=3; IntAct=EBI-644534, EBI-591370; CC Q9WTL8; P51449: RORC; Xeno; NbExp=2; IntAct=EBI-644534, EBI-3908771; CC Q9WTL8; P61964: WDR5; Xeno; NbExp=2; IntAct=EBI-644534, EBI-540834; CC Q9WTL8-2; O08785: Clock; NbExp=2; IntAct=EBI-644559, EBI-79859; CC Q9WTL8-2; P97784: Cry1; NbExp=4; IntAct=EBI-644559, EBI-1266607; CC Q9WTL8-4; O08785: Clock; NbExp=10; IntAct=EBI-644568, EBI-79859; CC Q9WTL8-4; P45481: Crebbp; NbExp=2; IntAct=EBI-644568, EBI-296306; CC Q9WTL8-4; P97784: Cry1; NbExp=4; IntAct=EBI-644568, EBI-1266607; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16980631, CC ECO:0000269|PubMed:22208286, ECO:0000269|PubMed:26776516}. Cytoplasm CC {ECO:0000269|PubMed:16980631}. Nucleus, PML body CC {ECO:0000269|PubMed:18644859}. Note=Shuttles between the nucleus and CC the cytoplasm and this nucleocytoplasmic shuttling is essential for the CC nuclear accumulation of CLOCK, target gene transcription and the CC degradation of the CLOCK-BMAL1 heterodimer. The sumoylated form CC localizes in the PML body. Sequestered to the cytoplasm in the presence CC of ID2. {ECO:0000269|PubMed:16980631, ECO:0000269|PubMed:18644859, CC ECO:0000269|PubMed:20861012}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=5; CC Name=1; Synonyms=b'; CC IsoId=Q9WTL8-1; Sequence=Displayed; CC Name=2; Synonyms=b; CC IsoId=Q9WTL8-2; Sequence=VSP_007992; CC Name=3; CC IsoId=Q9WTL8-3; Sequence=VSP_007993, VSP_007994; CC Name=4; CC IsoId=Q9WTL8-4; Sequence=VSP_007992, VSP_007994; CC Name=5; Synonyms=g'; CC IsoId=Q9WTL8-5; Sequence=VSP_007992, VSP_007995, VSP_007996; CC -!- TISSUE SPECIFICITY: Expressed in liver and testis (at protein level). CC Expressed in the suprachiasmatic nucleus (SCN) in a circadian manner CC (PubMed:29138967). {ECO:0000269|PubMed:16790549, CC ECO:0000269|PubMed:22900038, ECO:0000269|PubMed:23531614, CC ECO:0000269|PubMed:24154698, ECO:0000269|PubMed:24603368, CC ECO:0000269|PubMed:28903391, ECO:0000269|PubMed:29138967}. CC -!- INDUCTION: Expressed in a circadian manner in the liver. CC {ECO:0000269|PubMed:16790549, ECO:0000269|PubMed:20385766, CC ECO:0000269|PubMed:23531614, ECO:0000269|PubMed:24603368}. CC -!- PTM: Ubiquitinated, leading to its proteasomal degradation CC (PubMed:16980631, PubMed:18644859, PubMed:23185022, PubMed:26776516). CC Deubiquitinated by USP9X (PubMed:29626158). CC {ECO:0000269|PubMed:16980631, ECO:0000269|PubMed:18644859, CC ECO:0000269|PubMed:23185022, ECO:0000269|PubMed:26776516, CC ECO:0000269|PubMed:29626158}. CC -!- PTM: O-glycosylated; contains O-GlcNAc. O-glycosylation by OGT prevents CC protein degradation by inhibiting ubiquitination. It also stabilizes CC the CLOCK-BMAL1 heterodimer thereby increasing CLOCK-BMAL1-mediated CC transcription of genes in the negative loop of the circadian clock such CC as PER1/2/3 and CRY1/2. {ECO:0000269|PubMed:23337503, CC ECO:0000269|PubMed:23395176}. CC -!- PTM: Acetylated on Lys-544 by CLOCK during the repression phase of the CC circadian cycle (PubMed:18075593, PubMed:31294688). Acetylation CC facilitates recruitment of CRY1 protein and initiates the repression CC phase of the circadian cycle (PubMed:18075593). Acetylated at Lys-544 CC by KAT5 during the activation phase of the cycle, leading to CC recruitment of the positive transcription elongation factor b (P-TEFb) CC and BRD4, followed by productive elongation of circadian transcripts CC (PubMed:31294688). Deacetylated by SIRT1, which may result in decreased CC protein stability (PubMed:18662547). {ECO:0000269|PubMed:18075593, CC ECO:0000269|PubMed:18662547, ECO:0000269|PubMed:31294688}. CC -!