ID BMAL1_HUMAN Reviewed; 626 AA.
AC O00327; A2I2N6; A8K645; B5ME11; B7WPG7; D3DQW6; O00313; O00314; O00315;
AC O00316; O00317; Q4G136; Q8IUT4; Q99631; Q99649;
DT 15-DEC-1998, integrated into UniProtKB/Swiss-Prot.
DT 15-AUG-2003, sequence version 2.
DT 28-JUN-2023, entry version 222.
DE RecName: Full=Basic helix-loop-helix ARNT-like protein 1 {ECO:0000312|HGNC:HGNC:701};
DE AltName: Full=Aryl hydrocarbon receptor nuclear translocator-like protein 1;
DE AltName: Full=Basic-helix-loop-helix-PAS protein MOP3;
DE AltName: Full=Brain and muscle ARNT-like 1;
DE AltName: Full=Class E basic helix-loop-helix protein 5;
DE Short=bHLHe5;
DE AltName: Full=Member of PAS protein 3;
DE AltName: Full=PAS domain-containing protein 3;
DE AltName: Full=bHLH-PAS protein JAP3;
GN Name=BMAL1 {ECO:0000312|HGNC:HGNC:701};
GN Synonyms=ARNTL, BHLHE5, MOP3 {ECO:0000303|PubMed:9576906}, PASD3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], AND ALTERNATIVE SPLICING
RP (ISOFORMS BMAL1A; BMAL1B; BMAL1C; BMAL1D; BMAL1E AND BMAL1F).
RC TISSUE=Brain;
RX PubMed=9144434; DOI=10.1006/bbrc.1997.6371;
RA Ikeda M., Nomura M.;
RT "cDNA cloning and tissue-specific expression of a novel basic helix-loop-
RT helix/PAS protein (BMAL1) and identification of alternatively spliced
RT variants with alternative translation initiation site usage.";
RL Biochem. Biophys. Res. Commun. 233:258-264(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM MOP3), AND INTERACTION WITH HSP90 AND
RP AHR.
RC TISSUE=Fetal brain;
RX PubMed=9079689; DOI=10.1074/jbc.272.13.8581;
RA Hogenesch J.B., Chan W.K., Jackiw V.H., Brown R.C., Gu Y.-Z.,
RA Pray-Grant M., Perdew G.H., Bradfield C.A.;
RT "Characterization of a subset of the basic-helix-loop-helix-PAS superfamily
RT that interacts with components of the dioxin signaling pathway.";
RL J. Biol. Chem. 272:8581-8593(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM BMAL1B).
RA Tian H., Russell D.W., McKnight S.L.;
RT "JAP3: a novel ARNT-like bHLH-PAS protein.";
RL Submitted (DEC-1996) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM BMAL1B).
RX PubMed=9576906; DOI=10.1073/pnas.95.10.5474;
RA Hogenesch J.B., Gu Y.Z., Jain S., Bradfield C.A.;
RT "The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active
RT complexes with circadian and hypoxia factors.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:5474-5479(1998).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS BMAL1B AND 9).
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Kripke D.F., Klimecki W.;
RT "ARNTL resequence.";
RL Submitted (SEP-2006) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 8 AND BMAL1A).
RC TISSUE=Brain, and Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
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 [11]
RP FUNCTION, DNA-BINDING, AND ACTIVITY REGULATION.
RX PubMed=11441146; DOI=10.1126/science.1060698;
RA Rutter J., Reick M., Wu L.C., McKnight S.L.;
RT "Regulation of clock and NPAS2 DNA binding by the redox state of NAD
RT cofactors.";
RL Science 293:510-514(2001).
RN [12]
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 [13]
RP INTERACTION WITH KAT2B AND EP300.
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 [14]
RP MUTAGENESIS OF SER-9; SER-10; ALA-611 AND GLY-612.
