ID CLOCK_MOUSE Reviewed; 855 AA. AC O08785; DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot. DT 01-JUL-1997, sequence version 1. DT 27-MAR-2024, entry version 217. DE RecName: Full=Circadian locomoter output cycles protein kaput; DE Short=mCLOCK; DE EC=2.3.1.48; GN Name=Clock; 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] (ISOFORM LONG). RC STRAIN=129; RX PubMed=9160756; DOI=10.1016/s0092-8674(00)80246-9; RA Antoch M.P., Song E.J., Chang A.M., Vitaterna M.H., Zhao Y., RA Wilsbacher L.D., Sangoram A.M., King D.P., Pinto L.H., Takahashi J.S.; RT "Functional identification of the mouse circadian clock gene by transgenic RT BAC rescue."; RL Cell 89:655-667(1997). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS LONG AND SHORT), TISSUE RP SPECIFICITY, IDENTIFICATION OF CLOCK VARIANT, AND POLYMORPHISM. RC STRAIN=C57BL/6 X BALB/c; TISSUE=Suprachiasmatic nucleus; RX PubMed=9160755; DOI=10.1016/s0092-8674(00)80245-7; RA King D.P., Zhao Y., Sangoram A.M., Wilsbacher L.D., Tanaka M., Antoch M.P., RA Steeves T.D.L., Vitaterna M.H., Kornhauser J.M., Lowrey P.L., Turek F.W., RA Takahashi J.S.; RT "Positional cloning of the mouse circadian clock gene."; RL Cell 89:641-653(1997). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RC STRAIN=129/Sv; RX PubMed=11116088; DOI=10.1101/gr.10.12.1928; RA Wilsbacher L.D., Sangoram A.M., Antoch M.P., Takahashi J.S.; RT "The mouse Clock locus: sequence and comparative analysis of 204 kb from RT mouse chromosome 5."; RL Genome Res. 10:1928-1940(2000). RN [4] RP INTERACTION WITH BMAL1. 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 BMAL1; PER1; PER2; CRY1; CRY2; CSNK1D AND RP CSNK1E, PHOSPHORYLATION, SUBCELLULAR LOCATION, AND INDUCTION. 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 BMAL1, PHOSPHORYLATION, SUBCELLULAR LOCATION, AND RP INDUCTION. 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 [7] RP FUNCTION. RX PubMed=12738229; DOI=10.1016/s0022-2828(03)00051-8; RA Schoenhard J.A., Smith L.H., Painter C.A., Eren M., Johnson C.H., RA Vaughan D.E.; RT "Regulation of the PAI-1 promoter by circadian clock components: RT differential activation by BMAL1 and BMAL2."; RL J. Mol. Cell. Cardiol. 35:473-481(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 INDUCTION. RX PubMed=14645221; DOI=10.1074/jbc.m311973200; RA Curtis A.M., Seo S.B., Westgate E.J., Rudic R.D., Smyth E.M., RA Chakravarti D., FitzGerald G.A., McNamara P.; RT "Histone acetyltransferase-dependent chromatin remodeling and the vascular RT clock."; RL J. Biol. Chem. 279:7091-7097(2004). RN [10] RP MUTAGENESIS OF PRO-656; TYR-658; ASN-659; GLY-669; SER-670 AND VAL-672, RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=16678094; DOI=10.1016/j.cell.2006.03.033; RA Doi M., Hirayama J., Sassone-Corsi P.; RT "Circadian regulator CLOCK is a histone acetyltransferase."; RL Cell 125:497-508(2006). RN [11] RP INTERACTION WITH EZH2; BMAL1; 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, INTERACTION WITH BMAL1, UBIQUITINATION, AND RP 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 SUBCELLULAR LOCATION, AND INTERACTION WITH CIPC. RX PubMed=17310242; DOI=10.1038/ncb1539; RA Zhao W.N., Malinin N., Yang F.C., Staknis D., Gekakis N., Maier B., RA Reischl S., Kramer A., Weitz C.J.; RT "CIPC is a mammalian circadian clock protein without invertebrate RT homologues."; RL Nat. Cell Biol. 9:268-275(2007). RN [14] RP FUNCTION. RX PubMed=17417633; DOI=10.1038/nn1884; RA DeBruyne J.P., Weaver D.R., Reppert S.M.; RT "CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian RT clock."; RL Nat. Neurosci. 10:543-545(2007). RN [15] RP FUNCTION IN ACETYLATION OF BMAL1. 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 [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-408, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=17242355; DOI=10.1073/pnas.0609836104; RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.; RT "Large-scale phosphorylation analysis of mouse liver."; RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007). RN [17] RP INTERACTION WITH 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 [18] RP SUBCELLULAR LOCATION, AND INTERACTION WITH SIRT1; BMAL1; PER2 AND CRY1. 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 [19] RP 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 [20] 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 [21] RP PHOSPHORYLATION AT SER-427 AND SER-431, MUTAGENESIS OF SER-427 AND SER-431, RP AND INTERACTION WITH GSK3B AND BMAL1. 