- PTM: Phosphorylated upon dimerization with CLOCK. Phosphorylation CC enhances the transcriptional activity, alters the subcellular CC localization and decreases the stability of the CLOCK-BMAL1 heterodimer CC by promoting its degradation. Phosphorylation shows circadian CC variations in the liver with a peak between CT10 to CT14. CC Phosphorylation at Ser-97 by CK2 is essential for its nuclear CC localization, its interaction with CLOCK and controls CLOCK nuclear CC entry. Dephosphorylation at Ser-85 is important for dimerization with CC CLOCK and transcriptional activity (By similarity). CC {ECO:0000250|UniProtKB:O00327, ECO:0000269|PubMed:11779462, CC ECO:0000269|PubMed:12897057, ECO:0000269|PubMed:19330005, CC ECO:0000269|PubMed:19414601, ECO:0000269|PubMed:19946213, CC ECO:0000269|PubMed:20049328}. CC -!- PTM: Sumoylated on Lys-266 upon dimerization with CLOCK. Predominantly CC conjugated to poly-SUMO2/3 rather than SUMO1 and the level of these CC conjugates undergo rhythmic variation, peaking at CT9-CT12. Sumoylation CC localizes it exclusively to the PML body and promotes its CC ubiquitination in the PML body, ubiquitin-dependent proteasomal CC degradation and the transcriptional activity of the CLOCK-BMAL1 CC heterodimer. {ECO:0000269|PubMed:16109848, CC ECO:0000269|PubMed:18644859}. CC -!- PTM: Undergoes lysosome-mediated degradation in a time-dependent manner CC in the liver. {ECO:0000269|PubMed:29937374}. CC -!- DISRUPTION PHENOTYPE: Mice are characterized by reduced lifespan, and CC the presence of a number of pathologies characteristic of pre-mature CC aging and increased oxidative stress. They show impaired functional CC connectivity, increased oxidative damage and severe astrogliosis in the CC brain. They also exhibit accelerated thrombosis with elevated levels of CC thrombogenic factors, including VWF, SERPINE1/PAI1, and fibrinogen. CC Both male and female mice are infertile and male mice have low CC testosterone and high luteinizing hormone serum levels and a CC significant decrease in sperm count (PubMed:18258755, PubMed:22101268, CC PubMed:24270424, PubMed:24481314). Conditional knockout in myeloid CC cells increases the risk of sepsis lethality which is associated with CC elevated lactate production and CD274 expression in macrophages CC (PubMed:29996098). Myeloid-cell-specific BMAL1 and PKM2 double knockout CC reduces the risk of sepsis lethality which is associated with reduced CC serum lactate levels and reduced CD274 expression in macrophages CC (PubMed:29996098). Conditional knockout in skeletal muscle leads to CC impaired skeletal muscle triglyceride biosynthesis, accumulation of CC bioactive lipids and amino acids and reduced mitochondrial efficiency CC (PubMed:30096135). {ECO:0000269|PubMed:18258755, CC ECO:0000269|PubMed:22101268, ECO:0000269|PubMed:24270424, CC ECO:0000269|PubMed:24481314, ECO:0000269|PubMed:29996098, CC ECO:0000269|PubMed:30096135}. 