BMAL1_MOUSE
ID BMAL1_MOUSE Reviewed; 632 AA.
AC Q9WTL8; O88295; Q921S4; Q9R0U2; Q9WTL9;
DT 15-AUG-2003, integrated into UniProtKB/Swiss-Prot.
DT 15-AUG-2003, sequence version 2.
DT 03-AUG-2022, entry version 192.
DE RecName: Full=Aryl hydrocarbon receptor nuclear translocator-like protein 1;
DE AltName: Full=Arnt3;
DE AltName: Full=Brain and muscle ARNT-like 1;
GN Name=Arntl; Synonyms=Bmal1;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 5).
RC TISSUE=Brain;
RX PubMed=10403839; DOI=10.1006/bbrc.1999.0970;
RA Yu W., Ikeda M., Abe H., Honma S., Ebisawa T., Yamauchi T., Honma K.,
RA Nomura M.;
RT "Characterization of three splice variants and genomic organization of the
RT mouse BMAL1 gene.";
RL Biochem. Biophys. Res. Commun. 260:760-767(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
RX PubMed=9704006; DOI=10.1006/bbrc.1998.9012;
RA Takahata S., Sogawa K., Kobayashi A., Ema M., Mimura J., Ozaki N.,
RA Fujii-Kuriyama Y.;
RT "Transcriptionally active heterodimer formation of an Arnt-like PAS
RT protein, Arnt3, with HIF-1a, HLF, and clock.";
RL Biochem. Biophys. Res. Commun. 248:789-794(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 4).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP INTERACTION WITH CLOCK.
RX PubMed=9616112; DOI=10.1126/science.280.5369.1564;
RA Gekakis N., Staknis D., Nguyen H.B., Davis F.C., Wilsbacher L.D.,
RA King D.P., Takahashi J.S., Weitz C.J.;
RT "Role of the CLOCK protein in the mammalian circadian mechanism.";
RL Science 280:1564-1569(1998).
RN [5]
RP IDENTIFICATION IN A COMPLEX WITH CLOCK; PER1; PER2; CRY1; CRY2; CSNK1D AND
RP CSNK1E, PHOSPHORYLATION, AND SUBCELLULAR LOCATION.
RX PubMed=11779462; DOI=10.1016/s0092-8674(01)00610-9;
RA Lee C., Etchegaray J.-P., Cagampang F.R.A., Loudon A.S.I., Reppert S.M.;
RT "Posttranslational mechanisms regulate the mammalian circadian clock.";
RL Cell 107:855-867(2001).
RN [6]
RP INTERACTION WITH BHLHE40 AND BHLHE41.
RX PubMed=12397359; DOI=10.1038/nature01123;
RA Honma S., Kawamoto T., Takagi Y., Fujimoto K., Sato F., Noshiro M.,
RA Kato Y., Honma K.I.;
RT "Dec1 and Dec2 are regulators of the mammalian molecular clock.";
RL Nature 419:841-844(2002).
RN [7]
RP PHOSPHORYLATION, AND SUBCELLULAR LOCATION.
RX PubMed=12897057; DOI=10.1101/gad.1099503;
RA Kondratov R.V., Chernov M.V., Kondratova A.A., Gorbacheva V.Y.,
RA Gudkov A.V., Antoch M.P.;
RT "BMAL1-dependent circadian oscillation of nuclear CLOCK: posttranslational
RT events induced by dimerization of transcriptional activators of the
RT mammalian clock system.";
RL Genes Dev. 17:1921-1932(2003).
RN [8]
RP FUNCTION.
RX PubMed=14672706; DOI=10.1016/j.bbrc.2003.11.099;
RA Kawamoto T., Noshiro M., Sato F., Maemura K., Takeda N., Nagai R.,
RA Iwata T., Fujimoto K., Furukawa M., Miyazaki K., Honma S., Honma K.I.,
RA Kato Y.;
RT "A novel autofeedback loop of Dec1 transcription involved in circadian
RT rhythm regulation.";
RL Biochem. Biophys. Res. Commun. 313:117-124(2004).
RN [9]
RP SUMOYLATION AT LYS-266, AND MUTAGENESIS OF LYS-230; LYS-236; LYS-266 AND
RP LYS-279.
RX PubMed=16109848; DOI=10.1126/science.1110689;
RA Cardone L., Hirayama J., Giordano F., Tamaru T., Palvimo J.J.,
RA Sassone-Corsi P.;
RT "Circadian clock control by SUMOylation of BMAL1.";
RL Science 309:1390-1394(2005).
RN [10]
RP INTERACTION WITH NPAS2.
RX PubMed=16628007; DOI=10.4161/cc.5.8.2684;
RA Kondratov R.V., Kondratova A.A., Lee C., Gorbacheva V.Y., Chernov M.V.,
RA Antoch M.P.;
RT "Post-translational regulation of circadian transcriptional
RT CLOCK(NPAS2)/BMAL1 complex by CRYPTOCHROMES.";
RL Cell Cycle 5:890-895(2006).
RN [11]
RP INTERACTION WITH EZH2; CLOCK; PER1; PER2; CRY1 AND CRY2.
RX PubMed=16717091; DOI=10.1074/jbc.m603722200;
RA Etchegaray J.P., Yang X., DeBruyne J.P., Peters A.H., Weaver D.R.,
RA Jenuwein T., Reppert S.M.;
RT "The polycomb group protein EZH2 is required for mammalian circadian clock
RT function.";
RL J. Biol. Chem. 281:21209-21215(2006).
RN [12]
RP SUBCELLULAR LOCATION, NUCLEAR LOCALIZATION SIGNAL, NUCLEAR EXPORT SIGNAL,
RP INTERACTION WITH CLOCK, MUTAGENESIS OF 38-LYS-ARG-39; LEU-154; LEU-157;
RP LEU-370 AND LEU-374, UBIQUITINATION, AND PROTEASOMAL DEGRADATION.
RX PubMed=16980631; DOI=10.1128/mcb.00337-06;
RA Kwon I., Lee J., Chang S.H., Jung N.C., Lee B.J., Son G.H., Kim K.,
RA Lee K.H.;
RT "BMAL1 shuttling controls transactivation and degradation of the
RT CLOCK/BMAL1 heterodimer.";
RL Mol. Cell. Biol. 26:7318-7330(2006).
RN [13]
RP TISSUE SPECIFICITY, AND INDUCTION.
RX PubMed=16790549; DOI=10.1073/pnas.0604138103;
RA Partch C.L., Shields K.F., Thompson C.L., Selby C.P., Sancar A.;
RT "Posttranslational regulation of the mammalian circadian clock by
RT cryptochrome and protein phosphatase 5.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:10467-10472(2006).
RN [14]
RP ACETYLATION AT LYS-544.
RX PubMed=18075593; DOI=10.1038/nature06394;
RA Hirayama J., Sahar S., Grimaldi B., Tamaru T., Takamatsu K., Nakahata Y.,
RA Sassone-Corsi P.;
RT "CLOCK-mediated acetylation of BMAL1 controls circadian function.";
RL Nature 450:1086-1090(2007).
RN [15]
RP INTERACTION WITH CRY1; CRY2 AND PER2.
RX PubMed=18430226; DOI=10.1186/1471-2199-9-41;
RA Langmesser S., Tallone T., Bordon A., Rusconi S., Albrecht U.;
RT "Interaction of circadian clock proteins PER2 and CRY with BMAL1 and
RT CLOCK.";
RL BMC Mol. Biol. 9:41-41(2008).
RN [16]
RP INTERACTION WITH SIRT1 AND CLOCK.
RX PubMed=18662546; DOI=10.1016/j.cell.2008.06.050;
RA Asher G., Gatfield D., Stratmann M., Reinke H., Dibner C., Kreppel F.,
RA Mostoslavsky R., Alt F.W., Schibler U.;
RT "SIRT1 regulates circadian clock gene expression through PER2
RT deacetylation.";
RL Cell 134:317-328(2008).
RN [17]
RP ACETYLATION AT LYS-544, DEACETYLATION, AND INTERACTION WITH SIRT1.
RX PubMed=18662547; DOI=10.1016/j.cell.2008.07.002;
RA Nakahata Y., Kaluzova M., Grimaldi B., Sahar S., Hirayama J., Chen D.,
RA Guarente L.P., Sassone-Corsi P.;
RT "The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin
RT remodeling and circadian control.";
RL Cell 134:329-340(2008).
RN [18]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=18258755; DOI=10.1177/0748730407311254;
RA Alvarez J.D., Hansen A., Ord T., Bebas P., Chappell P.E.,
RA Giebultowicz J.M., Williams C., Moss S., Sehgal A.;
RT "The circadian clock protein BMAL1 is necessary for fertility and proper
RT testosterone production in mice.";
RL J. Biol. Rhythms 23:26-36(2008).
RN [19]
RP FUNCTION.
RX PubMed=18316400; DOI=10.1128/mcb.01931-07;
RA Bertolucci C., Cavallari N., Colognesi I., Aguzzi J., Chen Z., Caruso P.,
RA Foa A., Tosini G., Bernardi F., Pinotti M.;
RT "Evidence for an overlapping role of CLOCK and NPAS2 transcription factors
RT in liver circadian oscillators.";
RL Mol. Cell. Biol. 28:3070-3075(2008).
RN [20]
RP SUMOYLATION AT LYS-259, SUBCELLULAR LOCATION, INTERACTION WITH SUMO3,
RP MUTAGENESIS OF LYS-259, UBIQUITINATION, AND PROTEASOMAL DEGRADATION.
RX PubMed=18644859; DOI=10.1128/mcb.00583-08;
RA Lee J., Lee Y., Lee M.J., Park E., Kang S.H., Chung C.H., Lee K.H., Kim K.;
RT "Dual modification of BMAL1 by SUMO2/3 and ubiquitin promotes circadian
RT activation of the CLOCK/BMAL1 complex.";
RL Mol. Cell. Biol. 28:6056-6065(2008).
RN [21]
RP INTERACTION WITH GSK3B AND CLOCK, AND PHOSPHORYLATION.
RX PubMed=19946213; DOI=10.4161/cc.8.24.10273;
RA Spengler M.L., Kuropatwinski K.K., Schumer M., Antoch M.P.;
RT "A serine cluster mediates BMAL1-dependent CLOCK phosphorylation and
RT degradation.";
RL Cell Cycle 8:4138-4146(2009).