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, AND INTERACTION WITH NR3C1. 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. 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 SUBCELLULAR LOCATION, NUCLEAR LOCALIZATION SIGNAL, PHOSPHORYLATION AT RP SER-38; SER-42 AND SER-427, AND MUTAGENESIS OF SER-38; SER-42 AND SER-427. 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 INTERACTION WITH MYBBP1A. RX PubMed=19129230; DOI=10.1093/nar/gkn1013; RA Hara Y., Onishi Y., Oishi K., Miyazaki K., Fukamizu A., Ishida N.; RT "Molecular characterization of Mybbp1a as a co-repressor on the Period2 RT promoter."; RL Nucleic Acids Res. 37:1115-1126(2009). RN [26] RP FUNCTION. 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. 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 [29] RP 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 [30] RP FUNCTION. 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 [31] 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 [32] 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 [33] 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 [34] 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 [35] 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 [36] RP PHOSPHORYLATION BY CSNK1D AND CKSN1E. RX PubMed=21930935; DOI=10.1073/pnas.1107178108; RA Lee H.M., Chen R., Kim H., Etchegaray J.P., Weaver D.R., Lee C.; RT "The period of the circadian oscillator is primarily determined by the RT balance between casein kinase 1 and protein phosphatase 1."; RL Proc. Natl. Acad. Sci. U.S.A. 108:16451-16456(2011). RN [37] 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 [38] RP FUNCTION. RX PubMed=22284746; DOI=10.1111/j.1538-7836.2012.04643.x; RA Tracey C.J., Pan X., Catterson J.H., Harmar A.J., Hussain M.M., RA Hartley P.S.; RT "Diurnal expression of the thrombopoietin gene is regulated by CLOCK."; RL J. Thromb. Haemost. 10:662-669(2012). RN [39] 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 [40] RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND INTERACTION WITH RP EIF4E; PIWIL1 AND 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 [41] RP FUNCTION, AND INTERACTION WITH RELA/P65. RX PubMed=22895791; DOI=10.1073/pnas.1206274109; RA Spengler M.L., Kuropatwinski K.K., Comas M., Gasparian A.V., Fedtsova N., RA Gleiberman A.S., Gitlin I.I., Artemicheva N.M., Deluca K.A., Gudkov A.V., RA Antoch M.P.; RT "Core circadian protein CLOCK is a positive regulator of NF-kappaB-mediated RT transcription."; RL Proc. Natl. Acad. Sci. U.S.A. 109:E2457-E2465(2012). RN [42] 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 [43] 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 [44] 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 [45] RP GLYCOSYLATION, AND INTERACTION WITH OGA. RX PubMed=23395175; DOI=10.1016/j.cmet.2012.12.017; RA Kaasik K., Kivimae S., Allen J.J., Chalkley R.J., Huang Y., Baer K., RA Kissel H., Burlingame A.L., Shokat K.M., Ptacek L.J., Fu Y.H.; RT "Glucose sensor O-GlcNAcylation coordinates with phosphorylation to RT regulate circadian clock."; RL Cell Metab. 17:291-302(2013). RN [46] RP GLYCOSYLATION, AND UBIQUITINATION. 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 [47] RP REVIEW. RX PubMed=23756047; DOI=10.1016/j.conb.2013.05.002; RA Franken P.; RT "A role for clock genes in sleep homeostasis."; RL Curr. Opin. Neurobiol. 23:864-872(2013). RN [48] RP PHOSPHORYLATION AT THR-451 AND THR-461, AND INTERACTION WITH THE COMPLEX RP P35/CDK5. RX PubMed=24235147; DOI=10.1074/jbc.m113.494856; RA Kwak Y., Jeong J., Lee S., Park Y.U., Lee S.A., Han D.H., Kim J.H., RA Ohshima T., Mikoshiba K., Suh Y.H., Cho S., Park S.K.; RT "Cyclin-dependent kinase 5 (Cdk5) regulates the function of CLOCK protein RT by direct phosphorylation."; RL J. Biol. Chem. 288:36878-36889(2013). RN [49] RP FUNCTION. 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 [50] RP FUNCTION. RX PubMed=23785138; DOI=10.1523/jneurosci.2757-12.2013; RA Baeza-Raja B., Eckel-Mahan K., Zhang L., Vagena E., Tsigelny I.F., RA Sassone-Corsi P., Ptacek L.J., Akassoglou K.; RT "p75 neurotrophin receptor is a clock gene that regulates oscillatory RT components of circadian and metabolic networks."; RL J. Neurosci. 33:10221-10234(2013). RN [51] 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 [52] RP SUMOYLATION AT LYS-67 AND LYS-851, DESUMOYLATION, INTERACTION WITH ESR1, RP AND MUTAGENESIS OF LYS-67 AND LYS-851. RX PubMed=23160374; DOI=10.1038/onc.2012.518; RA Li S., Wang M., Ao X., Chang A.K., Yang C., Zhao F., Bi H., Liu Y., RA Xiao L., Wu H.; RT "CLOCK is a substrate of SUMO and sumoylation of CLOCK upregulates the RT transcriptional activity of estrogen receptor-alpha."; RL Oncogene 32:4883-4891(2013). RN [53] 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 [54] RP INTERACTION WITH THRAP3 AND MED1. 