RX PubMed=16474406; DOI=10.1038/ng1745;
RA Sato T.K., Yamada R.G., Ukai H., Baggs J.E., Miraglia L.J., Kobayashi T.J.,
RA Welsh D.K., Kay S.A., Ueda H.R., Hogenesch J.B.;
RT "Feedback repression is required for mammalian circadian clock function.";
RL Nat. Genet. 38:312-319(2006).
RN [15]
RP FUNCTION.
RX PubMed=18587630; DOI=10.1007/s11010-008-9846-x;
RA Li R., Yue J., Zhang Y., Zhou L., Hao W., Yuan J., Qiang B., Ding J.M.,
RA Peng X., Cao J.M.;
RT "CLOCK/BMAL1 regulates human nocturnin transcription through binding to the
RT E-box of nocturnin promoter.";
RL Mol. Cell. Biochem. 317:169-177(2008).
RN [16]
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 [17]
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 [18]
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 [19]
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 [20]
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 [21]
RP 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 [22]
RP FUNCTION IN HAIR GROWTH, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=24005054; DOI=10.1038/jid.2013.366;
RA Al-Nuaimi Y., Hardman J.A., Biro T., Haslam I.S., Philpott M.P., Toth B.I.,
RA Farjo N., Farjo B., Baier G., Watson R.E., Grimaldi B., Kloepper J.E.,
RA Paus R.;
RT "A meeting of two chronobiological systems: circadian proteins Period1 and
RT BMAL1 modulate the human hair cycle clock.";
RL J. Invest. Dermatol. 134:610-619(2014).
RN [23]
RP INTERACTION WITH UBE3A, UBIQUITINATION, AND PROTEASOMAL DEGRADATION.
RX PubMed=24728990; DOI=10.1093/nar/gku225;
RA Gossan N.C., Zhang F., Guo B., Jin D., Yoshitane H., Yao A., Glossop N.,
RA Zhang Y.Q., Fukada Y., Meng Q.J.;
RT "The E3 ubiquitin ligase UBE3A is an integral component of the molecular
RT circadian clock through regulating the BMAL1 transcription factor.";
RL Nucleic Acids Res. 42:5765-5775(2014).
RN [24]
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 [25]
RP INTERACTION WITH PASD1.
RX PubMed=25936801; DOI=10.1016/j.molcel.2015.03.031;
RA Michael A.K., Harvey S.L., Sammons P.J., Anderson A.P., Kopalle H.M.,
RA Banham A.H., Partch C.L.;
RT "Cancer/testis antigen PASD1 silences the circadian clock.";
RL Mol. Cell 58:743-754(2015).
RN [26]
RP FUNCTION, AND INTERACTION WITH CLOCK.
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 [27]
RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-259, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=28112733; DOI=10.1038/nsmb.3366;
RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C.,
RA Nielsen M.L.;
RT "Site-specific mapping of the human SUMO proteome reveals co-modification
RT with phosphorylation.";
RL Nat. Struct. Mol. Biol. 24:325-336(2017).
RN [28]
RP INTERACTION WITH PIWIL2.
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 [29]
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 [30]
RP INTERACTION WITH HNF4A.
RX PubMed=30530698; DOI=10.1073/pnas.1816411115;
RA Qu M., Duffy T., Hirota T., Kay S.A.;
RT "Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modulates tissue-
RT specific circadian networks.";
RL Proc. Natl. Acad. Sci. U.S.A. 115:E12305-E12312(2018).
RN [31]
RP FUNCTION (MICROBIAL INFECTION).
RX PubMed=34545347; DOI=10.1016/j.isci.2021.103144;
RA Zhuang X., Tsukuda S., Wrensch F., Wing P.A.C., Schilling M., Harris J.M.,
RA Borrmann H., Morgan S.B., Cane J.L., Mailly L., Thakur N., Conceicao C.,
RA Sanghani H., Heydmann L., Bach C., Ashton A., Walsh S., Tan T.K.,
RA Schimanski L., Huang K.A., Schuster C., Watashi K., Hinks T.S.C.,
RA Jagannath A., Vausdevan S.R., Bailey D., Baumert T.F., McKeating J.A.;
RT "The circadian clock component BMAL1 regulates SARS-CoV-2 entry and
RT replication in lung epithelial cells.";
RL IScience 24:103144-103144(2021).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 66-128 IN COMPLEX WITH CLOCK AND
RP DNA, FUNCTION, ACTIVITY REGULATION, SUBUNIT, PHOSPHORYLATION AT SER-78, AND
RP MUTAGENESIS OF SER-78; MET-88; SER-90 AND LEU-125.