RN [22]
RP FUNCTION.
RX PubMed=19141540; DOI=10.1096/fj.08-117697;
RA Nader N., Chrousos G.P., Kino T.;
RT "Circadian rhythm transcription factor CLOCK regulates the transcriptional
RT activity of the glucocorticoid receptor by acetylating its hinge region
RT lysine cluster: potential physiological implications.";
RL FASEB J. 23:1572-1583(2009).
RN [23]
RP FUNCTION, AND INTERACTION WITH PER2.
RX PubMed=19605937; DOI=10.1074/jbc.m109.040758;
RA Sasaki M., Yoshitane H., Du N.H., Okano T., Fukada Y.;
RT "Preferential inhibition of BMAL2-CLOCK activity by PER2 reemphasizes its
RT negative role and a positive role of BMAL2 in the circadian
RT transcription.";
RL J. Biol. Chem. 284:25149-25159(2009).
RN [24]
RP PHOSPHORYLATION.
RX PubMed=19414601; DOI=10.1128/mcb.01864-08;
RA Yoshitane H., Takao T., Satomi Y., Du N.H., Okano T., Fukada Y.;
RT "Roles of CLOCK phosphorylation in suppression of E-box-dependent
RT transcription.";
RL Mol. Cell. Biol. 29:3675-3686(2009).
RN [25]
RP PHOSPHORYLATION AT SER-97, SUBCELLULAR LOCATION, MUTAGENESIS OF SER-97, AND
RP INTERACTION WITH CLOCK.
RX PubMed=19330005; DOI=10.1038/nsmb.1578;
RA Tamaru T., Hirayama J., Isojima Y., Nagai K., Norioka S., Takamatsu K.,
RA Sassone-Corsi P.;
RT "CK2alpha phosphorylates BMAL1 to regulate the mammalian clock.";
RL Nat. Struct. Mol. Biol. 16:446-448(2009).
RN [26]
RP FUNCTION, AND INTERACTION WITH SIRT1.
RX PubMed=19299583; DOI=10.1126/science.1171641;
RA Ramsey K.M., Yoshino J., Brace C.S., Abrassart D., Kobayashi Y.,
RA Marcheva B., Hong H.K., Chong J.L., Buhr E.D., Lee C., Takahashi J.S.,
RA Imai S., Bass J.;
RT "Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis.";
RL Science 324:651-654(2009).
RN [27]
RP FUNCTION.
RX PubMed=19286518; DOI=10.1126/science.1170803;
RA Nakahata Y., Sahar S., Astarita G., Kaluzova M., Sassone-Corsi P.;
RT "Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1.";
RL Science 324:654-657(2009).
RN [28]
RP FUNCTION, AND INTERACTION WITH CRY2.
RX PubMed=20840750; DOI=10.1186/1471-2199-11-69;
RA Ozber N., Baris I., Tatlici G., Gur I., Kilinc S., Unal E.B., Kavakli I.H.;
RT "Identification of two amino acids in the C-terminal domain of mouse CRY2
RT essential for PER2 interaction.";
RL BMC Mol. Biol. 11:69-69(2010).
RN [29]
RP FUNCTION.
RX PubMed=20153195; DOI=10.1016/j.cub.2009.12.034;
RA Shi S., Hida A., McGuinness O.P., Wasserman D.H., Yamazaki S.,
RA Johnson C.H.;
RT "Circadian clock gene Bmal1 is not essential; functional replacement with
RT its paralog, Bmal2.";
RL Curr. Biol. 20:316-321(2010).
RN [30]
RP FUNCTION.
RX PubMed=20430893; DOI=10.1074/jbc.m110.110361;
RA Doi R., Oishi K., Ishida N.;
RT "CLOCK regulates circadian rhythms of hepatic glycogen synthesis through
RT transcriptional activation of Gys2.";
RL J. Biol. Chem. 285:22114-22121(2010).
RN [31]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH ID1; ID2 AND ID3.
RX PubMed=20861012; DOI=10.1074/jbc.m110.175182;
RA Ward S.M., Fernando S.J., Hou T.Y., Duffield G.E.;
RT "The transcriptional repressor ID2 can interact with the canonical clock
RT components CLOCK and BMAL1 and mediate inhibitory effects on mPer1
RT expression.";
RL J. Biol. Chem. 285:38987-39000(2010).
RN [32]
RP FUNCTION, AND INDUCTION.
RX PubMed=20385766; DOI=10.1128/mcb.01141-09;
RA Guillaumond F., Grechez-Cassiau A., Subramaniam M., Brangolo S.,
RA Peteri-Brunback B., Staels B., Fievet C., Spelsberg T.C., Delaunay F.,
RA Teboul M.;
RT "Kruppel-like factor KLF10 is a link between the circadian clock and
RT metabolism in liver.";
RL Mol. Cell. Biol. 30:3059-3070(2010).
RN [33]
RP INTERACTION WITH KMT2A.
RX PubMed=21113167; DOI=10.1038/nsmb.1961;
RA Katada S., Sassone-Corsi P.;
RT "The histone methyltransferase MLL1 permits the oscillation of circadian
RT gene expression.";
RL Nat. Struct. Mol. Biol. 17:1414-1421(2010).
RN [34]
RP FUNCTION.
RX PubMed=20562852; DOI=10.1038/nature09253;
RA Marcheva B., Ramsey K.M., Buhr E.D., Kobayashi Y., Su H., Ko C.H.,
RA Ivanova G., Omura C., Mo S., Vitaterna M.H., Lopez J.P., Philipson L.H.,
RA Bradfield C.A., Crosby S.D., Je Bailey L., Wang X., Takahashi J.S.,
RA Bass J.;
RT "Disruption of the clock components CLOCK and BMAL1 leads to
RT hypoinsulinaemia and diabetes.";
RL Nature 466:627-631(2010).
RN [35]
RP PHOSPHORYLATION AT SER-17 AND THR-21, AND INTERACTION WITH GSK3B.
RX PubMed=20049328; DOI=10.1371/journal.pone.0008561;
RA Sahar S., Zocchi L., Kinoshita C., Borrelli E., Sassone-Corsi P.;
RT "Regulation of BMAL1 protein stability and circadian function by GSK3beta-
RT mediated phosphorylation.";
RL PLoS ONE 5:E8561-E8561(2010).
RN [36]
RP FUNCTION.
RX PubMed=20956306; DOI=10.1073/pnas.1014523107;
RA Andrews J.L., Zhang X., McCarthy J.J., McDearmon E.L., Hornberger T.A.,
RA Russell B., Campbell K.S., Arbogast S., Reid M.B., Walker J.R.,
RA Hogenesch J.B., Takahashi J.S., Esser K.A.;
RT "CLOCK and BMAL1 regulate MyoD and are necessary for maintenance of
RT skeletal muscle phenotype and function.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:19090-19095(2010).
RN [37]
RP INTERACTION WITH RACK1 AND PRKCA, SUBCELLULAR LOCATION, AND IDENTIFICATION
RP BY MASS SPECTROMETRY.
RX PubMed=20093473; DOI=10.1126/science.1180067;
RA Robles M.S., Boyault C., Knutti D., Padmanabhan K., Weitz C.J.;
RT "Identification of RACK1 and protein kinase Calpha as integral components
RT of the mammalian circadian clock.";
RL Science 327:463-466(2010).
RN [38]
RP INTERACTION WITH AHR.
RX PubMed=20106950; DOI=10.1093/toxsci/kfq022;
RA Xu C.X., Krager S.L., Liao D.F., Tischkau S.A.;
RT "Disruption of CLOCK-BMAL1 transcriptional activity is responsible for aryl
RT hydrocarbon receptor-mediated regulation of Period1 gene.";
RL Toxicol. Sci. 115:98-108(2010).
RN [39]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=22101268; DOI=10.4161/cc.10.23.18381;
RA Khapre R.V., Kondratova A.A., Susova O., Kondratov R.V.;
RT "Circadian clock protein BMAL1 regulates cellular senescence in vivo.";
RL Cell Cycle 10:4162-4169(2011).
RN [40]
RP FUNCTION.
RX PubMed=22045262; DOI=10.4161/isl.3.6.18157;
RA Lee J., Kim M.S., Li R., Liu V.Y., Fu L., Moore D.D., Ma K., Yechoor V.K.;
RT "Loss of Bmal1 leads to uncoupling and impaired glucose-stimulated insulin
RT secretion in beta-cells.";
RL Islets 3:381-388(2011).
RN [41]
RP INTERACTION WITH CLOCK; CRY1 AND PER2.
RX PubMed=21613214; DOI=10.1074/jbc.m111.254680;
RA Ye R., Selby C.P., Ozturk N., Annayev Y., Sancar A.;
RT "Biochemical analysis of the canonical model for the mammalian circadian
RT clock.";
RL J. Biol. Chem. 286:25891-25902(2011).
RN [42]
RP FUNCTION.
RX PubMed=21768648; DOI=10.1074/jbc.m111.258970;
RA Koyanagi S., Hamdan A.M., Horiguchi M., Kusunose N., Okamoto A.,
RA Matsunaga N., Ohdo S.;
RT "cAMP-response element (CRE)-mediated transcription by activating
RT transcription factor-4 (ATF4) is essential for circadian expression of the
RT Period2 gene.";
RL J. Biol. Chem. 286:32416-32423(2011).
RN [43]
RP FUNCTION.
RX PubMed=20658528; DOI=10.1002/jcp.22314;
RA Somanath P.R., Podrez E.A., Chen J., Ma Y., Marchant K., Antoch M.,
RA Byzova T.V.;
RT "Deficiency in core circadian protein Bmal1 is associated with a
RT prothrombotic and vascular phenotype.";
RL J. Cell. Physiol. 226:132-140(2011).
RN [44]
RP INTERACTION WITH MAGEL2, AND SUBCELLULAR LOCATION.
RX PubMed=22208286; DOI=10.1186/1740-3391-9-12;
RA Devos J., Weselake S.V., Wevrick R.;
RT "Magel2, a Prader-Willi syndrome candidate gene, modulates the activities
RT of circadian rhythm proteins in cultured cells.";
RL J. Circadian. Rhythms. 9:12-12(2011).