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 [55] RP FUNCTION. RX PubMed=24333415; DOI=10.1016/j.bbrc.2013.12.022; RA Gao Y., Meng D., Sun N., Zhu Z., Zhao R., Lu C., Chen S., Hua L., Qian R.; RT "Clock upregulates intercellular adhesion molecule-1 expression and RT promotes mononuclear cells adhesion to endothelial cells."; RL Biochem. Biophys. Res. Commun. 443:586-591(2014). RN [56] 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 [57] 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 [58] 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 [59] RP FUNCTION. 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 [60] 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 [61] 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 [62] RP FUNCTION, AND INTERACTION WITH ASS1. 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 [63] 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 [64] 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 [65] 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). RN [66] RP X-RAY CRYSTALLOGRAPHY (2.27 ANGSTROMS) OF 26-384 IN COMPLEX WITH BMAL1, RP FUNCTION, INTERACTION WITH BMAL1, AND MUTAGENESIS OF LEU-57; LEU-74 AND RP TRP-284. 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. Regulates the circadian CC expression of ICAM1, VCAM1, CCL2, THPO and MPL and also acts as an CC enhancer of the transactivation potential of NF-kappaB. Plays an CC important role in the homeostatic regulation of sleep. The CLOCK-BMAL1 CC heterodimer regulates the circadian expression of SERPINE1/PAI1, VWF, CC B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, CC NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10 and also genes implicated CC in glucose and lipid metabolism. Promotes rhythmic chromatin opening, CC regulating the DNA accessibility of other transcription factors. May CC play a role in spermatogenesis; contributes to the chromatoid body CC assembly and physiology. The CLOCK-BMAL2 heterodimer activates the CC transcription of SERPINE1/PAI1 and BHLHE40/DEC1. The preferred binding CC motif for the CLOCK-BMAL1 heterodimer is 5'-CACGTGA-3', which contains CC a flanking adenine nucleotide at the 3-prime end of the canonical 6- CC nucleotide E-box sequence (By similarity). CLOCK specifically binds to CC the half-site 5'-CAC-3', while BMAL1 binds to the half-site 5'-GTGA-3' CC (By similarity). The CLOCK-BMAL1 heterodimer also recognizes the non- CC canonical E-box motifs 5'-AACGTGA-3' and 5'-CATGTGA-3'. CLOCK has an CC intrinsic acetyltransferase activity, which enables circadian chromatin CC remodeling by acetylating histones and nonhistone proteins, including CC its own partner BMAL1. Represses glucocorticoid receptor NR3C1/GR- CC induced transcriptional activity by reducing the association of CC NR3C1/GR to glucocorticoid response elements (GREs) via the acetylation CC of multiple lysine residues located in its hinge region. The CC acetyltransferase activity of CLOCK is as important as its CC transcription activity in circadian control. Acetylates metabolic CC enzymes IMPDH2 and NDUFA9 in a circadian manner (By similarity). CC Facilitated by BMAL1, rhythmically interacts and acetylates CC argininosuccinate synthase 1 (ASS1) leading to enzymatic inhibition of CC ASS1 as well as the circadian oscillation of arginine biosynthesis and CC subsequent ureagenesis (PubMed:28985504). Drives the circadian rhythm CC of blood pressure through transcriptional activation of ATP1B1 CC (PubMed:30012868). {ECO:0000250|UniProtKB:O15516, CC ECO:0000269|PubMed:12738229, ECO:0000269|PubMed:14672706, CC ECO:0000269|PubMed:16678094, ECO:0000269|PubMed:17417633, CC ECO:0000269|PubMed:18075593, 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:20385766, ECO:0000269|PubMed:20430893, CC ECO:0000269|PubMed:20562852, ECO:0000269|PubMed:20658528, CC ECO:0000269|PubMed:20956306, ECO:0000269|PubMed:21768648, CC ECO:0000269|PubMed:22284746, ECO:0000269|PubMed:22653727, CC ECO:0000269|PubMed:22895791, ECO:0000269|PubMed:22900038, CC ECO:0000269|PubMed:22981862, ECO:0000269|PubMed:23291174, CC ECO:0000269|PubMed:23785138, ECO:0000269|PubMed:24089055, CC ECO:0000269|PubMed:24270424, ECO:0000269|PubMed:24333415, CC ECO:0000269|PubMed:24378737, ECO:0000269|PubMed:24385426, CC ECO:0000269|PubMed:24395244, ECO:0000269|PubMed:24442997, CC ECO:0000269|PubMed:28985504, ECO:0000269|PubMed:30012868}. CC -!