RX PubMed=23229515; DOI=10.1038/cr.2012.170;
RA Wang Z., Wu Y., Li L., Su X.D.;
RT "Intermolecular recognition revealed by the complex structure of human
RT CLOCK-BMAL1 basic helix-loop-helix domains with E-box DNA.";
RL Cell Res. 23:213-224(2013).
CC -!- FUNCTION: Transcriptional activator which forms a core component of the
CC circadian clock. The circadian clock, an internal time-keeping system,
CC regulates various physiological processes through the generation of
CC approximately 24 hour circadian rhythms in gene expression, which are
CC translated into rhythms in metabolism and behavior. It is derived from
CC the Latin roots 'circa' (about) and 'diem' (day) and acts as an
CC important regulator of a wide array of physiological functions
CC including metabolism, sleep, body temperature, blood pressure,
CC endocrine, immune, cardiovascular, and renal function. Consists of two
CC major components: the central clock, residing in the suprachiasmatic
CC nucleus (SCN) of the brain, and the peripheral clocks that are present
CC in nearly every tissue and organ system. Both the central and
CC peripheral clocks can be reset by environmental cues, also known as
CC Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the
CC central clock is light, which is sensed by retina and signals directly
CC to the SCN. The central clock entrains the peripheral clocks through
CC neuronal and hormonal signals, body temperature and feeding-related
CC cues, aligning all clocks with the external light/dark cycle. Circadian
CC rhythms allow an organism to achieve temporal homeostasis with its
CC environment at the molecular level by regulating gene expression to
CC create a peak of protein expression once every 24 hours to control when
CC a particular physiological process is most active with respect to the
CC solar day. Transcription and translation of core clock components
CC (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a
CC critical role in rhythm generation, whereas delays imposed by post-
CC translational modifications (PTMs) are important for determining the
CC period (tau) of the rhythms (tau refers to the period of a rhythm and
CC is the length, in time, of one complete cycle). A diurnal rhythm is
CC synchronized with the day/night cycle, while the ultradian and
CC infradian rhythms have a period shorter and longer than 24 hours,
CC respectively. Disruptions in the circadian rhythms contribute to the
CC pathology of cardiovascular diseases, cancer, metabolic syndromes and
CC aging. A transcription/translation feedback loop (TTFL) forms the core
CC of the molecular circadian clock mechanism. Transcription factors,
CC CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the
CC feedback loop, act in the form of a heterodimer and activate the
CC transcription of core clock genes and clock-controlled genes (involved
CC in key metabolic processes), harboring E-box elements (5'-CACGTG-3')
CC within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which
CC are transcriptional repressors form the negative limb of the feedback
CC loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer
CC inhibiting its activity and thereby negatively regulating their own
CC expression. This heterodimer also activates nuclear receptors NR1D1/2
CC and RORA/B/G, which form a second feedback loop and which activate and
CC repressBMAL1 transcription, respectively.BMAL1 positively regulates
CC myogenesis and negatively regulates adipogenesis via the
CC transcriptional control of the genes of the canonical Wnt signaling
CC pathway. Plays a role in normal pancreatic beta-cell function;
CC regulates glucose-stimulated insulin secretion via the regulation of
CC antioxidant genes NFE2L2/NRF2 and its targets SESN2, PRDX3, CCLC and
CC CCLM. Negatively regulates the mTORC1 signaling pathway; regulates the
CC expression of MTOR and DEPTOR. Controls diurnal oscillations of Ly6C
CC inflammatory monocytes; rhythmic recruitment of the PRC2 complex
CC imparts diurnal variation to chemokine expression that is necessary to
CC sustain Ly6C monocyte rhythms. Regulates the expression of HSD3B2,
CC STAR, PTGS2, CYP11A1, CYP19A1 and LHCGR in the ovary and also the genes
CC involved in hair growth. Plays an important role in adult hippocampal
CC neurogenesis by regulating the timely entry of neural stem/progenitor
CC cells (NSPCs) into the cell cycle and the number of cell divisions that
CC take place prior to cell-cycle exit. Regulates the circadian expression
CC of CIART and KLF11. The CLOCK-BMAL1 heterodimer regulates the circadian
CC expression of SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1,
CC PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4,
CC MTA1, KLF10 and also genes implicated in glucose and lipid metabolism.