RN [45]
RP FUNCTION.
RX PubMed=21966465; DOI=10.1371/journal.pone.0025231;
RA Shimba S., Ogawa T., Hitosugi S., Ichihashi Y., Nakadaira Y., Kobayashi M.,
RA Tezuka M., Kosuge Y., Ishige K., Ito Y., Komiyama K., Okamatsu-Ogura Y.,
RA Kimura K., Saito M.;
RT "Deficient of a clock gene, brain and muscle Arnt-like protein-1 (BMAL1),
RT induces dyslipidemia and ectopic fat formation.";
RL PLoS ONE 6:E25231-E25231(2011).
RN [46]
RP INTERACTION WITH KDM5A.
RX PubMed=21960634; DOI=10.1126/science.1206022;
RA DiTacchio L., Le H.D., Vollmers C., Hatori M., Witcher M., Secombe J.,
RA Panda S.;
RT "Histone lysine demethylase JARID1a activates CLOCK-BMAL1 and influences
RT the circadian clock.";
RL Science 333:1881-1885(2011).
RN [47]
RP INTERACTION WITH RELB.
RX PubMed=22894897; DOI=10.4161/cc.21669;
RA Bellet M.M., Zocchi L., Sassone-Corsi P.;
RT "The RelB subunit of NFkappaB acts as a negative regulator of circadian
RT gene expression.";
RL Cell Cycle 11:3304-3311(2012).
RN [48]
RP FUNCTION.
RX PubMed=22611086; DOI=10.1096/fj.12-205781;
RA Guo B., Chatterjee S., Li L., Kim J.M., Lee J., Yechoor V.K., Minze L.J.,
RA Hsueh W., Ma K.;
RT "The clock gene, brain and muscle Arnt-like 1, regulates adipogenesis via
RT Wnt signaling pathway.";
RL FASEB J. 26:3453-3463(2012).
RN [49]
RP FUNCTION.
RX PubMed=22981862; DOI=10.1016/j.molcel.2012.08.012;
RA Stratmann M., Suter D.M., Molina N., Naef F., Schibler U.;
RT "Circadian Dbp transcription relies on highly dynamic BMAL1-CLOCK
RT interaction with E boxes and requires the proteasome.";
RL Mol. Cell 48:277-287(2012).
RN [50]
RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND INTERACTION WITH
RP DDX4.
RX PubMed=22900038; DOI=10.1371/journal.pone.0042695;
RA Peruquetti R.L., de Mateo S., Sassone-Corsi P.;
RT "Circadian proteins CLOCK and BMAL1 in the chromatoid body, a RNA
RT processing granule of male germ cells.";
RL PLoS ONE 7:E42695-E42695(2012).
RN [51]
RP INTERACTION WITH PRKCG, UBIQUITINATION, AND PROTEASOMAL DEGRADATION.
RX PubMed=23185022; DOI=10.1073/pnas.1218699110;
RA Zhang L., Abraham D., Lin S.T., Oster H., Eichele G., Fu Y.H., Ptacek L.J.;
RT "PKCgamma participates in food entrainment by regulating BMAL1.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:20679-20684(2012).
RN [52]
RP INTERACTION WITH PER1, AND TISSUE SPECIFICITY.
RX PubMed=24154698; DOI=10.1152/ajprenal.00472.2013;
RA Richards J., Cheng K.Y., All S., Skopis G., Jeffers L., Lynch I.J.,
RA Wingo C.S., Gumz M.L.;
RT "A role for the circadian clock protein Per1 in the regulation of
RT aldosterone levels and renal Na+ retention.";
RL Am. J. Physiol. 305:F1697-F1704(2013).
RN [53]
RP TISSUE SPECIFICITY, AND INDUCTION.
RX PubMed=23531614; DOI=10.1152/ajpendo.00512.2012;
RA Barclay J.L., Shostak A., Leliavski A., Tsang A.H., Johren O.,
RA Muller-Fielitz H., Landgraf D., Naujokat N., van der Horst G.T., Oster H.;
RT "High-fat diet-induced hyperinsulinemia and tissue-specific insulin
RT resistance in Cry-deficient mice.";
RL Am. J. Physiol. 304:E1053-E1063(2013).
RN [54]
RP REVIEW.
RX PubMed=23576606; DOI=10.1152/ajpregu.00066.2013;
RA Richards J., Gumz M.L.;
RT "Mechanism of the circadian clock in physiology.";
RL Am. J. Physiol. 304:R1053-R1064(2013).
RN [55]
RP FUNCTION.
RX PubMed=23955654; DOI=10.1007/s00403-013-1403-0;
RA Watabe Y., Tomioka M., Watabe A., Aihara M., Shimba S., Inoue H.;
RT "The clock gene brain and muscle Arnt-like protein-1 (BMAL1) is involved in
RT hair growth.";
RL Arch. Dermatol. Res. 305:755-761(2013).
RN [56]
RP FUNCTION.
RX PubMed=23291174; DOI=10.1016/j.bbrc.2012.12.098;
RA Oishi K., Koyanagi S., Ohkura N.;
RT "The molecular clock regulates circadian transcription of tissue factor
RT gene.";
RL Biochem. Biophys. Res. Commun. 431:332-335(2013).
RN [57]
RP GLYCOSYLATION, AND INTERACTION WITH OGT.
RX PubMed=23337503; DOI=10.1016/j.bbrc.2013.01.043;
RA Ma Y.T., Luo H., Guan W.J., Zhang H., Chen C., Wang Z., Li J.D.;
RT "O-GlcNAcylation of BMAL1 regulates circadian rhythms in NIH3T3
RT fibroblasts.";
RL Biochem. Biophys. Res. Commun. 431:382-387(2013).
RN [58]
RP DNA-BINDING.
RX PubMed=23831463; DOI=10.1016/j.bbrc.2013.06.086;
RA Yoshii K., Ishijima S., Sagami I.;
RT "Effects of NAD(P)H and its derivatives on the DNA-binding activity of
RT NPAS2, a mammalian circadian transcription factor.";
RL Biochem. Biophys. Res. Commun. 437:386-391(2013).
RN [59]
RP GLYCOSYLATION, UBIQUITINATION, AND MUTAGENESIS OF SER-418.
RX PubMed=23395176; DOI=10.1016/j.cmet.2012.12.015;
RA Li M.D., Ruan H.B., Hughes M.E., Lee J.S., Singh J.P., Jones S.P.,
RA Nitabach M.N., Yang X.;
RT "O-GlcNAc signaling entrains the circadian clock by inhibiting BMAL1/CLOCK
RT ubiquitination.";
RL Cell Metab. 17:303-310(2013).
RN [60]
RP FUNCTION.
RX PubMed=24268780; DOI=10.1016/j.celrep.2013.10.037;
RA Bouchard-Cannon P., Mendoza-Viveros L., Yuen A., Kaern M., Cheng H.Y.;
RT "The circadian molecular clock regulates adult hippocampal neurogenesis by
RT controlling the timing of cell-cycle entry and exit.";
RL Cell Rep. 5:961-973(2013).
RN [61]
RP FUNCTION.
RX PubMed=23525013; DOI=10.1242/jcs.120519;
RA Chatterjee S., Nam D., Guo B., Kim J.M., Winnier G.E., Lee J., Berdeaux R.,
RA Yechoor V.K., Ma K.;
RT "Brain and muscle Arnt-like 1 is a key regulator of myogenesis.";
RL J. Cell Sci. 126:2213-2224(2013).
RN [62]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=24270424; DOI=10.1172/jci70317;
RA Musiek E.S., Lim M.M., Yang G., Bauer A.Q., Qi L., Lee Y., Roh J.H.,
RA Ortiz-Gonzalez X., Dearborn J.T., Culver J.P., Herzog E.D., Hogenesch J.B.,
RA Wozniak D.F., Dikranian K., Giasson B.I., Weaver D.R., Holtzman D.M.,
RA Fitzgerald G.A.;
RT "Circadian clock proteins regulate neuronal redox homeostasis and
RT neurodegeneration.";
RL J. Clin. Invest. 123:5389-5400(2013).
RN [63]
RP FUNCTION.
RX PubMed=24048828; DOI=10.1523/jneurosci.2039-13.2013;
RA Hwang C.K., Chaurasia S.S., Jackson C.R., Chan G.C., Storm D.R.,
RA Iuvone P.M.;
RT "Circadian rhythm of contrast sensitivity is regulated by a dopamine-
RT neuronal PAS-domain protein 2-adenylyl cyclase 1 signaling pathway in
RT retinal ganglion cells.";
RL J. Neurosci. 33:14989-14997(2013).
RN [64]
RP FUNCTION.
RX PubMed=23547261; DOI=10.1128/mcb.01421-12;
RA Lee J., Moulik M., Fang Z., Saha P., Zou F., Xu Y., Nelson D.L., Ma K.,
RA Moore D.D., Yechoor V.K.;
RT "Bmal1 and beta-cell clock are required for adaptation to circadian
RT disruption, and their loss of function leads to oxidative stress-induced
RT beta-cell failure in mice.";
RL Mol. Cell. Biol. 33:2327-2338(2013).
RN [65]
RP FUNCTION, AND INTERACTION WITH MTA1.
RX PubMed=24089055; DOI=10.1038/ncomms3545;
RA Li D.Q., Pakala S.B., Reddy S.D., Peng S., Balasenthil S., Deng C.X.,
RA Lee C.C., Rea M.A., Kumar R.;
RT "Metastasis-associated protein 1 is an integral component of the circadian
RT molecular machinery.";
RL Nat. Commun. 4:2545-2545(2013).
RN [66]
RP FUNCTION.
RX PubMed=23750248; DOI=10.1371/journal.pone.0065255;
RA Kennaway D.J., Varcoe T.J., Voultsios A., Boden M.J.;
RT "Global loss of Bmal1 expression alters adipose tissue hormones, gene
RT expression and glucose metabolism.";
RL PLoS ONE 8:E65255-E65255(2013).
RN [67]
RP REVIEW.
RX PubMed=23303907; DOI=10.1152/physrev.00016.2012;
RA Eckel-Mahan K., Sassone-Corsi P.;
RT "Metabolism and the circadian clock converge.";
RL Physiol. Rev. 93:107-135(2013).