- CATALYTIC ACTIVITY: CC Reaction=acetyl-CoA + L-lysyl-[protein] = CoA + H(+) + N(6)-acetyl-L- CC lysyl-[protein]; Xref=Rhea:RHEA:45948, Rhea:RHEA-COMP:9752, CC Rhea:RHEA-COMP:10731, ChEBI:CHEBI:15378, ChEBI:CHEBI:29969, CC ChEBI:CHEBI:57287, ChEBI:CHEBI:57288, ChEBI:CHEBI:61930; EC=2.3.1.48; CC Evidence={ECO:0000269|PubMed:16678094}; CC -!- SUBUNIT: Component of the circadian clock oscillator which includes the CC CRY proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, CC TIMELESS and the PER proteins (PubMed:11779462). Forms a heterodimer CC with BMAL1 (PubMed:9616112, PubMed:12897057, PubMed:16717091, CC PubMed:16980631, PubMed:18662546, PubMed:19946213, PubMed:22653727). CC The CLOCK-BMAL1 heterodimer is required for E-box-dependent CC transactivation, for CLOCK nuclear translocation and degradation, and CC for phosphorylation of both CLOCK and BMAL1 (PubMed:12897057). CC Interacts with NR3C1 in a ligand-dependent fashion (PubMed:19141540). CC Interacts with ESR1 and estrogen stimulates this interaction (By CC similarity). Interacts with the complex p35/CDK5 (PubMed:24235147). CC Interacts with RELA/p65 (PubMed:22895791). Interacts with KAT2B, CREBBP CC and EP300 (By similarity). Interacts with ID1 and ID3 CC (PubMed:20861012). Interacts with ID2 (PubMed:20861012). Interacts with CC MTA1 (PubMed:24089055). Interacts with OGA (PubMed:23395175). Interacts CC with SIRT1 (PubMed:18662546, PubMed:18662547). Interacts with CIPC CC (PubMed:17310242). Interacts with EZH2 (PubMed:16717091). Interacts CC with EIF4E, PIWIL1 and DDX4 (PubMed:22900038). Interacts with PER1, CC PER2, CRY1 and CRY2 and this interaction requires a translocation to CC the nucleus (PubMed:16717091, PubMed:18430226, PubMed:18662546). CC Interaction of the CLOCK-BMAL1 heterodimer with PER or CRY inhibits CC transcription activation. Interaction of the CLOCK-BMAL1 with CRY1 is CC independent of DNA but with PER2 is off DNA (By similarity). The CLOCK- CC BMAL1 heterodimer interacts with GSK3B (PubMed:19946213). Interacts CC with KDM5A (PubMed:21960634). Interacts with KMT2A; in a circadian CC manner (PubMed:21113167). Interacts with MYBBP1A (PubMed:19129230). CC Interacts with THRAP3 (PubMed:24043798). Interacts with MED1; this CC interaction requires the presence of THRAP3 (PubMed:24043798). CC Interacts with NCOA2 (PubMed:24529706). The CLOCK-BMAL1 heterodimer CC interacts with PASD1. Interacts with NDUFA9. Interacts with IMPDH2; in CC a circadian manner (By similarity). Interacts with ASS1; in a circadian CC manner (PubMed:28985504). Interacts with PIWIL2 (via PIWI domain) CC (PubMed:28903391). Interacts with HNF4A (By similarity). CC {ECO:0000250|UniProtKB:O15516, ECO:0000269|PubMed:11779462, CC ECO:0000269|PubMed:12897057, ECO:0000269|PubMed:16717091, CC ECO:0000269|PubMed:16980631, ECO:0000269|PubMed:17310242, CC ECO:0000269|PubMed:18430226, ECO:0000269|PubMed:18662546, CC ECO:0000269|PubMed:18662547, ECO:0000269|PubMed:19129230, CC ECO:0000269|PubMed:19141540, ECO:0000269|PubMed:19946213, CC ECO:0000269|PubMed:20861012, ECO:0000269|PubMed:21113167, CC ECO:0000269|PubMed:21960634, ECO:0000269|PubMed:22653727, CC ECO:0000269|PubMed:22895791, ECO:0000269|PubMed:22900038, CC ECO:0000269|PubMed:23160374, ECO:0000269|PubMed:23395175, CC ECO:0000269|PubMed:24043798, ECO:0000269|PubMed:24089055, CC ECO:0000269|PubMed:24154698, ECO:0000269|PubMed:24235147, CC ECO:0000269|PubMed:24529706, ECO:0000269|PubMed:28903391, CC ECO:0000269|PubMed:28985504, ECO:0000269|PubMed:9616112}. CC -!- INTERACTION: CC O08785; Q9WTL8: Bmal1; NbExp=39; IntAct=EBI-79859, EBI-644534; CC O08785; Q9WTL8-2: Bmal1; NbExp=2; IntAct=EBI-79859, EBI-644559; CC O08785; Q9WTL8-4: Bmal1; NbExp=10; IntAct=EBI-79859, EBI-644568; CC O08785; P97784: Cry1; NbExp=10; IntAct=EBI-79859, EBI-1266607; CC O08785; Q9JMK2: Csnk1e; NbExp=2; IntAct=EBI-79859, EBI-771709; CC O08785; Q3U1J4: Ddb1; NbExp=4; IntAct=EBI-79859, EBI-2552275; CC O08785; O54943: Per2; NbExp=10; IntAct=EBI-79859, EBI-1266779; CC O08785; P20444: Prkca; NbExp=3; IntAct=EBI-79859, EBI-6976815; CC O08785; Q923E4: Sirt1; NbExp=11; IntAct=EBI-79859, EBI-1802585; CC O08785; P67870: CSNK2B; Xeno; NbExp=2; IntAct=EBI-79859, EBI-348169; CC O08785; Q03164: KMT2A; Xeno; NbExp=3; IntAct=EBI-79859, EBI-591370; CC O08785; Q14995: NR1D2; Xeno; NbExp=2; IntAct=EBI-79859, EBI-6144053; CC O08785; P62136: PPP1CA; Xeno; NbExp=2; IntAct=EBI-79859, EBI-357253; CC O08785; P62140: PPP1CB; Xeno; NbExp=2; IntAct=EBI-79859, EBI-352350; CC O08785; P36873: PPP1CC; Xeno; NbExp=2; IntAct=EBI-79859, EBI-356283; CC O08785; P30154: PPP2R1B; Xeno; NbExp=2; IntAct=EBI-79859, EBI-357094; CC O08785; Q14738: PPP2R5D; Xeno; NbExp=2; IntAct=EBI-79859, EBI-396563; CC O08785; Q92753: RORB; Xeno; NbExp=2; IntAct=EBI-79859, EBI-6144615; CC O08785; P51449: RORC; Xeno; NbExp=2; IntAct=EBI-79859, EBI-3908771; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:11779462, CC ECO:0000269|PubMed:12897057, ECO:0000269|PubMed:16980631, CC ECO:0000269|PubMed:17310242, ECO:0000269|PubMed:18662546, CC ECO:0000269|PubMed:19414601}. Cytoplasm {ECO:0000269|PubMed:12897057, CC ECO:0000269|PubMed:16980631}. Cytoplasm, cytosol CC {ECO:0000250|UniProtKB:O15516}. Note=Localizes to sites of DNA damage CC in a H2AX-independent manner (By similarity). Shuttling between the CC cytoplasm and the nucleus is under circadian regulation and is BMAL1- CC dependent. Phosphorylated form located in the nucleus predominantly CC between CT12 and CT21. Nonphosphorylated form found only in the CC cytoplasm. Sequestered to the cytoplasm in the presence of ID2. CC {ECO:0000250|UniProtKB:O15516, ECO:0000269|PubMed:11779462, CC ECO:0000269|PubMed:16980631, ECO:0000269|PubMed:20861012}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=Long; CC IsoId=O08785-1; Sequence=Displayed; CC Name=Short; CC IsoId=O08785-2; Sequence=VSP_002103; CC -!- TISSUE SPECIFICITY: Expressed equally in brain, eye, testes, ovaries, CC liver, heart, lung, kidney. In the brain, expression is abundant in the CC suprachiasmatic nuclei (SCN), in the pyriform cortex, and in the CC hippocampus. Low expression throughout the rest of the brain. CC Expression does not appear to undergo circadian oscillations. CC {ECO:0000269|PubMed:22900038, ECO:0000269|PubMed:24154698, CC ECO:0000269|PubMed:28903391, ECO:0000269|PubMed:9160755}. CC -!- INDUCTION: In the SCN, nuclear expression is lowest between CT7 and CC CT13. Cytoplasmic expression is highest at these times. In liver, peak CC levels from CT21 to CT3. Expression of both phosphorylated and CC unphosphorylated forms of BMAL1 with other circadian clock proteins CC occurs between CT15 and CT18. Expression in the heart oscillates in a CC circadian manner. {ECO:0000269|PubMed:11779462, CC ECO:0000269|PubMed:12897057, ECO:0000269|PubMed:14645221}. CC -!- DOMAIN: Contains a Gln-rich C-terminal domain which could correspond to CC the transactivation domain. CC -!- PTM: Ubiquitinated, leading to its proteasomal degradation. CC {ECO:0000269|PubMed:16980631}. 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 transcriptional activation of PER1/2/3 and CRY1/2. CC {ECO:0000269|PubMed:23395175, ECO:0000269|PubMed:23395176}. CC -!- PTM: Phosphorylation is dependent on the CLOCK-BMAL1 heterodimer CC formation. Phosphorylation enhances the transcriptional activity, CC alters the subcellular localization and decreases the stability of the CC heterodimer by promoting its degradation. Phosphorylation shows CC circadian variations in the liver: the hyperphosphorylated form peaks CC at midnight (CT18), while the hypophosphorylated form is abundant CC throughout the day. May be phosphorylated by CSNK1D and CKSN1E. CC {ECO:0000269|PubMed:11779462, ECO:0000269|PubMed:12897057, CC ECO:0000269|PubMed:19414601, ECO:0000269|PubMed:19946213, CC ECO:0000269|PubMed:21930935, ECO:0000269|PubMed:24235147}. CC -!- PTM: Sumoylation enhances its transcriptional activity and interaction CC with ESR1, resulting in up-regulation of ESR1 activity. Estrogen CC stimulates sumoylation. Desumoylation by SENP1 negatively regulates its CC transcriptional activity. {ECO:0000269|PubMed:23160374}. CC -!- PTM: Undergoes lysosome-mediated degradation in a time-dependent manner CC in the liver. {ECO:0000269|PubMed:29937374}. CC -!- POLYMORPHISM: The naturally-occurring CLOCK variant, missing exon 19 CC (deletion of AA 514-564) due to an A-->T nucleotide transversion in a CC splice donor site, forms a heterodimer with DNA, but fails to activate CC transcription. Homozygous CLOCK mutants have a circadian rhythm that is CC increased from 3 to 4 hours and usually the circadian rhythmicity is CC lost at constant darkness. Expression of CLOCK is also reduced. There CC also exists an alternative spliced CLOCK variant missing both exon 18 CC and exon 19 (AA 484-564). {ECO:0000269|PubMed:9160755}. 