CC Promotes rhythmic chromatin opening, regulating the DNA accessibility
CC of other transcription factors. The NPAS2-BMAL1 heterodimer positively
CC regulates the expression of MAOA, F7 and LDHA and modulates the
CC circadian rhythm of daytime contrast sensitivity by regulating the
CC rhythmic expression of adenylate cyclase type 1 (ADCY1) in the retina.
CC The preferred binding motif for the CLOCK-BMAL1 heterodimer is 5'-
CC CACGTGA-3', which contains a flanking Ala residue in addition to the
CC canonical 6-nucleotide E-box sequence (PubMed:23229515). CLOCK
CC specifically binds to the half-site 5'-CAC-3', while BMAL1 binds to the
CC half-site 5'-GTGA-3' (PubMed:23229515). The CLOCK-BMAL1 heterodimer
CC also recognizes the non-canonical E-box motifs 5'-AACGTGA-3' and 5'-
CC CATGTGA-3' (PubMed:23229515). Essential for the rhythmic interaction of
CC CLOCK with ASS1 and plays a critical role in positively regulating
CC CLOCK-mediated acetylation of ASS1 (PubMed:28985504). Plays a role in
CC protecting against lethal sepsis by limiting the expression of immune
CC checkpoint protein CD274 in macrophages in a PKM2-dependent manner (By
CC similarity). Regulates the diurnal rhythms of skeletal muscle
CC metabolism via transcriptional activation of genes promoting
CC triglyceride synthesis (DGAT2) and metabolic efficiency (COQ10B) (By
CC similarity). {ECO:0000250|UniProtKB:Q9WTL8,
CC ECO:0000269|PubMed:11441146, ECO:0000269|PubMed:12738229,
CC ECO:0000269|PubMed:18587630, ECO:0000269|PubMed:23785138,
CC ECO:0000269|PubMed:23955654, ECO:0000269|PubMed:24005054,
CC ECO:0000269|PubMed:28985504}.
CC -!- FUNCTION: (Microbial infection) Regulates SARS coronavirus-2/SARS-CoV-2
CC entry and replication in lung epithelial cells probably through the
CC post-transcriptional regulation of ACE2 and interferon-stimulated gene
CC expression. {ECO:0000269|PubMed:34545347}.
CC -!- ACTIVITY REGULATION: There is conflicting data about the effect of NAD
CC cofactors on activity. PubMed:11441146 suggests that the redox state of
CC the cell can modulate the transcriptional activity of the CLOCK-BMAL1
CC heterodimer; NADH and NADPH enhance the DNA-binding activity of the
CC heterodimer. PubMed:23229515 reports that NADH and NADPH have no
CC significant effect on DNA-binding activity of the CLOCK-BMAL1
CC heterodimer. {ECO:0000269|PubMed:11441146,
CC ECO:0000269|PubMed:23229515}.
