CLOCK_MOUSE
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 03-AUG-2022, entry version 208.
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 ARNTL.
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 ARNTL; 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 ARNTL, 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; ARNTL; 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 ARNTL, 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 ARNTL.
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; ARNTL; 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 ARNTL.
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 ARNTL,
RP FUNCTION, INTERACTION WITH ARNTL, 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, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and
CC CRY2) plays a critical role in rhythm generation, whereas delays
CC imposed by post-translational modifications (PTMs) are important for
CC determining the period (tau) of the rhythms (tau refers to the period
CC of a rhythm and is the length, in time, of one complete cycle). A
CC diurnal rhythm is synchronized with the day/night cycle, while the
CC ultradian and infradian rhythms have a period shorter and longer than
CC 24 hours, respectively. Disruptions in the circadian rhythms contribute
CC to the pathology of cardiovascular diseases, cancer, metabolic
CC syndromes and aging. A transcription/translation feedback loop (TTFL)
CC forms the core of the molecular circadian clock mechanism.
CC Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2,
CC form the positive limb of the feedback loop, act in the form of a
CC heterodimer and activate the transcription of core clock genes and
CC clock-controlled genes (involved in key metabolic processes), harboring
CC E-box elements (5'-CACGTG-3') within their promoters. The core clock
CC genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form
CC the negative limb of the feedback loop and interact with the
CC CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its
CC activity and thereby negatively regulating their own expression. This
CC heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G,
CC which form a second feedback loop and which activate and repress
CC ARNTL/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-
CC ARNTL/BMAL1 heterodimer regulates the circadian expression of
CC SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A,
CC PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10
CC and also genes implicated in glucose and lipid metabolism. Promotes
CC rhythmic chromatin opening, regulating the DNA accessibility of other
CC transcription factors. May play a role in spermatogenesis; contributes
CC to the chromatoid body assembly and physiology. The CLOCK-ARNTL2/BMAL2
CC heterodimer activates the transcription of SERPINE1/PAI1 and
CC BHLHE40/DEC1. The preferred binding motif for the CLOCK-ARNTL/BMAL1
CC heterodimer is 5'-CACGTGA-3', which contains a flanking Ala residue in
CC addition to the canonical 6-nucleotide E-box sequence (By similarity).
CC CLOCK specifically binds to the half-site 5'-CAC-3', while ARNTL binds
CC to the half-site 5'-GTGA-3' (By similarity). The CLOCK-ARNTL/BMAL1
CC heterodimer also recognizes the non-canonical E-box motifs 5'-AACGTGA-
CC 3' and 5'-CATGTGA-3'. CLOCK has an intrinsic acetyltransferase
CC activity, which enables circadian chromatin remodeling by acetylating
CC histones and nonhistone proteins, including its own partner
CC ARNTL/BMAL1. Represses glucocorticoid receptor NR3C1/GR-induced
CC transcriptional activity by reducing the association of NR3C1/GR to
CC glucocorticoid response elements (GREs) via the acetylation of multiple
CC lysine residues located in its hinge region. The acetyltransferase
CC activity of CLOCK is as important as its transcription activity in
CC circadian control. Acetylates metabolic enzymes IMPDH2 and NDUFA9 in a
CC circadian manner (By similarity). Facilitated by BMAL1, rhythmically
CC interacts and acetylates argininosuccinate synthase 1 (ASS1) leading to
CC enzymatic inhibition of ASS1 as well as the circadian oscillation of
CC arginine biosynthesis and subsequent ureagenesis (PubMed:28985504).
CC Drives the circadian rhythm of blood pressure through transcriptional
CC activation of ATP1B1 (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, ARNTL/BMAL1 or ARNTL2/BMAL2, CSNK1D
CC and/or CSNK1E, TIMELESS and the PER proteins (PubMed:11779462). Forms a
CC heterodimer with ARNTL/BMAL1 (PubMed:9616112, PubMed:12897057,
CC PubMed:16717091, PubMed:16980631, PubMed:18662546, PubMed:19946213,
CC PubMed:22653727). The CLOCK-ARNTL/BMAL1 heterodimer is required for E-
CC box-dependent transactivation, for CLOCK nuclear translocation and
CC degradation, and for phosphorylation of both CLOCK and ARNTL/BMAL1
CC (PubMed:12897057). Interacts with NR3C1 in a ligand-dependent fashion
CC (PubMed:19141540). Interacts with ESR1 and estrogen stimulates this
CC interaction (By similarity). Interacts with the complex p35/CDK5
CC (PubMed:24235147). Interacts with RELA/p65 (PubMed:22895791). Interacts
CC with KAT2B, CREBBP and EP300 (By similarity). Interacts with ID1 and
CC ID3 (PubMed:20861012). Interacts with ID2 (PubMed:20861012). Interacts
CC with MTA1 (PubMed:24089055). Interacts with OGA (PubMed:23395175).