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; AB012601; BAA76414.1; -; mRNA. DR EMBL; AB015203; BAA81898.1; -; mRNA. DR EMBL; AB012602; BAA76415.1; -; mRNA. DR EMBL; AB014494; BAA32208.1; -; mRNA. DR EMBL; BC025973; AAH25973.1; -; mRNA. DR EMBL; BC011080; AAH11080.1; -; mRNA. DR CCDS; CCDS40092.1; -. [Q9WTL8-4] DR CCDS; CCDS85390.1; -. [Q9WTL8-3] DR PIR; JE0270; JE0270. DR RefSeq; NP_001229977.1; NM_001243048.1. [Q9WTL8-3] DR RefSeq; NP_031515.1; NM_007489.4. [Q9WTL8-4] DR RefSeq; XP_006507314.1; XM_006507251.2. DR RefSeq; XP_017177438.1; XM_017321949.1. DR RefSeq; XP_017177439.1; XM_017321950.1. [Q9WTL8-2] DR PDB; 4F3L; X-ray; 2.27 A; B=69-453. DR PDB; 8OSJ; EM; 6.20 A; N=69-447. DR PDB; 8OSK; EM; 3.60 A; N=69-447. DR PDB; 8OSL; EM; 4.90 A; N/P=69-447. DR PDBsum; 4F3L; -. DR PDBsum; 8OSJ; -. DR PDBsum; 8OSK; -. DR PDBsum; 8OSL; -. DR AlphaFoldDB; Q9WTL8; -. DR EMDB; EMD-17155; -. DR EMDB; EMD-17157; -. DR EMDB; EMD-17160; -. DR SASBDB; Q9WTL8; -. DR SMR; Q9WTL8; -. DR BioGRID; 198207; 20. DR ComplexPortal; CPX-3225; CLOCK-BMAL1 transcription complex. DR CORUM; Q9WTL8; -. DR DIP; DIP-43977N; -. DR IntAct; Q9WTL8; 32. DR MINT; Q9WTL8; -. DR STRING; 10090.ENSMUSP00000147989; -. DR GlyGen; Q9WTL8; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q9WTL8; -. DR PhosphoSitePlus; Q9WTL8; -. DR MaxQB; Q9WTL8; -. DR PaxDb; 10090-ENSMUSP00000046235; -. DR ProteomicsDB; 265307; -. [Q9WTL8-1] DR ProteomicsDB; 265308; -. [Q9WTL8-2] DR ProteomicsDB; 265309; -. [Q9WTL8-3] DR ProteomicsDB; 265310; -. [Q9WTL8-4] DR ProteomicsDB; 265311; -. [Q9WTL8-5] DR Antibodypedia; 11861; 649 antibodies from 45 providers. DR DNASU; 11865; -. DR Ensembl; ENSMUST00000047321.9; ENSMUSP00000046235.8; ENSMUSG00000055116.9. [Q9WTL8-4] DR Ensembl; ENSMUST00000210074.2; ENSMUSP00000147764.2; ENSMUSG00000055116.9. [Q9WTL8-3] DR Ensembl; ENSMUST00000210238.2; ENSMUSP00000147989.2; ENSMUSG00000055116.9. [Q9WTL8-4] DR GeneID; 11865; -. DR KEGG; mmu:11865; -. DR UCSC; uc009jhf.2; mouse. [Q9WTL8-3] DR UCSC; uc009jhi.2; mouse. [Q9WTL8-2] DR UCSC; uc009jhj.2; mouse. [Q9WTL8-1] DR AGR; MGI:1096381; -. DR CTD; 406; -. DR MGI; MGI:1096381; Bmal1. DR VEuPathDB; HostDB:ENSMUSG00000055116; -. DR eggNOG; KOG3561; Eukaryota. DR GeneTree; ENSGT00940000157523; -. DR HOGENOM; CLU_011864_2_2_1; -. DR InParanoid; Q9WTL8; -. DR OMA; TTGCHRR; -. DR PhylomeDB; Q9WTL8; -. DR TreeFam; TF319983; -. DR Reactome; R-MMU-9768919; NPAS4 regulates expression of target genes. DR BioGRID-ORCS; 11865; 4 hits in 83 CRISPR screens. DR ChiTaRS; Arntl; mouse. DR PRO; PR:Q9WTL8; -. DR Proteomes; UP000000589; Chromosome 7. DR RNAct; Q9WTL8; Protein. DR Bgee; ENSMUSG00000055116; Expressed in animal zygote and 244 other cell types or tissues. DR ExpressionAtlas; Q9WTL8; baseline and differential. DR GO; GO:0034751; C:aryl hydrocarbon receptor complex; IBA:GO_Central. DR GO; GO:0033391; C:chromatoid body; IDA:UniProtKB. DR GO; GO:1990513; C:CLOCK-BMAL transcription complex; IPI:ComplexPortal. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI. DR GO; GO:0016604; C:nuclear body; IDA:MGI. DR GO; GO:0005654; C:nucleoplasm; ISO:MGI. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0016605; C:PML body; IEA:UniProtKB-SubCell. DR GO; GO:0005667; C:transcription regulator complex; IDA:UniProtKB. DR GO; GO:0017162; F:aryl hydrocarbon receptor binding; ISO:MGI. DR GO; GO:0043425; F:bHLH transcription factor binding; IPI:BHF-UCL. DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB. DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:BHF-UCL. DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:UniProtKB. DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IDA:BHF-UCL. DR GO; GO:0140297; F:DNA-binding transcription factor binding; ISO:MGI. DR GO; GO:0070888; F:E-box binding; IDA:UniProtKB. DR GO; GO:0051879; F:Hsp90 protein binding; ISO:MGI. DR GO; GO:0046982; F:protein heterodimerization activity; IPI:BHF-UCL. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:UniProtKB. DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:UniProtKB. DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:MGI. DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:UniProtKB. DR GO; GO:0006914; P:autophagy; IMP:MGI. DR GO; GO:0032922; P:circadian regulation of gene expression; IDA:UniProtKB. DR GO; GO:0007623; P:circadian rhythm; IDA:UniProtKB. DR GO; GO:0010467; P:gene expression; IMP:MGI. DR GO; GO:0060137; P:maternal process involved in parturition; IMP:CACAO. DR GO; GO:0120163; P:negative regulation of cold-induced thermogenesis; IMP:YuBioLab. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0045599; P:negative regulation of fat cell differentiation; IMP:UniProtKB. DR GO; GO:2000323; P:negative regulation of glucocorticoid receptor signaling pathway; IMP:UniProtKB. DR GO; GO:0032007; P:negative regulation of TOR signaling; IMP:UniProtKB. DR GO; GO:0090403; P:oxidative stress-induced premature senescence; IMP:UniProtKB. DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; IMP:UniProtKB. DR GO; GO:0042753; P:positive regulation of circadian rhythm; IMP:UniProtKB. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:1901985; P:positive regulation of protein acetylation; IMP:UniProtKB. DR GO; GO:2001016; P:positive regulation of skeletal muscle cell differentiation; IMP:UniProtKB. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:BHF-UCL. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IMP:UniProtKB. DR GO; GO:0006606; P:protein import into nucleus; IDA:MGI. DR GO; GO:0051726; P:regulation of cell cycle; IMP:UniProtKB. DR GO; GO:2000772; P:regulation of cellular senescence; IMP:UniProtKB. DR GO; GO:0006355; P:regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0042634; P:regulation of hair cycle; ISS:UniProtKB. DR GO; GO:0050796; P:regulation of insulin secretion; IMP:UniProtKB. DR GO; GO:0050767; P:regulation of neurogenesis; IMP:UniProtKB. DR GO; GO:0042176; P:regulation of protein catabolic process; IDA:MGI. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central. DR GO; GO:2000074; P:regulation of type B pancreatic cell development; IMP:UniProtKB. DR GO; GO:0051775; P:response to redox state; IDA:UniProtKB. DR GO; GO:0007283; P:spermatogenesis; IMP:UniProtKB. DR CDD; cd11438; bHLH-PAS_ARNTL_PASD3; 1. DR CDD; cd00130; PAS; 2. DR Gene3D; 4.10.280.10; Helix-loop-helix DNA-binding domain; 1. DR Gene3D; 3.30.450.20; PAS domain; 2. DR InterPro; IPR011598; bHLH_dom. DR InterPro; IPR036638; HLH_DNA-bd_sf. DR InterPro; IPR001067; Nuc_translocat. DR InterPro; IPR001610; PAC. DR InterPro; IPR000014; PAS. DR InterPro; IPR035965; PAS-like_dom_sf. DR InterPro; IPR013767; PAS_fold. DR NCBIfam; TIGR00229; sensory_box; 1. DR PANTHER; PTHR23042:SF52; ARYL HYDROCARBON RECEPTOR NUCLEAR TRANSLOCATOR-LIKE PROTEIN 1; 1. DR PANTHER; PTHR23042; CIRCADIAN PROTEIN CLOCK/ARNT/BMAL/PAS; 1. DR Pfam; PF00010; HLH; 1. DR Pfam; PF00989; PAS; 1. DR Pfam; PF14598; PAS_11; 1. DR PRINTS; PR00785; NCTRNSLOCATR. DR SMART; SM00353; HLH; 1. DR SMART; SM00086; PAC; 1. DR SMART; SM00091; PAS; 2. DR SUPFAM; SSF47459; HLH, helix-loop-helix DNA-binding domain; 1. DR SUPFAM; SSF55785; PYP-like sensor domain (PAS domain); 2. DR PROSITE; PS50888; BHLH; 1. DR PROSITE; PS50112; PAS; 2. DR Genevisible; Q9WTL8; MM. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Activator; Alternative splicing; KW Biological rhythms; Cytoplasm; DNA-binding; Glycoprotein; Isopeptide bond; KW Nucleus; Phosphoprotein; Reference proteome; Repeat; Transcription; KW Transcription regulation; Ubl conjugation. FT CHAIN 1..632 FT /note="Basic helix-loop-helix ARNT-like protein 1" FT /id="PRO_0000127158" FT DOMAIN 79..132 FT /note="bHLH" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981" FT DOMAIN 150..222 FT /note="PAS 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140" FT DOMAIN 333..403 FT /note="PAS 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140" FT DOMAIN 408..451 FT /note="PAC" FT REGION 1..39 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 465..498 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 514..594 FT /note="Interaction with CIART" FT REGION 517..601 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 36..41 FT /note="Nuclear localization signal" FT /evidence="ECO:0000269|PubMed:16980631" FT MOTIF 149..159 FT /note="Nuclear export signal 1" FT /evidence="ECO:0000269|PubMed:16980631" FT MOTIF 367..375 FT /note="Nuclear export signal 2" FT /evidence="ECO:0000269|PubMed:16980631" FT COMPBIAS 1..32 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 518..538 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 558..580 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT SITE 84 FT /note="Interaction with E-box DNA" FT /evidence="ECO:0000250|UniProtKB:O00327" FT SITE 87 FT /note="Interaction with E-box DNA" FT /evidence="ECO:0000250|UniProtKB:O00327" FT SITE 88 FT /note="Interaction with E-box DNA" FT /evidence="ECO:0000250|UniProtKB:O00327" FT SITE 92 FT /note="Interaction with E-box DNA" FT /evidence="ECO:0000250|UniProtKB:O00327" FT SITE 132 FT /note="Important for interaction with CLOCK" FT /evidence="ECO:0000250|UniProtKB:O00327" FT MOD_RES 17 FT /note="Phosphoserine; by GSK3-beta" FT /evidence="ECO:0000269|PubMed:20049328" FT MOD_RES 21 FT /note="Phosphothreonine; by GSK3-beta" FT /evidence="ECO:0000269|PubMed:20049328" FT MOD_RES 85 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O00327" FT MOD_RES 97 FT /note="Phosphoserine; by CK2" FT /evidence="ECO:0000269|PubMed:19330005" FT MOD_RES 544 FT /note="N6-acetyllysine" FT /evidence="ECO:0000269|PubMed:18075593, FT ECO:0000269|PubMed:18662547, ECO:0000269|PubMed:31294688" FT CROSSLNK 259 