RN [68]
RP INTERACTION WITH THRAP3.
RX PubMed=24043798; DOI=10.1073/pnas.1305980110;
RA Lande-Diner L., Boyault C., Kim J.Y., Weitz C.J.;
RT "A positive feedback loop links circadian clock factor CLOCK-BMAL1 to the
RT basic transcriptional machinery.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:16021-16026(2013).
RN [69]
RP FUNCTION, AND INTERACTION WITH CLOCK; EED; EZH2 AND SUZ12.
RX PubMed=23970558; DOI=10.1126/science.1240636;
RA Nguyen K.D., Fentress S.J., Qiu Y., Yun K., Cox J.S., Chawla A.;
RT "Circadian gene Bmal1 regulates diurnal oscillations of Ly6C(hi)
RT inflammatory monocytes.";
RL Science 341:1483-1488(2013).
RN [70]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=24481314; DOI=10.18632/aging.100633;
RA Khapre R.V., Kondratova A.A., Patel S., Dubrovsky Y., Wrobel M.,
RA Antoch M.P., Kondratov R.V.;
RT "BMAL1-dependent regulation of the mTOR signaling pathway delays aging.";
RL Aging (Albany NY) 6:48-57(2014).
RN [71]
RP INTERACTION WITH NCOA2.
RX PubMed=24529706; DOI=10.1016/j.celrep.2014.01.027;
RA Stashi E., Lanz R.B., Mao J., Michailidis G., Zhu B., Kettner N.M.,
RA Putluri N., Reineke E.L., Reineke L.C., Dasgupta S., Dean A.,
RA Stevenson C.R., Sivasubramanian N., Sreekumar A., Demayo F., York B.,
RA Fu L., O'Malley B.W.;
RT "SRC-2 is an essential coactivator for orchestrating metabolism and
RT circadian rhythm.";
RL Cell Rep. 6:633-645(2014).
RN [72]
RP INDUCTION, AND TISSUE SPECIFICITY.
RX PubMed=24603368; DOI=10.1038/emm.2013.153;
RA Noh J.Y., Han D.H., Kim M.H., Ko I.G., Kim S.E., Park N., Kyoung Choe H.,
RA Kim K.H., Kim K., Kim C.J., Cho S.;
RT "Presence of multiple peripheral circadian oscillators in the tissues
RT controlling voiding function in mice.";
RL Exp. Mol. Med. 46:E81-E81(2014).
RN [73]
RP FUNCTION.
RX PubMed=24395244; DOI=10.1101/gad.228536.113;
RA Menet J.S., Pescatore S., Rosbash M.;
RT "CLOCK:BMAL1 is a pioneer-like transcription factor.";
RL Genes Dev. 28:8-13(2014).
RN [74]
RP FUNCTION.
RX PubMed=24442997; DOI=10.1002/hep.26992;
RA Zhou B., Zhang Y., Zhang F., Xia Y., Liu J., Huang R., Wang Y., Hu Y.,
RA Wu J., Dai C., Wang H., Tu Y., Peng X., Wang Y., Zhai Q.;
RT "CLOCK/BMAL1 regulates circadian change of mouse hepatic insulin
RT sensitivity via SIRT1.";
RL Hepatology 59:2196-2206(2014).
RN [75]
RP FUNCTION, AND INTERACTION WITH CIART.
RX PubMed=24385426; DOI=10.1074/jbc.m113.534651;
RA Annayev Y., Adar S., Chiou Y.Y., Lieb J., Sancar A., Ye R.;
RT "Gene model 129 (Gm129) encodes a novel transcriptional repressor that
RT modulates circadian gene expression.";
RL J. Biol. Chem. 289:5013-5024(2014).
RN [76]
RP FUNCTION IN GR REPRESSION.
RX PubMed=24378737; DOI=10.1016/j.mce.2013.12.013;
RA Han D.H., Lee Y.J., Kim K., Kim C.J., Cho S.;
RT "Modulation of glucocorticoid receptor induction properties by core
RT circadian clock proteins.";
RL Mol. Cell. Endocrinol. 383:170-180(2014).
RN [77]
RP FUNCTION, AND INTERACTION WITH CIART.
RX PubMed=24736997; DOI=10.1371/journal.pbio.1001839;
RA Goriki A., Hatanaka F., Myung J., Kim J.K., Yoritaka T., Tanoue S., Abe T.,
RA Kiyonari H., Fujimoto K., Kato Y., Todo T., Matsubara A., Forger D.,
RA Takumi T.;
RT "A novel protein, CHRONO, functions as a core component of the mammalian
RT circadian clock.";
RL PLoS Biol. 12:E1001839-E1001839(2014).
RN [78]
RP REVIEW.
RX PubMed=23916625; DOI=10.1016/j.tcb.2013.07.002;
RA Partch C.L., Green C.B., Takahashi J.S.;
RT "Molecular architecture of the mammalian circadian clock.";
RL Trends Cell Biol. 24:90-99(2014).
RN [79]
RP SUBCELLULAR LOCATION, INTERACTION WITH HDAC3 AND CRY1, AND UBIQUITINATION
RP AND PROTEASOMAL DEGRADATION.
RX PubMed=26776516; DOI=10.1016/j.celrep.2015.12.076;
RA Shi G., Xie P., Qu Z., Zhang Z., Dong Z., An Y., Xing L., Liu Z., Dong Y.,
RA Xu G., Yang L., Liu Y., Xu Y.;
RT "Distinct roles of HDAC3 in the core circadian negative feedback loop are
RT critical for clock function.";
RL Cell Rep. 14:823-834(2016).
RN [80]
RP FUNCTION.
RX PubMed=28985504; DOI=10.1016/j.molcel.2017.09.008;
RA Lin R., Mo Y., Zha H., Qu Z., Xie P., Zhu Z.J., Xu Y., Xiong Y., Guan K.L.;
RT "CLOCK acetylates ASS1 to drive circadian rhythm of ureagenesis.";
RL Mol. Cell 68:198-209(2017).
RN [81]
RP INTERACTION WITH PIWIL2, AND TISSUE SPECIFICITY.
RX PubMed=28903391; DOI=10.18632/oncotarget.18973;
RA Lu Y., Zheng X., Hu W., Bian S., Zhang Z., Tao D., Liu Y., Ma Y.;
RT "Cancer/testis antigen PIWIL2 suppresses circadian rhythms by regulating
RT the stability and activity of BMAL1 and CLOCK.";
RL Oncotarget 8:54913-54924(2017).
RN [82]
RP DEUBIQUITINATION BY USP9X, AND INTERACTION WITH USP9X.
RX PubMed=29626158; DOI=10.1042/bcj20180005;
RA Zhang Y., Duan C., Yang J., Chen S., Liu Q., Zhou L., Huang Z., Xu Y.,
RA Xu G.;
RT "Deubiquitinating enzyme USP9X regulates cellular clock function by
RT modulating the ubiquitination and degradation of a core circadian protein
RT BMAL1.";
RL Biochem. J. 475:1507-1522(2018).
RN [83]
RP LYSOSOME-MEDIATED DEGRADATION.
RX PubMed=29937374; DOI=10.1016/j.cmet.2018.05.023;
RA Toledo M., Batista-Gonzalez A., Merheb E., Aoun M.L., Tarabra E., Feng D.,
RA Sarparanta J., Merlo P., Botre F., Schwartz G.J., Pessin J.E., Singh R.;
RT "Autophagy regulates the liver clock and glucose metabolism by degrading
RT CRY1.";
RL Cell Metab. 28:268-281(2018).
RN [84]
RP FUNCTION, DISRUPTION PHENOTYPE, AND MUTAGENESIS OF ILE-323.
RX PubMed=29996098; DOI=10.1016/j.celrep.2018.06.026;
RA Deng W., Zhu S., Zeng L., Liu J., Kang R., Yang M., Cao L., Wang H.,
RA Billiar T.R., Jiang J., Xie M., Tang D.;
RT "The circadian clock controls immune checkpoint pathway in sepsis.";
RL Cell Rep. 24:366-378(2018).
RN [85]
RP TISSUE SPECIFICITY.
RX PubMed=29138967; DOI=10.1007/s12031-017-0996-8;
RA Riedel C.S., Georg B., Joergensen H.L., Hannibal J., Fahrenkrug J.;
RT "Mice lacking EGR1 have impaired clock gene (BMAL1) oscillation, locomotor
RT activity, and body temperature.";
RL J. Mol. Neurosci. 64:9-19(2018).
RN [86]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=30096135; DOI=10.1371/journal.pbio.2005886;
RA Dyar K.A., Hubert M.J., Mir A.A., Ciciliot S., Lutter D., Greulich F.,
RA Quagliarini F., Kleinert M., Fischer K., Eichmann T.O., Wright L.E.,
RA Pena Paz M.I., Casarin A., Pertegato V., Romanello V., Albiero M.,
RA Mazzucco S., Rizzuto R., Salviati L., Biolo G., Blaauw B., Schiaffino S.,
RA Uhlenhaut N.H.;
RT "Transcriptional programming of lipid and amino acid metabolism by the
RT skeletal muscle circadian clock.";
RL PLoS Biol. 16:E2005886-E2005886(2018).
RN [87]
RP ACETYLATION AT LYS-544, AND MUTAGENESIS OF LYS-544.
RX PubMed=31294688; DOI=10.7554/elife.43235;
RA Petkau N., Budak H., Zhou X., Oster H., Eichele G.;
RT "Acetylation of BMAL1 by TIP60 controls BRD4-P-TEFb recruitment to
RT circadian promoters.";
RL Elife 8:0-0(2019).
RN [88]
RP X-RAY CRYSTALLOGRAPHY (2.27 ANGSTROMS) OF 69-453 IN COMPLEX WITH CLOCK,
RP FUNCTION, INTERACTION WITH CLOCK, AND MUTAGENESIS OF LEU-102; LEU-122 AND
RP ILE-323.
RX PubMed=22653727; DOI=10.1126/science.1222804;
RA Huang N., Chelliah Y., Shan Y., Taylor C.A., Yoo S.H., Partch C.,
RA Green C.B., Zhang H., Takahashi J.S.;
RT "Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional
RT activator complex.";
RL Science 337:189-194(2012).