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; AF000998; AAC53200.1; -; mRNA. DR EMBL; AF146793; AAD30565.1; -; Genomic_DNA. DR CCDS; CCDS19360.1; -. [O08785-1] DR RefSeq; NP_001276755.1; NM_001289826.1. [O08785-1] DR RefSeq; NP_031741.1; NM_007715.6. [O08785-1] DR RefSeq; XP_017176137.1; XM_017320648.1. [O08785-1] DR RefSeq; XP_017176139.1; XM_017320650.1. [O08785-2] DR PDB; 4F3L; X-ray; 2.27 A; A=26-384. DR PDB; 5VJI; X-ray; 1.86 A; A/B/D/E=516-560. DR PDB; 5VJX; X-ray; 2.69 A; B/C/E/F/H/I/K/L/N/O/S/T/V/W/Y/Z/b/c/e/f=515-560. DR PDB; 8OSJ; EM; 6.20 A; M=26-395. DR PDB; 8OSK; EM; 3.60 A; M=26-395. DR PDB; 8OSL; EM; 4.90 A; M/O=26-395. DR PDBsum; 4F3L; -. DR PDBsum; 5VJI; -. DR PDBsum; 5VJX; -. DR PDBsum; 8OSJ; -. DR PDBsum; 8OSK; -. DR PDBsum; 8OSL; -. DR AlphaFoldDB; O08785; -. DR EMDB; EMD-17155; -. DR EMDB; EMD-17157; -. DR EMDB; EMD-17160; -. DR SMR; O08785; -. DR BioGRID; 198756; 30. DR ComplexPortal; CPX-3225; CLOCK-BMAL1 transcription complex. DR ComplexPortal; CPX-3228; CLOCK-BMAL2 transcription complex. DR CORUM; O08785; -. DR DIP; DIP-30958N; -. DR IntAct; O08785; 35. DR MINT; O08785; -. DR STRING; 10090.ENSMUSP00000143939; -. DR GlyGen; O08785; 3 sites, 1 O-linked glycan (3 sites). DR iPTMnet; O08785; -. DR PhosphoSitePlus; O08785; -. DR MaxQB; O08785; -. DR PaxDb; 10090-ENSMUSP00000074656; -. DR PeptideAtlas; O08785; -. DR ProteomicsDB; 283858; -. [O08785-1] DR ProteomicsDB; 283859; -. [O08785-2] DR Pumba; O08785; -. DR Antibodypedia; 909; 607 antibodies from 41 providers. DR DNASU; 12753; -. DR Ensembl; ENSMUST00000075159.5; ENSMUSP00000074656.2; ENSMUSG00000029238.12. [O08785-1] DR Ensembl; ENSMUST00000202651.4; ENSMUSP00000143939.2; ENSMUSG00000029238.12. [O08785-1] DR GeneID; 12753; -. DR KEGG; mmu:12753; -. DR UCSC; uc008xuq.3; mouse. [O08785-1] DR AGR; MGI:99698; -. DR CTD; 9575; -. DR MGI; MGI:99698; Clock. DR VEuPathDB; HostDB:ENSMUSG00000029238; -. DR eggNOG; KOG3561; Eukaryota. DR GeneTree; ENSGT00940000157580; -. DR InParanoid; O08785; -. DR OMA; HVPNSAH; -. DR OrthoDB; 2899615at2759; -. DR PhylomeDB; O08785; -. DR TreeFam; TF324568; -. DR BioGRID-ORCS; 12753; 4 hits in 85 CRISPR screens. DR ChiTaRS; Clock; mouse. DR PRO; PR:O08785; -. DR Proteomes; UP000000589; Chromosome 5. DR RNAct; O08785; Protein. DR Bgee; ENSMUSG00000029238; Expressed in pigmented layer of retina and 252 other cell types or tissues. DR ExpressionAtlas; O08785; baseline and differential. DR GO; GO:0033391; C:chromatoid body; IDA:UniProtKB. DR GO; GO:0005694; C:chromosome; ISO:MGI. 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; ISS:UniProtKB. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI. DR GO; GO:0005654; C:nucleoplasm; ISO:MGI. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0005726; C:perichromatin fibrils; ISO:MGI. DR GO; GO:0005667; C:transcription regulator complex; IDA:UniProtKB. DR GO; GO:0031490; F:chromatin DNA binding; IDA:UniProtKB. DR GO; GO:0003677; F:DNA binding; ISS: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:0070888; F:E-box binding; IDA:UniProtKB. DR GO; GO:0004402; F:histone acetyltransferase activity; IMP:UniProtKB. DR GO; GO:0046983; F:protein dimerization activity; IEA:InterPro. 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:0071479; P:cellular response to ionizing radiation; ISO:MGI. DR GO; GO:0032922; P:circadian regulation of gene expression; IMP:UniProtKB. DR GO; GO:0007623; P:circadian rhythm; IDA:MGI. DR GO; GO:0000077; P:DNA damage checkpoint signaling; ISO:MGI. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:2000323; P:negative regulation of glucocorticoid receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0042753; P:positive regulation of circadian rhythm; IMP:ComplexPortal. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0050729; P:positive regulation of inflammatory response; IMP:UniProtKB. DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; 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; IDA:UniProtKB. DR GO; GO:0006473; P:protein acetylation; IDA:UniProtKB. DR GO; GO:0042752; P:regulation of circadian rhythm; 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: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; ISS:UniProtKB. DR GO; GO:0007283; P:spermatogenesis; IMP:UniProtKB. DR CDD; cd19734; bHLH-PAS_CLOCK; 1. DR CDD; cd00130; PAS; 2. DR DisProt; DP00734; -. 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; IPR047230; CLOCK-like. 