CC Interacts with SIRT1 (PubMed:18662546, PubMed:18662547). Interacts with
CC CIPC (PubMed:17310242). Interacts with EZH2 (PubMed:16717091).
CC Interacts with EIF4E, PIWIL1 and DDX4 (PubMed:22900038). Interacts with
CC PER1, PER2, CRY1 and CRY2 and this interaction requires a translocation
CC to the nucleus (PubMed:16717091, PubMed:18430226, PubMed:18662546).
CC Interaction of the CLOCK-ARNTL/BMAL1 heterodimer with PER or CRY
CC inhibits transcription activation. Interaction of the CLOCK-ARNTL/BMAL1
CC with CRY1 is independent of DNA but with PER2 is off DNA (By
CC similarity). The CLOCK-ARNTL/BMAL1 heterodimer interacts with GSK3B
CC (PubMed:19946213). Interacts with KDM5A (PubMed:21960634). Interacts
CC with KMT2A; in a circadian manner (PubMed:21113167). Interacts with
CC MYBBP1A (PubMed:19129230). Interacts with THRAP3 (PubMed:24043798).
CC Interacts with MED1; this interaction requires the presence of THRAP3
CC (PubMed:24043798). Interacts with NCOA2 (PubMed:24529706). The CLOCK-
CC ARNTL/BMAL1 heterodimer interacts with PASD1. Interacts with NDUFA9.
CC Interacts with IMPDH2; in a circadian manner (By similarity). Interacts
CC with ASS1; in a circadian manner (PubMed:28985504). Interacts with
CC PIWIL2 (via PIWI domain) (PubMed:28903391). Interacts with HNF4A (By
CC similarity). {ECO:0000250|UniProtKB:O15516,
CC ECO:0000269|PubMed:11779462, ECO:0000269|PubMed:12897057,
CC ECO:0000269|PubMed:16717091, ECO:0000269|PubMed:16980631,
CC ECO:0000269|PubMed:17310242, ECO:0000269|PubMed:18430226,
CC ECO:0000269|PubMed:18662546, ECO:0000269|PubMed:18662547,
CC ECO:0000269|PubMed:19129230, ECO:0000269|PubMed:19141540,
CC ECO:0000269|PubMed:19946213, ECO:0000269|PubMed:20861012,
CC ECO:0000269|PubMed:21113167, ECO:0000269|PubMed:21960634,
CC ECO:0000269|PubMed:22653727, ECO:0000269|PubMed:22895791,
CC ECO:0000269|PubMed:22900038, ECO:0000269|PubMed:23160374,
CC ECO:0000269|PubMed:23395175, ECO:0000269|PubMed:24043798,
CC ECO:0000269|PubMed:24089055, ECO:0000269|PubMed:24154698,
CC ECO:0000269|PubMed:24235147, ECO:0000269|PubMed:24529706,
CC ECO:0000269|PubMed:28903391, ECO:0000269|PubMed:28985504,
CC ECO:0000269|PubMed:9616112}.
CC -!- INTERACTION:
CC O08785; Q9WTL8: Arntl; NbExp=39; IntAct=EBI-79859, EBI-644534;
CC O08785; Q9WTL8-2: Arntl; NbExp=2; IntAct=EBI-79859, EBI-644559;
CC O08785; Q9WTL8-4: Arntl; 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
CC ARNTL/BMAL1-dependent. Phosphorylated form located in the nucleus
CC predominantly between CT12 and CT21. Nonphosphorylated form found only
CC in the 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 ARNTL/BMAL1 with other circadian clock
CC proteins occurs between CT15 and CT18. Expression in the heart
CC oscillates in a 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-ARNTL/BMAL1 heterodimer thereby increasing CLOCK-ARNTL/BMAL1-
CC mediated 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-ARNTL/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}.