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2 and SUMO3)" FT /evidence="ECO:0000269|PubMed:18644859" FT CROSSLNK 266 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO); alternate" FT /evidence="ECO:0000269|PubMed:16109848" FT CROSSLNK 266 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2); alternate" FT /evidence="ECO:0000250|UniProtKB:O00327" FT VAR_SEQ 48..54 FT /note="Missing (in isoform 2, isoform 4 and isoform 5)" FT /evidence="ECO:0000303|PubMed:10403839, FT ECO:0000303|PubMed:15489334, ECO:0000303|PubMed:9704006" FT /id="VSP_007992" FT VAR_SEQ 49..68 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_007993" FT VAR_SEQ 161..483 FT /note="AADGFLFVVGCDRGKILFVSESVFKILNYSQNDLIGQSLFDYLHPKDIAKVK FT EQLSSSDTAPRERLIDAKTGLPVKTDITPGPSRLCSGARRSFFCRMKCNRPSVKVEDKD FT FASTCSKKKDRKSFCTIHSTGYLKSWPPTKMGLDEDNEPDNEGCNLSCLVAIGRLHSHM FT VPQPANGEIRVKSMEYVSRHAIDGKFVFVDQRATAILAYLPQELLGTSCYEYFHQDDIG FT HLAECHRQVLQTREKITTNCYKFKIKDGSFITLRSRWFSFMNPWTKEVEYIVSTNTVVL FT ANVLEGGDPTFPQLTAPPHSMDSMLPSGEGGPKRT -> DVTEGRSSLSPSLSSRSSII FT ARMTLLARACLTTCIQKILPKLRNSYLPRTLRPGSDSLMPRLDFRLKRI (in FT isoform 5)" FT /evidence="ECO:0000303|PubMed:10403839" FT /id="VSP_007995" FT VAR_SEQ 280 FT /note="K -> KA (in isoform 3 and isoform 4)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:9704006" FT /id="VSP_007994" FT VAR_SEQ 484..632 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:10403839" FT /id="VSP_007996" FT MUTAGEN 38..39 FT /note="KR->AA: Loss of nuclear localization." FT /evidence="ECO:0000269|PubMed:16980631" FT MUTAGEN 97 FT /note="S->A: Impaired nuclear accumulation, decreased FT interaction with CLOCK and disruption of circadian clock FT function." FT /evidence="ECO:0000269|PubMed:19330005" FT MUTAGEN 102 FT /note="L->E: Reduced CLOCK binding. Abolishes FT transcriptional activation by the CLOCK-BMAL1 heterodimer." FT /evidence="ECO:0000269|PubMed:22653727" FT MUTAGEN 122 FT /note="L->E: Reduced CLOCK binding. Abolishes FT transcriptional activation by the CLOCK-BMAL1 heterodimer." FT /evidence="ECO:0000269|PubMed:22653727" FT MUTAGEN 154 FT /note="L->A: Significant reduction in nucleocytoplasmic FT shuttling; when associated with A-157." FT /evidence="ECO:0000269|PubMed:16980631" FT MUTAGEN 157 FT /note="L->A: Significant reduction in nucleocytoplasmic FT shuttling; when associated with A-154." FT /evidence="ECO:0000269|PubMed:16980631" FT MUTAGEN 230 FT /note="K->R: No effect on sumoylation." FT /evidence="ECO:0000269|PubMed:16109848" FT MUTAGEN 236 FT /note="K->R: No effect on sumoylation." FT /evidence="ECO:0000269|PubMed:16109848" FT MUTAGEN 259 FT /note="K->R: Significant decrease in; transcriptional FT activity, localization in PML body, ubiquitination and FT proteasome-mediated proteolysis." FT /evidence="ECO:0000269|PubMed:18644859" FT MUTAGEN 266 FT /note="K->R: Abolishes sumoylation." FT /evidence="ECO:0000269|PubMed:16109848" FT MUTAGEN 279 FT /note="K->R: No effect on sumoylation." FT /evidence="ECO:0000269|PubMed:16109848" FT MUTAGEN 323 FT /note="I->D: Reduced CLOCK binding. Slightly reduced FT transcriptional activation by the CLOCK-BMAL1 heterodimer. FT Impairs regulation of circadian clock. Loss of ability to FT inhibit the expression of CD274 in macrophages." FT /evidence="ECO:0000269|PubMed:22653727, FT ECO:0000269|PubMed:29996098" FT MUTAGEN 370 FT /note="L->A: Significant reduction in nucleocytoplasmic FT shuttling; when associated with A-374." FT /evidence="ECO:0000269|PubMed:16980631" FT MUTAGEN 374 FT /note="L->A: Significant reduction in nucleocytoplasmic FT shuttling; when associated with A-370." FT /evidence="ECO:0000269|PubMed:16980631" FT MUTAGEN 418 FT /note="S->A: Decreases without abolishing O-GlcNAcylation." FT /evidence="ECO:0000269|PubMed:23395176" FT MUTAGEN 544 FT /note="K->R: Decreased acetylation, leading to decreased FT transcription elongation during the activation phase of the FT circadian cycle." FT /evidence="ECO:0000269|PubMed:31294688" FT CONFLICT 254 FT /note="F -> L (in Ref. 1; BAA76414/BAA81898)" FT /evidence="ECO:0000305" FT HELIX 79..105 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 107..111 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 118..133 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 151..160 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 164..170 FT /evidence="ECO:0007829|PDB:4F3L" FT TURN 171..173 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 175..179 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 183..187 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 191..194 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 199..202 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 205..207 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 208..215 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 248..250 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 251..259 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 284..295 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 319..326 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 337..339 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 345..350 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 354..359 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 362..367 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 371..374 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 379..381 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 385..398 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 410..413 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 419..431 FT /evidence="ECO:0007829|PDB:4F3L" FT TURN 432..435 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 436..446 FT /evidence="ECO:0007829|PDB:4F3L" SQ SEQUENCE 632 AA; 69452 MW; 9669C3712A95C2DE CRC64; MADQRMDISS TISDFMSPGP TDLLSGSLGT SGVDCNRKRK GSATDYQLDD FAFEESMDTD KDDPHGRLEY AEHQGRIKNA REAHSQIEKR RRDKMNSFID ELASLVPTCN AMSRKLDKLT VLRMAVQHMK TLRGATNPYT EANYKPTFLS DDELKHLILR AADGFLFVVG CDRGKILFVS ESVFKILNYS QNDLIGQSLF DYLHPKDIAK VKEQLSSSDT APRERLIDAK TGLPVKTDIT PGPSRLCSGA RRSFFCRMKC NRPSVKVEDK DFASTCSKKK DRKSFCTIHS TGYLKSWPPT KMGLDEDNEP DNEGCNLSCL VAIGRLHSHM VPQPANGEIR VKSMEYVSRH AIDGKFVFVD QRATAILAYL PQELLGTSCY EYFHQDDIGH LAECHRQVLQ TREKITTNCY KFKIKDGSFI TLRSRWFSFM NPWTKEVEYI VSTNTVVLAN VLEGGDPTFP QLTAPPHSMD SMLPSGEGGP KRTHPTVPGI PGGTRAGAGK IGRMIAEEIM EIHRIRGSSP SSCGSSPLNI TSTPPPDASS PGGKKILNGG TPDIPSTGLL PGQAQETPGY PYSDSSSILG ENPHIGIDMI DNDQGSSSPS NDEAAMAVIM SLLEADAGLG GPVDFSDLPW PL //