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 PANTHER; PTHR46055; CIRCADIAN LOCOMOTER OUTPUT CYCLES PROTEIN KAPUT; 1. DR PANTHER; PTHR46055:SF2; CIRCADIAN LOCOMOTER OUTPUT CYCLES PROTEIN KAPUT; 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; O08785; MM. PE 1: Evidence at protein level; KW 3D-structure; Activator; Acyltransferase; Alternative splicing; KW Biological rhythms; Cytoplasm; DNA damage; DNA-binding; Glycoprotein; KW Isopeptide bond; Nucleus; Phosphoprotein; Reference proteome; Repeat; KW Transcription; Transcription regulation; Transferase; Ubl conjugation. FT CHAIN 1..855 FT /note="Circadian locomoter output cycles protein kaput" FT /id="PRO_0000127164" FT DOMAIN 34..84 FT /note="bHLH" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981" FT DOMAIN 107..177 FT /note="PAS 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140" FT DOMAIN 262..332 FT /note="PAS 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140" FT DOMAIN 336..379 FT /note="PAC" FT REGION 371..854 FT /note="Interaction with NR3C1" FT /evidence="ECO:0000269|PubMed:19141540" FT REGION 392..411 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 420..497 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 450..570 FT /note="Interaction with SIRT1" FT /evidence="ECO:0000269|PubMed:18662547" FT REGION 514..564 FT /note="Implicated in the circadian rhythmicity" FT REGION 613..650 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 752..791 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 814..855 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 32..47 FT /note="Nuclear localization signal" FT /evidence="ECO:0000269|PubMed:19414601" FT COMPBIAS 427..464 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 474..497 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT SITE 39 FT /note="Interaction with E-box DNA" FT /evidence="ECO:0000250|UniProtKB:O15516" FT SITE 43 FT /note="Interaction with E-box DNA" FT /evidence="ECO:0000250|UniProtKB:O15516" FT SITE 47 FT /note="Interaction with E-box DNA" FT /evidence="ECO:0000250|UniProtKB:O15516" FT SITE 84 FT /note="Important for interaction with BMAL1" FT /evidence="ECO:0000250|UniProtKB:O15516" FT MOD_RES 38 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:19414601" FT MOD_RES 42 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:19414601" FT MOD_RES 408 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:17242355" FT MOD_RES 427 FT /note="Phosphoserine; by GSK3-beta" FT /evidence="ECO:0000269|PubMed:19414601, FT ECO:0000269|PubMed:19946213" FT MOD_RES 431 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:19946213" FT MOD_RES 451 FT /note="Phosphothreonine; by CDK5" FT /evidence="ECO:0000269|PubMed:24235147" FT MOD_RES 461 FT /note="Phosphothreonine; by CDK5" FT /evidence="ECO:0000269|PubMed:24235147" FT CROSSLNK 67 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO1)" FT /evidence="ECO:0000269|PubMed:23160374" FT CROSSLNK 851 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO1)" FT /evidence="ECO:0000269|PubMed:23160374" FT VAR_SEQ 484..513 FT /note="Missing (in isoform Short)" FT /evidence="ECO:0000303|PubMed:9160755" FT /id="VSP_002103" FT MUTAGEN 38 FT /note="S->D: Significant decrease in transcriptional FT activation by the CLOCK-BMAL1 heterodimer. Significant FT decrease in transcriptional activation by the CLOCK-BMAL1 FT heterodimer, reduced nuclear localization and DNA-binding; FT when associated with D-42." FT /evidence="ECO:0000269|PubMed:19414601" FT MUTAGEN 42 FT /note="S->D: Significant decrease in transcriptional FT activation by the CLOCK-BMAL1 heterodimer. Significant FT decrease in transcriptional activation by the CLOCK-BMAL1 FT heterodimer, reduced nuclear localization and DNA-binding; FT when associated with D-38." FT /evidence="ECO:0000269|PubMed:19414601" FT MUTAGEN 57 FT /note="L->E: Reduced BMAL1 binding. Abolishes FT transcriptional activation by the CLOCK-BMAL1 heterodimer. FT Abolishes regulation of circadian clock." FT /evidence="ECO:0000269|PubMed:22653727" FT MUTAGEN 67 FT /note="K->R: Decrease in sumoylation and its FT transcriptional activity. Abolishes sumoylation and FT interaction with ESR1 and decrease in its transcriptional FT activity; when associated with R-851." FT /evidence="ECO:0000269|PubMed:23160374" FT MUTAGEN 74 FT /note="L->E: Reduced BMAL1 binding. Abolishes FT transcriptional activation by the CLOCK-BMAL1 heterodimer." FT /evidence="ECO:0000269|PubMed:22653727" FT MUTAGEN 284 FT /note="W->A: Reduced BMAL1 binding. Slightly reduced FT transcriptional activation by the CLOCK-BMAL1 heterodimer." FT /evidence="ECO:0000269|PubMed:22653727" FT MUTAGEN 427 FT /note="S->A: Significant loss