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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 PDBsum; 4F3L; -.
DR PDBsum; 5VJI; -.
DR PDBsum; 5VJX; -.
DR AlphaFoldDB; O08785; -.
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.ENSMUSP00000074656; -.
DR iPTMnet; O08785; -.
DR PhosphoSitePlus; O08785; -.
DR MaxQB; O08785; -.
DR PaxDb; O08785; -.
DR PeptideAtlas; O08785; -.
DR PRIDE; O08785; -.
DR ProteomicsDB; 283858; -. [O08785-1]
DR ProteomicsDB; 283859; -. [O08785-2]
DR Antibodypedia; 909; 536 antibodies from 41 providers.
DR DNASU; 12753; -.
DR Ensembl; ENSMUST00000075159; ENSMUSP00000074656; ENSMUSG00000029238. [O08785-1]
DR Ensembl; ENSMUST00000202651; ENSMUSP00000143939; ENSMUSG00000029238. [O08785-1]
DR GeneID; 12753; -.
DR KEGG; mmu:12753; -.
DR UCSC; uc008xuq.3; mouse. [O08785-1]
DR CTD; 9575; -.
DR MGI; MGI:99698; Clock.
DR VEuPathDB; HostDB:ENSMUSG00000029238; -.
DR eggNOG; KOG3561; Eukaryota.
DR GeneTree; ENSGT00940000157580; -.
DR InParanoid; O08785; -.
DR OMA; RPSYEEK; -.
DR OrthoDB; 205871at2759; -.
DR PhylomeDB; O08785; -.
DR TreeFam; TF324568; -.
DR BioGRID-ORCS; 12753; 3 hits in 79 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 249 other tissues.
DR ExpressionAtlas; O08785; baseline and differential.
DR Genevisible; O08785; MM.
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:0005730; C:nucleolus; 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:0005791; C:rough endoplasmic reticulum; 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:2000323; P:negative regulation of glucocorticoid receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0042753; P:positive regulation of circadian rhythm; IMP:ComplexPortal.
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:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
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: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:0006355; P:regulation of transcription, DNA-templated; IDA:UniProtKB.
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; cd00130; PAS; 2.
DR DisProt; DP00734; -.
DR Gene3D; 4.10.280.10; -; 1.
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 Pfam; PF00010; HLH; 1.
DR Pfam; PF00989; PAS; 1.
DR PRINTS; PR00785; NCTRNSLOCATR.
DR SMART; SM00353; HLH; 1.
DR SMART; SM00086; PAC; 1.
DR SMART; SM00091; PAS; 2.
DR SUPFAM; SSF47459; SSF47459; 1.
DR SUPFAM; SSF55785; SSF55785; 2.
DR PROSITE; PS50888; BHLH; 1.
DR PROSITE; PS50112; PAS; 2.
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 ARNTL/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-ARNTL/BMAL1 heterodimer.
FT Significant decrease in transcriptional activation by the
FT CLOCK-ARNTL/BMAL1 heterodimer, reduced nuclear localization
FT and DNA-binding; 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-ARNTL/BMAL1 heterodimer.
FT Significant decrease in transcriptional activation by the
FT CLOCK-ARNTL/BMAL1 heterodimer, reduced nuclear localization
FT and DNA-binding; when associated with D-38."
FT /evidence="ECO:0000269|PubMed:19414601"
FT MUTAGEN 57
FT /note="L->E: Reduced ARNTL/BMAL1 binding. Abolishes
FT transcriptional activation by the CLOCK-ARNTL/BMAL1
FT heterodimer. 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 ARNTL/BMAL1 binding. Abolishes
FT transcriptional activation by the CLOCK-ARNTL/BMAL1
FT heterodimer."
FT /evidence="ECO:0000269|PubMed:22653727"
FT MUTAGEN 284
FT /note="W->A: Reduced ARNTL/BMAL1 binding. Slightly reduced
FT transcriptional activation by the CLOCK-ARNTL/BMAL1
FT 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