CC -!- FUNCTION: Transcriptional activator which forms a core component of the
CC circadian clock. The circadian clock, an internal time-keeping system,
CC regulates various physiological processes through the generation of
CC approximately 24 hour circadian rhythms in gene expression, which are
CC translated into rhythms in metabolism and behavior. It is derived from
CC the Latin roots 'circa' (about) and 'diem' (day) and acts as an
CC important regulator of a wide array of physiological functions
CC including metabolism, sleep, body temperature, blood pressure,
CC endocrine, immune, cardiovascular, and renal function. Consists of two
CC major components: the central clock, residing in the suprachiasmatic
CC nucleus (SCN) of the brain, and the peripheral clocks that are present
CC in nearly every tissue and organ system. Both the central and
CC peripheral clocks can be reset by environmental cues, also known as
CC Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the
CC central clock is light, which is sensed by retina and signals directly
CC to the SCN. The central clock entrains the peripheral clocks through
CC neuronal and hormonal signals, body temperature and feeding-related
CC cues, aligning all clocks with the external light/dark cycle. Circadian
CC rhythms allow an organism to achieve temporal homeostasis with its
CC environment at the molecular level by regulating gene expression to
CC create a peak of protein expression once every 24 hours to control when
CC a particular physiological process is most active with respect to the
CC solar day. Transcription and translation of core clock components
CC (CLOCK, NPAS2, 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. ARNTL/BMAL1 positively
CC regulates myogenesis and negatively regulates adipogenesis via the
CC transcriptional control of the genes of the canonical Wnt signaling
CC pathway. Plays a role in normal pancreatic beta-cell function;
CC regulates glucose-stimulated insulin secretion via the regulation of
CC antioxidant genes NFE2L2/NRF2 and its targets SESN2, PRDX3, CCLC and
CC CCLM. Negatively regulates the mTORC1 signaling pathway; regulates the
CC expression of MTOR and DEPTOR. Controls diurnal oscillations of Ly6C
CC inflammatory monocytes; rhythmic recruitment of the PRC2 complex
CC imparts diurnal variation to chemokine expression that is necessary to
CC sustain Ly6C monocyte rhythms. Regulates the expression of HSD3B2,
CC STAR, PTGS2, CYP11A1, CYP19A1 and LHCGR in the ovary and also the genes
CC involved in hair growth. Plays an important role in adult hippocampal
CC neurogenesis by regulating the timely entry of neural stem/progenitor
CC cells (NSPCs) into the cell cycle and the number of cell divisions that
CC take place prior to cell-cycle exit. Regulates the circadian expression
CC of CIART and KLF11. The CLOCK-ARNTL/BMAL1 heterodimer regulates the
CC circadian expression of SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP,
CC MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1,
CC ATF4, MTA1, KLF10 and also genes implicated in glucose and lipid
CC metabolism. Promotes rhythmic chromatin opening, regulating the DNA
CC accessibility of other transcription factors. May play a role in
CC spermatogenesis; contributes to the chromatoid body assembly and
CC physiology. The NPAS2-ARNTL/BMAL1 heterodimer positively regulates the
CC expression of MAOA, F7 and LDHA and modulates the circadian rhythm of
CC daytime contrast sensitivity by regulating the rhythmic expression of
CC adenylate cyclase type 1 (ADCY1) in the retina. The preferred binding
CC motif for the CLOCK-ARNTL/BMAL1 heterodimer is 5'-CACGTGA-3', which
CC contains a flanking Ala residue in addition to the canonical 6-
CC nucleotide E-box sequence (By similarity). CLOCK specifically binds to
CC the half-site 5'-CAC-3', while ARNTL binds to the half-site 5'-GTGA-3'
CC (By similarity). The CLOCK-ARNTL/BMAL1 heterodimer also recognizes the
CC non-canonical E-box motifs 5'-AACGTGA-3' and 5'-CATGTGA-3' (By
CC similarity). Essential for the rhythmic interaction of CLOCK with ASS1
CC and plays a critical role in positively regulating CLOCK-mediated
CC acetylation of ASS1 (PubMed:28985504). Plays a role in protecting
CC against lethal sepsis by limiting the expression of immune checkpoint
CC protein CD274 in macrophages in a PKM2-dependent manner
CC (PubMed:29996098). Regulates the diurnal rhythms of skeletal muscle
CC metabolism via transcriptional activation of genes promoting
CC triglyceride synthesis (DGAT2) and metabolic efficiency (COQ10B)
CC (PubMed:30096135). {ECO:0000250|UniProtKB:O00327,
CC ECO:0000269|PubMed:14672706, ECO:0000269|PubMed:18258755,
CC ECO:0000269|PubMed:18316400, ECO:0000269|PubMed:19141540,
CC ECO:0000269|PubMed:19286518, ECO:0000269|PubMed:19299583,
CC ECO:0000269|PubMed:19605937, ECO:0000269|PubMed:20153195,
CC ECO:0000269|PubMed:20385766, ECO:0000269|PubMed:20430893,
CC ECO:0000269|PubMed:20562852, ECO:0000269|PubMed:20658528,
CC ECO:0000269|PubMed:20840750, ECO:0000269|PubMed:20956306,
CC ECO:0000269|PubMed:21768648, ECO:0000269|PubMed:21966465,
CC ECO:0000269|PubMed:22045262, ECO:0000269|PubMed:22101268,
CC ECO:0000269|PubMed:22611086, ECO:0000269|PubMed:22653727,
CC ECO:0000269|PubMed:22900038, ECO:0000269|PubMed:22981862,
CC ECO:0000269|PubMed:23291174, ECO:0000269|PubMed:23525013,
CC ECO:0000269|PubMed:23547261, ECO:0000269|PubMed:23750248,
CC ECO:0000269|PubMed:23955654, ECO:0000269|PubMed:23970558,
CC ECO:0000269|PubMed:24048828, ECO:0000269|PubMed:24089055,
CC ECO:0000269|PubMed:24268780, ECO:0000269|PubMed:24270424,
CC ECO:0000269|PubMed:24378737, ECO:0000269|PubMed:24385426,
CC ECO:0000269|PubMed:24395244, ECO:0000269|PubMed:24442997,
CC ECO:0000269|PubMed:24481314, ECO:0000269|PubMed:24736997,
CC ECO:0000269|PubMed:28985504, ECO:0000269|PubMed:29996098,
CC ECO:0000269|PubMed:30096135}.
CC -!- ACTIVITY REGULATION: The redox state of the cell can modulate the
CC transcriptional activity of the CLOCK-ARNTL/BMAL1 and NPAS2-ARNTL/BMAL1
CC heterodimers; NADH and NADPH enhance the DNA-binding activity of the
CC heterodimers. {ECO:0000250|UniProtKB:O00327}.
CC -!- SUBUNIT: Component of the circadian clock oscillator which includes the
CC CRY1/2 proteins, CLOCK or NPAS2, ARNTL/BMAL1 or ARNTL2/BMAL2, CSNK1D
CC and/or CSNK1E, TIMELESS and the PER1/2/3 proteins (PubMed:11779462).
CC Forms a heterodimer with CLOCK (PubMed:9616112, PubMed:16717091,
CC PubMed:16980631, PubMed:18662546, PubMed:19946213, PubMed:19330005,
CC PubMed:21613214, PubMed:23970558, PubMed:22653727). The CLOCK-
CC ARNTL/BMAL1 heterodimer is required for E-box-dependent
CC transactivation, for CLOCK nuclear translocation and degradation, and,
CC for phosphorylation of both CLOCK and ARNTL/BMAL1 (PubMed:11779462).
CC Part of a nuclear complex which also includes RACK1 and PRKCA; RACK1
CC and PRKCA are recruited to the complex in a circadian manner
CC (PubMed:20093473). Interacts with NPAS2 (PubMed:16628007). Interacts
CC with EZH2 (PubMed:16717091, PubMed:23970558). Interacts with SUMO3
CC (PubMed:18644859). Interacts with SIRT1 (PubMed:18662546,
CC PubMed:18662547, PubMed:19299583). Interacts with AHR
CC (PubMed:20106950). Interacts with ID1, ID2 and ID3 (PubMed:20861012).
CC Interacts with DDX4 (PubMed:22900038). Interacts with OGT
CC (PubMed:23337503). Interacts with EED and SUZ12 (PubMed:23970558).
CC Interacts with MTA1 (PubMed:24089055). Interacts with CIART
CC (PubMed:24385426, PubMed:24736997). Interacts with HSP90 (By
CC similarity). Interacts with KAT2B and EP300 (By similarity). Interacts
CC with BHLHE40/DEC1 and BHLHE41/DEC2 (PubMed:12397359). Interacts with
CC RELB and the interaction is enhanced in the presence of CLOCK
CC (PubMed:22894897). Interacts with PER1, PER2, CRY1 and CRY2 and this
CC interaction requires a translocation to the nucleus (PubMed:18430226,
CC PubMed:19605937, PubMed:20840750, PubMed:21613214, PubMed:24154698).
CC Interaction of the CLOCK-ARNTL/BMAL1 heterodimer with PER or CRY
CC inhibits transcription activation (PubMed:21613214). Interaction of the
CC CLOCK-ARNTL/BMAL1 with CRY1 is independent of DNA but with PER2 is off
CC DNA (PubMed:21613214). The CLOCK-ARNTL/BMAL1 heterodimer interacts with
CC GSK3B (PubMed:19946213, PubMed:20049328). Interacts with KDM5A
CC (PubMed:21960634). Interacts with KMT2A; in a circadian manner
CC (PubMed:21113167). Interacts with UBE3A (By similarity). Interacts with
CC PRKCG (PubMed:23185022). Interacts with MAGEL2 (PubMed:22208286).