of phosphorylation." FT /evidence="ECO:0000269|PubMed:19414601, FT ECO:0000269|PubMed:19946213" FT MUTAGEN 431 FT /note="S->A: Significant loss of phosphorylation." FT /evidence="ECO:0000269|PubMed:19946213" FT MUTAGEN 656 FT /note="P->A: Reduces histone acetyltransferase activity; FT when associated with A-658 and A-659." FT /evidence="ECO:0000269|PubMed:16678094" FT MUTAGEN 658 FT /note="Y->A: Reduces histone acetyltransferase activity; FT when associated with A-656 and A-659." FT /evidence="ECO:0000269|PubMed:16678094" FT MUTAGEN 659 FT /note="N->A: Reduces histone acetyltransferase activity; FT when associated with A-656 and A-658." FT /evidence="ECO:0000269|PubMed:16678094" FT MUTAGEN 669 FT /note="G->A: Reduces histone acetyltransferase activity; FT when associated with A-670 and A-672." FT /evidence="ECO:0000269|PubMed:16678094" FT MUTAGEN 670 FT /note="S->A: Reduces histone acetyltransferase activity; FT when associated with A-669 and A-672." FT /evidence="ECO:0000269|PubMed:16678094" FT MUTAGEN 672 FT /note="V->A: Reduces histone acetyltransferase activity; FT when associated with A-669 and A-670." FT /evidence="ECO:0000269|PubMed:16678094" FT MUTAGEN 851 FT /note="K->R: Decrease in sumoylation and its FT transcriptional activity. Abolishes sumoylation and FT interaction with ESR1 and decrease in its transcriptional FT activity; when associated with R-67." FT /evidence="ECO:0000269|PubMed:23160374" FT HELIX 43..59 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 63..65 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 70..88 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 94..96 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 107..117 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 120..126 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 129..134 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 138..142 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 146..149 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 154..157 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 160..162 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 163..172 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 179..181 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 183..185 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 187..189 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 190..198 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 204..206 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 210..221 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 249..259 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 262..266 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 270..272 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 275..280 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 284..289 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 294..297 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 301..304 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 309..312 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 315..331 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 332..335 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 339..342 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 346..359 FT /evidence="ECO:0007829|PDB:4F3L" FT TURN 361..363 FT /evidence="ECO:0007829|PDB:4F3L" FT STRAND 366..375 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 378..383 FT /evidence="ECO:0007829|PDB:4F3L" FT HELIX 516..555 FT /evidence="ECO:0007829|PDB:5VJI" SQ SEQUENCE 855 AA; 96393 MW; 9864D947049742F4 CRC64; MVFTVSCSKM SSIVDRDDSS IFDGLVEEDD KDKAKRVSRN KSEKKRRDQF NVLIKELGSM LPGNARKMDK STVLQKSIDF LRKHKETTAQ SDASEIRQDW KPTFLSNEEF TQLMLEALDG FFLAIMTDGS IIYVSESVTS LLEHLPSDLV DQSIFNFIPE GEHSEVYKIL STHLLESDSL TPEYLKSKNQ LEFCCHMLRG TIDPKEPSTY EYVRFIGNFK SLTSVSTSTH NGFEGTIQRT HRPSYEDRVC FVATVRLATP QFIKEMCTVE EPNEEFTSRH SLEWKFLFLD HRAPPIIGYL PFEVLGTSGY DYYHVDDLEN LAKCHEHLMQ YGKGKSCYYR FLTKGQQWIW LQTHYYITYH QWNSRPEFIV CTHTVVSYAE VRAERRRELG IEESLPETAA DKSQDSGSDN RINTVSLKEA LERFDHSPTP SASSRSSRKS SHTAVSDPSS TPTKIPTDTS TPPRQHLPAH EKMTQRRSSF SSQSINSQSV GPSLTQPAMS QAANLPIPQG MSQFQFSAQL GAMQHLKDQL EQRTRMIEAN IHRQQEELRK IQEQLQMVHG QGLQMFLQQS NPGLNFGSVQ LSSGNSNIQQ LTPVNMQGQV VPANQVQSGH ISTGQHMIQQ QTLQSTSTQQ SQQSVMSGHS QQTSLPSQTP STLTAPLYNT MVISQPAAGS MVQIPSSMPQ NSTQSATVTT FTQDRQIRFS QGQQLVTKLV TAPVACGAVM VPSTMLMGQV VTAYPTFATQ QQQAQTLSVT QQQQQQQQQP PQQQQQQQQS SQEQQLPSVQ QPAQAQLGQP PQQFLQTSRL LHGNPSTQLI LSAAFPLQQS TFPPSHHQQH QPQQQQQLPR HRTDSLTDPS KVQPQ //