CC -!- SUBUNIT: Component of the circadian clock oscillator which includes the
CC CRY1/2 proteins, CLOCK or NPAS2,BMAL1 or BMAL2, CSNK1D and/or CSNK1E,
CC TIMELESS and the PER1/2/3 proteins (By similarity). Forms a heterodimer
CC with CLOCK (PubMed:9616112, PubMed:23229515). The CLOCK-BMAL1
CC heterodimer is required for E-box-dependent transactivation, for CLOCK
CC nuclear translocation and degradation, and, for phosphorylation of both
CC CLOCK and BMAL1 (By similarity). Part of a nuclear complex which also
CC includes RACK1 and PRKCA; RACK1 and PRKCA are recruited to the complex
CC in a circadian manner (By similarity). Interacts with NPAS2 (By
CC similarity). Interacts with EZH2 (By similarity). Interacts with SUMO3
CC (By similarity). Interacts with SIRT1 (By similarity). Interacts with
CC AHR (PubMed:9079689). Interacts with ID1, ID2 and ID3 (By similarity).
CC Interacts with DDX4 (By similarity). Interacts with OGT (By
CC similarity). Interacts with EED and SUZ12 (By similarity). Interacts
CC with MTA1 (By similarity). Interacts with CIART (PubMed:24385426).
CC Interacts with HSP90 (PubMed:9079689). Interacts with KAT2B and EP300
CC (PubMed:14645221). Interacts with BHLHE40/DEC1 and BHLHE41/DEC2 (By
CC similarity). Interacts with RELB and the interaction is enhanced in the
CC presence of CLOCK (By similarity). Interacts with PER1, PER2, CRY1 and
CC CRY2 and this interaction requires a translocation to the nucleus (By
CC similarity). Interaction of the CLOCK-BMAL1 heterodimer with PER or CRY
CC inhibits transcription activation (By similarity). Interaction of the
CC CLOCK-BMAL1 with CRY1 is independent of DNA but with PER2 is off DNA
CC (By similarity). The CLOCK-BMAL1 heterodimer interacts with GSK3B (By
CC similarity). Interacts with KDM5A (PubMed:21960634). Interacts with
CC KMT2A; in a circadian manner (By similarity). Interacts with UBE3A
CC (PubMed:24728990). Interacts with PRKCG (By similarity). Interacts with
CC MAGEL2 (By similarity). Interacts with NCOA2 (By similarity). Interacts
CC with THRAP3 (By similarity). The CLOCK-BMAL1 heterodimer interacts with
CC PASD1 (PubMed:25936801). Interacts with PASD1 (PubMed:25936801).
CC Interacts with USP9X (PubMed:29626158). Interacts with PIWIL2 (via PIWI
CC domain) (PubMed:28903391). Interacts with HDAC3 (By similarity).
CC Interacts with HNF4A (PubMed:30530698). {ECO:0000250|UniProtKB:Q9WTL8,
CC ECO:0000269|PubMed:14645221, ECO:0000269|PubMed:21960634,
CC ECO:0000269|PubMed:23229515, ECO:0000269|PubMed:24385426,
CC ECO:0000269|PubMed:24728990, ECO:0000269|PubMed:25936801,
CC ECO:0000269|PubMed:28903391, ECO:0000269|PubMed:28985504,
CC ECO:0000269|PubMed:29626158, ECO:0000269|PubMed:30530698,
CC ECO:0000269|PubMed:9079689, ECO:0000269|PubMed:9616112}.
CC -!- INTERACTION:
CC O00327; O15516: CLOCK; NbExp=4; IntAct=EBI-1794206, EBI-1794265;
CC O00327; D0VY79: HIF1A; NbExp=3; IntAct=EBI-1794206, EBI-10179332;
CC O00327-8; O14977: AZIN1; NbExp=3; IntAct=EBI-11991546, EBI-1054824;
CC O00327-8; O15516: CLOCK; NbExp=6; IntAct=EBI-11991546, EBI-1794265;
CC O00327-8; Q96HY7: DHTKD1; NbExp=3; IntAct=EBI-11991546, EBI-11022401;
CC O00327-8; Q99814: EPAS1; NbExp=3; IntAct=EBI-11991546, EBI-447470;
CC O00327-8; Q99743: NPAS2; NbExp=10; IntAct=EBI-11991546, EBI-3932727;
CC O00327-8; Q8WVT3: TRAPPC12; NbExp=3; IntAct=EBI-11991546, EBI-2819919;
CC O00327-8; Q9H0C1: ZMYND12; NbExp=5; IntAct=EBI-11991546, EBI-12030590;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00981,
CC ECO:0000269|PubMed:24005054}. Cytoplasm {ECO:0000250|UniProtKB:Q9WTL8}.