CC Interacts with NCOA2 (PubMed:24529706). Interacts with THRAP3
CC (PubMed:24043798). The CLOCK-ARNTL/BMAL1 heterodimer interacts with
CC PASD1 (By similarity). Interacts with PASD1 (By similarity). Interacts
CC with USP9X (PubMed:29626158). Interacts with PIWIL2 (via PIWI domain)
CC (PubMed:28903391). Interacts with HDAC3 (PubMed:26776516). Interacts
CC with HNF4A (By similarity). {ECO:0000250|UniProtKB:O00327,
CC ECO:0000269|PubMed:12397359, ECO:0000269|PubMed:16628007,
CC ECO:0000269|PubMed:16717091, ECO:0000269|PubMed:16980631,
CC ECO:0000269|PubMed:18430226, ECO:0000269|PubMed:18644859,
CC ECO:0000269|PubMed:18662546, ECO:0000269|PubMed:18662547,
CC ECO:0000269|PubMed:19299583, ECO:0000269|PubMed:19330005,
CC ECO:0000269|PubMed:19605937, ECO:0000269|PubMed:19946213,
CC ECO:0000269|PubMed:20049328, ECO:0000269|PubMed:20093473,
CC ECO:0000269|PubMed:20106950, ECO:0000269|PubMed:20840750,
CC ECO:0000269|PubMed:20861012, ECO:0000269|PubMed:21113167,
CC ECO:0000269|PubMed:21613214, ECO:0000269|PubMed:21960634,
CC ECO:0000269|PubMed:22208286, ECO:0000269|PubMed:22653727,
CC ECO:0000269|PubMed:22894897, ECO:0000269|PubMed:22900038,
CC ECO:0000269|PubMed:23185022, ECO:0000269|PubMed:23337503,
CC ECO:0000269|PubMed:23970558, ECO:0000269|PubMed:24043798,
CC ECO:0000269|PubMed:24089055, ECO:0000269|PubMed:24154698,
CC ECO:0000269|PubMed:24385426, ECO:0000269|PubMed:24529706,
CC ECO:0000269|PubMed:24736997, ECO:0000269|PubMed:26776516,
CC ECO:0000269|PubMed:28903391, ECO:0000269|PubMed:29626158,
CC ECO:0000269|PubMed:9616112}.
CC -!- INTERACTION:
CC Q9WTL8; Q3TQ03: Ciart; NbExp=3; IntAct=EBI-644534, EBI-16101489;
CC Q9WTL8; O08785: Clock; NbExp=39; IntAct=EBI-644534, EBI-79859;
CC Q9WTL8; P97784: Cry1; NbExp=23; IntAct=EBI-644534, EBI-1266607;
CC Q9WTL8; Q99JJ1: Cry2; NbExp=4; IntAct=EBI-644534, EBI-1794634;
CC Q9WTL8; Q9R194: Cry2; NbExp=12; IntAct=EBI-644534, EBI-1266619;
CC Q9WTL8; Q60737: Csnk2a1; NbExp=5; IntAct=EBI-644534, EBI-771698;
CC Q9WTL8; P67871: Csnk2b; NbExp=8; IntAct=EBI-644534, EBI-348179;
CC Q9WTL8; P11103: Parp1; NbExp=7; IntAct=EBI-644534, EBI-642213;
CC Q9WTL8; O54943: Per2; NbExp=9; IntAct=EBI-644534, EBI-1266779;
CC Q9WTL8; P62137: Ppp1ca; NbExp=2; IntAct=EBI-644534, EBI-357187;
CC Q9WTL8; Q8N365: CIART; Xeno; NbExp=6; IntAct=EBI-644534, EBI-10265133;
CC Q9WTL8; P67870: CSNK2B; Xeno; NbExp=4; IntAct=EBI-644534, EBI-348169;
CC Q9WTL8; Q03164: KMT2A; Xeno; NbExp=3; IntAct=EBI-644534, EBI-591370;
CC Q9WTL8; P51449: RORC; Xeno; NbExp=2; IntAct=EBI-644534, EBI-3908771;
CC Q9WTL8; P61964: WDR5; Xeno; NbExp=2; IntAct=EBI-644534, EBI-540834;
CC Q9WTL8-2; O08785: Clock; NbExp=2; IntAct=EBI-644559, EBI-79859;
CC Q9WTL8-2; P97784: Cry1; NbExp=4; IntAct=EBI-644559, EBI-1266607;
CC Q9WTL8-4; O08785: Clock; NbExp=10; IntAct=EBI-644568, EBI-79859;
CC Q9WTL8-4; P45481: Crebbp; NbExp=2; IntAct=EBI-644568, EBI-296306;
CC Q9WTL8-4; P97784: Cry1; NbExp=4; IntAct=EBI-644568, EBI-1266607;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16980631,
CC ECO:0000269|PubMed:22208286, ECO:0000269|PubMed:26776516}. Cytoplasm
CC {ECO:0000269|PubMed:16980631}. Nucleus, PML body
CC {ECO:0000269|PubMed:18644859}. Note=Shuttles between the nucleus and
CC the cytoplasm and this nucleocytoplasmic shuttling is essential for the
CC nuclear accumulation of CLOCK, target gene transcription and the
CC degradation of the CLOCK-ARNTL/BMAL1 heterodimer. The sumoylated form
CC localizes in the PML body. Sequestered to the cytoplasm in the presence
CC of ID2. {ECO:0000269|PubMed:16980631, ECO:0000269|PubMed:18644859,
CC ECO:0000269|PubMed:20861012}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1; Synonyms=b';
CC IsoId=Q9WTL8-1; Sequence=Displayed;
CC Name=2; Synonyms=b;
CC IsoId=Q9WTL8-2; Sequence=VSP_007992;
CC Name=3;
CC IsoId=Q9WTL8-3; Sequence=VSP_007993, VSP_007994;
CC Name=4;
CC IsoId=Q9WTL8-4; Sequence=VSP_007992, VSP_007994;
CC Name=5; Synonyms=g';
CC IsoId=Q9WTL8-5; Sequence=VSP_007992, VSP_007995, VSP_007996;
CC -!- TISSUE SPECIFICITY: Expressed in liver and testis (at protein level).
CC Expressed in the suprachiasmatic nucleus (SCN) in a circadian manner
CC (PubMed:29138967). {ECO:0000269|PubMed:16790549,
CC ECO:0000269|PubMed:22900038, ECO:0000269|PubMed:23531614,
CC ECO:0000269|PubMed:24154698, ECO:0000269|PubMed:24603368,
CC ECO:0000269|PubMed:28903391, ECO:0000269|PubMed:29138967}.
CC -!- INDUCTION: Expressed in a circadian manner in the liver.
CC {ECO:0000269|PubMed:16790549, ECO:0000269|PubMed:20385766,
CC ECO:0000269|PubMed:23531614, ECO:0000269|PubMed:24603368}.
CC -!- PTM: Ubiquitinated, leading to its proteasomal degradation
CC (PubMed:16980631, PubMed:18644859, PubMed:23185022, PubMed:26776516).
CC Deubiquitinated by USP9X (PubMed:29626158).
CC {ECO:0000269|PubMed:16980631, ECO:0000269|PubMed:18644859,
CC ECO:0000269|PubMed:23185022, ECO:0000269|PubMed:26776516,
CC ECO:0000269|PubMed:29626158}.
CC -!- PTM: O-glycosylated; contains O-GlcNAc. O-glycosylation by OGT prevents
CC protein degradation by inhibiting ubiquitination. It also stabilizes
CC the CLOCK-ARNTL/BMAL1 heterodimer thereby increasing CLOCK-ARNTL/BMAL1-
CC mediated transcription of genes in the negative loop of the circadian
CC clock such as PER1/2/3 and CRY1/2. {ECO:0000269|PubMed:23337503,
CC ECO:0000269|PubMed:23395176}.
CC -!- PTM: Acetylated on Lys-544 by CLOCK during the repression phase of the
CC circadian cycle (PubMed:18075593, PubMed:31294688). Acetylation
CC facilitates recruitment of CRY1 protein and initiates the repression
CC phase of the circadian cycle (PubMed:18075593). Acetylated at Lys-544
CC by KAT5 during the activation phase of the cycle, leading to
CC recruitment of the positive transcription elongation factor b (P-TEFb)
CC and BRD4, followed by productive elongation of circadian transcripts
CC (PubMed:31294688). Deacetylated by SIRT1, which may result in decreased
CC protein stability (PubMed:18662547). {ECO:0000269|PubMed:18075593,
CC ECO:0000269|PubMed:18662547, ECO:0000269|PubMed:31294688}.
CC -!- PTM: Phosphorylated upon dimerization with CLOCK. Phosphorylation
CC enhances the transcriptional activity, alters the subcellular
CC localization and decreases the stability of the CLOCK-ARNTL/BMAL1
CC heterodimer by promoting its degradation. Phosphorylation shows
CC circadian variations in the liver with a peak between CT10 to CT14.
CC Phosphorylation at Ser-97 by CK2 is essential for its nuclear
CC localization, its interaction with CLOCK and controls CLOCK nuclear
CC entry. Dephosphorylation at Ser-85 is important for dimerization with
CC CLOCK and transcriptional activity (By similarity).
CC {ECO:0000250|UniProtKB:O00327, ECO:0000269|PubMed:11779462,
CC ECO:0000269|PubMed:12897057, ECO:0000269|PubMed:19330005,
CC ECO:0000269|PubMed:19414601, ECO:0000269|PubMed:19946213,
CC ECO:0000269|PubMed:20049328}.
CC -!- PTM: Sumoylated on Lys-266 upon dimerization with CLOCK. Predominantly
CC conjugated to poly-SUMO2/3 rather than SUMO1 and the level of these
CC conjugates undergo rhythmic variation, peaking at CT9-CT12. Sumoylation
CC localizes it exclusively to the PML body and promotes its
CC ubiquitination in the PML body, ubiquitin-dependent proteasomal
CC degradation and the transcriptional activity of the CLOCK-ARNTL/BMAL1
CC heterodimer. {ECO:0000269|PubMed:16109848,
CC ECO:0000269|PubMed:18644859}.
CC -!- PTM: Undergoes lysosome-mediated degradation in a time-dependent manner
CC in the liver. {ECO:0000269|PubMed:29937374}.
CC -!- DISRUPTION PHENOTYPE: Mice are characterized by reduced lifespan, and
CC the presence of a number of pathologies characteristic of pre-mature
CC aging and increased oxidative stress. They show impaired functional
CC connectivity, increased oxidative damage and severe astrogliosis in the
CC brain. They also exhibit accelerated thrombosis with elevated levels of
CC thrombogenic factors, including VWF, SERPINE1/PAI1, and fibrinogen.
CC Both male and female mice are infertile and male mice have low
CC testosterone and high luteinizing hormone serum levels and a
CC significant decrease in sperm count (PubMed:18258755, PubMed:22101268,
CC PubMed:24270424, PubMed:24481314). Conditional knockout in myeloid
CC cells increases the risk of sepsis lethality which is associated with
CC elevated lactate production and CD274 expression in macrophages
CC (PubMed:29996098). Myeloid-cell-specific ARNTL/BMAL1 and PKM2 double
CC knockout reduces the risk of sepsis lethality which is associated with
CC reduced serum lactate levels and reduced CD274 expression in
CC macrophages (PubMed:29996098). Conditional knockout in skeletal muscle
CC leads to impaired skeletal muscle triglyceride biosynthesis,
CC accumulation of bioactive lipids and amino acids and reduced
CC mitochondrial efficiency (PubMed:30096135).
CC {ECO:0000269|PubMed:18258755, ECO:0000269|PubMed:22101268,
CC ECO:0000269|PubMed:24270424, ECO:0000269|PubMed:24481314,
CC ECO:0000269|PubMed:29996098, ECO:0000269|PubMed:30096135}.
CC ---------------------------------------------------------------------------
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DR EMBL; AB012601; BAA76414.1; -; mRNA.
DR EMBL; AB015203; BAA81898.1; -; mRNA.
DR EMBL; AB012602; BAA76415.1; -; mRNA.
DR EMBL; AB014494; BAA32208.1; -; mRNA.
DR EMBL; BC025973; AAH25973.1; -; mRNA.
DR EMBL; BC011080; AAH11080.1; -; mRNA.
DR CCDS; CCDS40092.1; -. [Q9WTL8-4]
DR CCDS; CCDS85390.1; -. [Q9WTL8-3]
DR PIR; JE0270; JE0270.
DR RefSeq; NP_001229977.1; NM_001243048.1. [Q9WTL8-3]
DR RefSeq; NP_031515.1; NM_007489.4. [Q9WTL8-4]
DR RefSeq; XP_006507314.1; XM_006507251.2.
DR RefSeq; XP_017177438.1; XM_017321949.1.
DR RefSeq; XP_017177439.1; XM_017321950.1. [Q9WTL8-2]
DR PDB; 4F3L; X-ray; 2.27 A; B=69-453.
DR PDBsum; 4F3L; -.
DR AlphaFoldDB; Q9WTL8; -.
DR SASBDB; Q9WTL8; -.
DR SMR; Q9WTL8; -.
DR BioGRID; 198207; 20.
DR ComplexPortal; CPX-3225; CLOCK-BMAL1 transcription complex.
DR CORUM; Q9WTL8; -.
DR DIP; DIP-43977N; -.
DR IntAct; Q9WTL8; 32.
DR MINT; Q9WTL8; -.
DR STRING; 10090.ENSMUSP00000046235; -.
DR iPTMnet; Q9WTL8; -.
DR PhosphoSitePlus; Q9WTL8; -.
DR MaxQB; Q9WTL8; -.
DR PaxDb; Q9WTL8; -.
DR PRIDE; Q9WTL8; -.
DR ProteomicsDB; 265307; -. [Q9WTL8-1]
DR ProteomicsDB; 265308; -. [Q9WTL8-2]
DR ProteomicsDB; 265309; -. [Q9WTL8-3]
DR ProteomicsDB; 265310; -. [Q9WTL8-4]
DR ProteomicsDB; 265311; -. [Q9WTL8-5]
DR Antibodypedia; 11861; 556 antibodies from 45 providers.
DR DNASU; 11865; -.
DR Ensembl; ENSMUST00000047321; ENSMUSP00000046235; ENSMUSG00000055116. [Q9WTL8-4]
DR Ensembl; ENSMUST00000210074; ENSMUSP00000147764; ENSMUSG00000055116. [Q9WTL8-3]
DR Ensembl; ENSMUST00000210238; ENSMUSP00000147989; ENSMUSG00000055116. [Q9WTL8-4]
DR GeneID; 11865; -.
DR KEGG; mmu:11865; -.
DR UCSC; uc009jhf.2; mouse. [Q9WTL8-3]
DR UCSC; uc009jhi.2; mouse. [Q9WTL8-2]
DR UCSC; uc009jhj.2; mouse. [Q9WTL8-1]
DR CTD; 406; -.
DR MGI; MGI:1096381; Arntl.
DR VEuPathDB; HostDB:ENSMUSG00000055116; -.
DR eggNOG; KOG3561; Eukaryota.
DR GeneTree; ENSGT00940000157523; -.
DR HOGENOM; CLU_011864_2_2_1; -.
DR InParanoid; Q9WTL8; -.
DR OMA; YHHEDIP; -.
DR PhylomeDB; Q9WTL8; -.
DR TreeFam; TF319983; -.
DR BioGRID-ORCS; 11865; 4 hits in 77 CRISPR screens.
DR ChiTaRS; Arntl; mouse.
DR PRO; PR:Q9WTL8; -.
DR Proteomes; UP000000589; Chromosome 7.
DR RNAct; Q9WTL8; protein.
DR Bgee; ENSMUSG00000055116; Expressed in animal zygote and 240 other tissues.
DR ExpressionAtlas; Q9WTL8; baseline and differential.
DR Genevisible; Q9WTL8; MM.
DR GO; GO:0034751; C:aryl hydrocarbon receptor complex; IBA:GO_Central.
DR GO; GO:0033391; C:chromatoid body; IDA:UniProtKB.
DR GO; GO:1990513; C:CLOCK-BMAL transcription complex; IPI:ComplexPortal.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI.
DR GO; GO:0016604; C:nuclear body; IDA:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0016605; C:PML body; IEA:UniProtKB-SubCell.
DR GO; GO:0005667; C:transcription regulator complex; IDA:UniProtKB.
DR GO; GO:0017162; F:aryl hydrocarbon receptor binding; ISO:MGI.
DR GO; GO:0043425; F:bHLH transcription factor binding; IPI:BHF-UCL.
DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:BHF-UCL.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:UniProtKB.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IDA:BHF-UCL.
DR GO; GO:0140297; F:DNA-binding transcription factor binding; ISO:MGI.
DR GO; GO:0070888; F:E-box binding; IDA:UniProtKB.
DR GO; GO:0051879; F:Hsp90 protein binding; ISO:MGI.
DR GO; GO:0046982; F:protein heterodimerization activity; IPI:BHF-UCL.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:UniProtKB.
DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:UniProtKB.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:MGI.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:UniProtKB.
DR GO; GO:0032922; P:circadian regulation of gene expression; IDA:UniProtKB.
DR GO; GO:0007623; P:circadian rhythm; IDA:UniProtKB.
DR GO; GO:0060137; P:maternal process involved in parturition; IMP:CACAO.
DR GO; GO:0120163; P:negative regulation of cold-induced thermogenesis; IMP:YuBioLab.
DR GO; GO:0045599; P:negative regulation of fat cell differentiation; IMP:UniProtKB.
DR GO; GO:2000323; P:negative regulation of glucocorticoid receptor signaling pathway; IMP:UniProtKB.
DR GO; GO:0032007; P:negative regulation of TOR signaling; IMP:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0090403; P:oxidative stress-induced premature senescence; IMP:UniProtKB.
DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; IMP:UniProtKB.
DR GO; GO:0042753; P:positive regulation of circadian rhythm; IMP:UniProtKB.
DR GO; GO:1901985; P:positive regulation of protein acetylation; IMP:UniProtKB.
DR GO; GO:2001016; P:positive regulation of skeletal muscle cell differentiation; IMP:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:BHF-UCL.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
DR GO; GO:0006606; P:protein import into nucleus; IDA:MGI.
DR GO; GO:0051726; P:regulation of cell cycle; IMP:UniProtKB.
DR GO; GO:2000772; P:regulation of cellular senescence; IMP:UniProtKB.
DR GO; GO:0042634; P:regulation of hair cycle; ISS:UniProtKB.
DR GO; GO:0050796; P:regulation of insulin secretion; IMP:UniProtKB.
DR GO; GO:0050767; P:regulation of neurogenesis; IMP:UniProtKB.
DR GO; GO:0042176; P:regulation of protein catabolic process; IDA:MGI.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO: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; IDA:UniProtKB.
DR GO; GO:0007283; P:spermatogenesis; IMP:UniProtKB.
DR CDD; cd00130; PAS; 2.
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 TIGRFAMs; TIGR00229; sensory_box; 1.
DR PROSITE; PS50888; BHLH; 1.
DR PROSITE; PS50112; PAS; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Activator; Alternative splicing;
KW Biological rhythms; Cytoplasm; DNA-binding; Glycoprotein; Isopeptide bond;
KW Nucleus; Phosphoprotein; Reference proteome; Repeat; Transcription;
KW Transcription regulation; Ubl conjugation.