CC Nucleus, PML body {ECO:0000250|UniProtKB:Q9WTL8}. Note=Shuttles between
CC the nucleus and the cytoplasm and this nucleocytoplasmic shuttling is
CC essential for the nuclear accumulation of CLOCK, target gene
CC transcription and the degradation of the CLOCK-BMAL1 heterodimer. The
CC sumoylated form localizes in the PML body. Sequestered to the cytoplasm
CC in the presence of ID2. {ECO:0000250|UniProtKB:Q9WTL8}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=9;
CC Comment=Additional isoforms seem to exist.;
CC Name=BMAL1B; Synonyms=JAP3;
CC IsoId=O00327-2; Sequence=Displayed;
CC Name=BMAL1A;
CC IsoId=O00327-1; Sequence=VSP_002094;
CC Name=BMAL1C;
CC IsoId=O00327-3; Sequence=VSP_002096, VSP_002097;
CC Name=BMAL1D;
CC IsoId=O00327-4; Sequence=VSP_002098;
CC Name=BMAL1E;
CC IsoId=O00327-5; Sequence=VSP_002099, VSP_002100;
CC Name=BMAL1F;
CC IsoId=O00327-6; Sequence=VSP_002101, VSP_002102;
CC Name=MOP3;
CC IsoId=O00327-7; Sequence=VSP_002095;
CC Name=8;
CC IsoId=O00327-8; Sequence=VSP_035457;
CC Name=9;
CC IsoId=O00327-9; Sequence=VSP_002094, VSP_035457;
CC -!- TISSUE SPECIFICITY: Hair follicles (at protein level). Highly expressed
CC in the adult brain, skeletal muscle and heart.
CC {ECO:0000269|PubMed:24005054}.
CC -!- PTM: Ubiquitinated, leading to its proteasomal degradation
CC (PubMed:24728990). Deubiquitinated by USP9X (PubMed:29626158).
CC {ECO:0000269|PubMed:24728990, ECO:0000269|PubMed:29626158}.
CC -!- PTM: O-glycosylated; contains O-GlcNAc. O-glycosylation by OGT prevents
CC protein degradation by inhibiting ubiquitination. It also stabilizes
CC the CLOCK-BMAL1 heterodimer thereby increasing CLOCK-BMAL1-mediated
CC transcription of genes in the negative loop of the circadian clock such
CC as PER1/2/3 and CRY1/2. {ECO:0000250|UniProtKB:Q9WTL8}.
CC -!- PTM: Acetylated on Lys-538 by CLOCK during the repression phase of the
CC circadian cycle. Acetylation facilitates recruitment of CRY1 protein
CC and initiates the repression phase of the circadian cycle. Acetylated
CC at Lys-538 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 Deacetylated by SIRT1, which may result in decreased protein stability.
CC {ECO:0000250|UniProtKB:Q9WTL8}.
CC -!- PTM: Phosphorylated upon dimerization with CLOCK. Phosphorylation
CC enhances the transcriptional activity, alters the subcellular
CC localization and decreases the stability of the CLOCK-BMAL1 heterodimer
CC by promoting its degradation. Phosphorylation shows circadian
CC variations in the liver with a peak between CT10 to CT14.
CC Phosphorylation at Ser-90 by CK2 is essential for its nuclear
CC localization, its interaction with CLOCK and controls CLOCK nuclear
CC entry (By similarity). Dephosphorylation at Ser-78 is important for
CC dimerization with CLOCK and transcriptional activity (PubMed:23229515).
CC {ECO:0000250|UniProtKB:Q9WTL8, ECO:0000269|PubMed:23229515}.