FT CHAIN 1..632
FT /note="Aryl hydrocarbon receptor nuclear translocator-like
FT protein 1"
FT /id="PRO_0000127158"
FT DOMAIN 79..132
FT /note="bHLH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981"
FT DOMAIN 150..222
FT /note="PAS 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140"
FT DOMAIN 333..403
FT /note="PAS 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140"
FT DOMAIN 408..451
FT /note="PAC"
FT REGION 1..39
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 465..498
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 514..594
FT /note="Interaction with CIART"
FT REGION 517..601
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 36..41
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000269|PubMed:16980631"
FT MOTIF 149..159
FT /note="Nuclear export signal 1"
FT /evidence="ECO:0000269|PubMed:16980631"
FT MOTIF 367..375
FT /note="Nuclear export signal 2"
FT /evidence="ECO:0000269|PubMed:16980631"
FT COMPBIAS 1..32
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 518..538
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 558..580
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 84
FT /note="Interaction with E-box DNA"
FT /evidence="ECO:0000250|UniProtKB:O00327"
FT SITE 87
FT /note="Interaction with E-box DNA"
FT /evidence="ECO:0000250|UniProtKB:O00327"
FT SITE 88
FT /note="Interaction with E-box DNA"
FT /evidence="ECO:0000250|UniProtKB:O00327"
FT SITE 92
FT /note="Interaction with E-box DNA"
FT /evidence="ECO:0000250|UniProtKB:O00327"
FT SITE 132
FT /note="Important for interaction with CLOCK"
FT /evidence="ECO:0000250|UniProtKB:O00327"
FT MOD_RES 17
FT /note="Phosphoserine; by GSK3-beta"
FT /evidence="ECO:0000269|PubMed:20049328"
FT MOD_RES 21
FT /note="Phosphothreonine; by GSK3-beta"
FT /evidence="ECO:0000269|PubMed:20049328"
FT MOD_RES 85
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O00327"
FT MOD_RES 97
FT /note="Phosphoserine; by CK2"
FT /evidence="ECO:0000269|PubMed:19330005"
FT MOD_RES 544
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:18075593,
FT ECO:0000269|PubMed:18662547, ECO:0000269|PubMed:31294688"
FT CROSSLNK 259
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2 and SUMO3)"
FT /evidence="ECO:0000269|PubMed:18644859"
FT CROSSLNK 266
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO); alternate"
FT /evidence="ECO:0000269|PubMed:16109848"
FT CROSSLNK 266
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2); alternate"
FT /evidence="ECO:0000250|UniProtKB:O00327"
FT VAR_SEQ 48..54
FT /note="Missing (in isoform 2, isoform 4 and isoform 5)"
FT /evidence="ECO:0000303|PubMed:10403839,
FT ECO:0000303|PubMed:15489334, ECO:0000303|PubMed:9704006"
FT /id="VSP_007992"
FT VAR_SEQ 49..68
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_007993"
FT VAR_SEQ 161..483
FT /note="AADGFLFVVGCDRGKILFVSESVFKILNYSQNDLIGQSLFDYLHPKDIAKVK
FT EQLSSSDTAPRERLIDAKTGLPVKTDITPGPSRLCSGARRSFFCRMKCNRPSVKVEDKD
FT FASTCSKKKDRKSFCTIHSTGYLKSWPPTKMGLDEDNEPDNEGCNLSCLVAIGRLHSHM
FT VPQPANGEIRVKSMEYVSRHAIDGKFVFVDQRATAILAYLPQELLGTSCYEYFHQDDIG
FT HLAECHRQVLQTREKITTNCYKFKIKDGSFITLRSRWFSFMNPWTKEVEYIVSTNTVVL
FT ANVLEGGDPTFPQLTAPPHSMDSMLPSGEGGPKRT -> DVTEGRSSLSPSLSSRSSII
FT ARMTLLARACLTTCIQKILPKLRNSYLPRTLRPGSDSLMPRLDFRLKRI (in
FT isoform 5)"
FT /evidence="ECO:0000303|PubMed:10403839"
FT /id="VSP_007995"
FT VAR_SEQ 280
FT /note="K -> KA (in isoform 3 and isoform 4)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:9704006"
FT /id="VSP_007994"
FT VAR_SEQ 484..632
FT /note="Missing (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:10403839"
FT /id="VSP_007996"
FT MUTAGEN 38..39
FT /note="KR->AA: Loss of nuclear localization."
FT /evidence="ECO:0000269|PubMed:16980631"
FT MUTAGEN 97
FT /note="S->A: Impaired nuclear accumulation, decreased
FT interaction with CLOCK and disruption of circadian clock
FT function."
FT /evidence="ECO:0000269|PubMed:19330005"
FT MUTAGEN 102
FT /note="L->E: Reduced CLOCK binding. Abolishes
FT transcriptional activation by the CLOCK-ARNTL/BMAL1
FT heterodimer."
FT /evidence="ECO:0000269|PubMed:22653727"
FT MUTAGEN 122
FT /note="L->E: Reduced CLOCK binding. Abolishes
FT transcriptional activation by the CLOCK-ARNTL/BMAL1
FT heterodimer."
FT /evidence="ECO:0000269|PubMed:22653727"
FT MUTAGEN 154
FT /note="L->A: Significant reduction in nucleocytoplasmic
FT shuttling; when associated with A-157."
FT /evidence="ECO:0000269|PubMed:16980631"
FT MUTAGEN 157
FT /note="L->A: Significant reduction in nucleocytoplasmic
FT shuttling; when associated with A-154."
FT /evidence="ECO:0000269|PubMed:16980631"
FT MUTAGEN 230
FT /note="K->R: No effect on sumoylation."
FT /evidence="ECO:0000269|PubMed:16109848"
FT MUTAGEN 236
FT /note="K->R: No effect on sumoylation."
FT /evidence="ECO:0000269|PubMed:16109848"
FT MUTAGEN 259
FT /note="K->R: Significant decrease in; transcriptional
FT activity, localization in PML body, ubiquitination and
FT proteasome-mediated proteolysis."
FT /evidence="ECO:0000269|PubMed:18644859"
FT MUTAGEN 266
FT /note="K->R: Abolishes sumoylation."
FT /evidence="ECO:0000269|PubMed:16109848"
FT MUTAGEN 279
FT /note="K->R: No effect on sumoylation."
FT /evidence="ECO:0000269|PubMed:16109848"
FT MUTAGEN 323
FT /note="I->D: Reduced CLOCK binding. Slightly reduced
FT transcriptional activation by the CLOCK-ARNTL/BMAL1
FT heterodimer. Impairs regulation of circadian clock. Loss of
FT ability to inhibit the expression of CD274 in macrophages."
FT /evidence="ECO:0000269|PubMed:22653727,
FT ECO:0000269|PubMed:29996098"
FT MUTAGEN 370
FT /note="L->A: Significant reduction in nucleocytoplasmic
FT shuttling; when associated with A-374."
FT /evidence="ECO:0000269|PubMed:16980631"
FT MUTAGEN 374
FT /note="L->A: Significant reduction in nucleocytoplasmic
FT shuttling; when associated with A-370."
FT /evidence="ECO:0000269|PubMed:16980631"
FT MUTAGEN 418
FT /note="S->A: Decreases without abolishing O-GlcNAcylation."
FT /evidence="ECO:0000269|PubMed:23395176"
FT MUTAGEN 544
FT /note="K->R: Decreased acetylation, leading to decreased
FT transcription elongation during the activation phase of the
FT circadian cycle."
FT /evidence="ECO:0000269|PubMed:31294688"
FT CONFLICT 254
FT /note="F -> L (in Ref. 1; BAA76414/BAA81898)"
FT /evidence="ECO:0000305"
FT HELIX 79..105
FT /evidence="ECO:0007829|PDB:4F3L"
FT HELIX 107..111
FT /evidence="ECO:0007829|PDB:4F3L"
FT HELIX 118..133
FT /evidence="ECO:0007829|PDB:4F3L"
FT HELIX 151..160
FT /evidence="ECO:0007829|PDB:4F3L"
FT STRAND 164..170
FT /evidence="ECO:0007829|PDB:4F3L"
FT TURN 171..173
FT /evidence="ECO:0007829|PDB:4F3L"
FT STRAND 175..179
FT /evidence="ECO:0007829|PDB:4F3L"
FT HELIX 183..187
FT /evidence="ECO:0007829|PDB:4F3L"
FT HELIX 191..194
FT /evidence="ECO:0007829|PDB:4F3L"
FT HELIX 199..202
FT /evidence="ECO:0007829|PDB:4F3L"
FT HELIX 205..207
FT /evidence="ECO:0007829|PDB:4F3L"
FT HELIX 208..215
FT /evidence="ECO:0007829|PDB:4F3L"
FT HELIX 248..250
FT /evidence="ECO:0007829|PDB:4F3L"
FT STRAND 251..259
FT /evidence="ECO:0007829|PDB:4F3L"
FT STRAND 284..295
FT /evidence="ECO:0007829|PDB:4F3L"
FT STRAND 319..326
FT /evidence="ECO:0007829|PDB:4F3L"
FT STRAND 337..339
FT /evidence="ECO:0007829|PDB:4F3L"
FT STRAND 345..350
FT /evidence="ECO:0007829|PDB:4F3L"
FT STRAND 354..359
FT /evidence="ECO:0007829|PDB:4F3L"
FT HELIX 362..367
FT /evidence="ECO:0007829|PDB:4F3L"
FT HELIX 371..374
FT /evidence="ECO:0007829|PDB:4F3L"
FT HELIX 379..381
FT /evidence="ECO:0007829|PDB:4F3L"
FT HELIX 385..398
FT /evidence="ECO:0007829|PDB:4F3L"
FT STRAND 410..413
FT /evidence="ECO:0007829|PDB:4F3L"
FT STRAND 419..431
FT /evidence="ECO:0007829|PDB:4F3L"
FT TURN 432..435
FT /evidence="ECO:0007829|PDB:4F3L"
FT STRAND 436..446
FT /evidence="ECO:0007829|PDB:4F3L"
SQ SEQUENCE 632 AA; 69452 MW; 9669C3712A95C2DE CRC64;
MADQRMDISS TISDFMSPGP TDLLSGSLGT SGVDCNRKRK GSATDYQLDD FAFEESMDTD
KDDPHGRLEY AEHQGRIKNA REAHSQIEKR RRDKMNSFID ELASLVPTCN AMSRKLDKLT
VLRMAVQHMK TLRGATNPYT EANYKPTFLS DDELKHLILR AADGFLFVVG CDRGKILFVS
ESVFKILNYS QNDLIGQSLF DYLHPKDIAK VKEQLSSSDT APRERLIDAK TGLPVKTDIT
PGPSRLCSGA RRSFFCRMKC NRPSVKVEDK DFASTCSKKK DRKSFCTIHS TGYLKSWPPT
KMGLDEDNEP DNEGCNLSCL VAIGRLHSHM VPQPANGEIR VKSMEYVSRH AIDGKFVFVD
QRATAILAYL PQELLGTSCY EYFHQDDIGH LAECHRQVLQ TREKITTNCY KFKIKDGSFI
TLRSRWFSFM NPWTKEVEYI VSTNTVVLAN VLEGGDPTFP QLTAPPHSMD SMLPSGEGGP
KRTHPTVPGI PGGTRAGAGK IGRMIAEEIM EIHRIRGSSP SSCGSSPLNI TSTPPPDASS
PGGKKILNGG TPDIPSTGLL PGQAQETPGY PYSDSSSILG ENPHIGIDMI DNDQGSSSPS
NDEAAMAVIM SLLEADAGLG GPVDFSDLPW PL