CC -!- PTM: Sumoylated on Lys-259 upon dimerization with CLOCK. Predominantly
CC conjugated to poly-SUMO2/3 rather than SUMO1 and the level of these
CC conjugates undergo rhythmic variation, peaking at CT9-CT12. Sumoylation
CC localizes it exclusively to the PML body and promotes its
CC ubiquitination in the PML body, ubiquitin-dependent proteasomal
CC degradation and the transcriptional activity of the CLOCK-BMAL1
CC heterodimer. {ECO:0000250|UniProtKB:Q9WTL8}.
CC -!- PTM: Undergoes lysosome-mediated degradation in a time-dependent manner
CC in the liver. {ECO:0000250|UniProtKB:Q9WTL8}.
CC -!- MISCELLANEOUS: CLOCK-BMAL1 double mutations within the PAS domains
CC result in synergistic desensitization to high levels of CRY on
CC repression of CLOCK-BMAL1 transcriptional activity of PER1 and, disrupt
CC circadian rhythmicity.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; D89722; BAA19968.1; -; mRNA.
DR EMBL; AB000812; BAA19935.1; -; mRNA.
DR EMBL; AB000813; BAA19936.1; -; Genomic_DNA.
DR EMBL; AB000814; BAA19937.1; -; mRNA.
DR EMBL; AB000815; BAA19938.1; -; mRNA.
DR EMBL; AB000816; BAA19939.1; -; mRNA.
DR EMBL; U51627; AAC51213.1; -; mRNA.
DR EMBL; U60415; AAB37248.1; -; mRNA.
DR EMBL; AF044288; AAC24353.1; -; mRNA.
DR EMBL; AK095749; BAG53120.1; -; mRNA.
DR EMBL; AK291510; BAF84199.1; -; mRNA.
DR EMBL; EF015894; ABM64205.1; -; Genomic_DNA.
DR EMBL; AC016884; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC022878; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471064; EAW68504.1; -; Genomic_DNA.
DR EMBL; CH471064; EAW68505.1; -; Genomic_DNA.
DR EMBL; CH471064; EAW68510.1; -; Genomic_DNA.
DR EMBL; CH471064; EAW68511.1; -; Genomic_DNA.
DR EMBL; CH471064; EAW68513.1; -; Genomic_DNA.
DR EMBL; BC016674; AAH16674.1; -; mRNA.
DR EMBL; BC031214; AAH31214.1; -; mRNA.
DR EMBL; BC041129; AAH41129.2; -; mRNA.
DR CCDS; CCDS44543.1; -. [O00327-9]
DR CCDS; CCDS73259.1; -. [O00327-2]
DR PIR; JC5405; JC5405.
DR PIR; JC5407; JC5407.
DR PIR; PC4288; PC4288.
DR PIR; PC4289; PC4289.
DR RefSeq; NP_001025443.1; NM_001030272.2. [O00327-8]
DR RefSeq; NP_001025444.1; NM_001030273.2. [O00327-9]
DR RefSeq; NP_001169.3; NM_001178.5. [O00327-8]
DR RefSeq; NP_001284648.1; NM_001297719.1. [O00327-2]
DR RefSeq; NP_001284651.1; NM_001297722.1. [O00327-2]
DR RefSeq; NP_001284653.1; NM_001297724.1. [O00327-1]
DR RefSeq; XP_011518414.1; XM_011520112.2.
DR RefSeq; XP_011518415.1; XM_011520113.1.
DR RefSeq; XP_016873231.1; XM_017017742.1.
DR RefSeq; XP_016873232.1; XM_017017743.1.
DR RefSeq; XP_016873235.1; XM_017017746.1.
DR RefSeq; XP_016873236.1; XM_017017747.1.
DR RefSeq; XP_016873237.1; XM_017017748.1.
DR PDB; 4H10; X-ray; 2.40 A; A=66-128.
DR PDBsum; 4H10; -.
DR AlphaFoldDB; O00327; -.
DR SMR; O00327; -.
DR BioGRID; 106899; 102.
DR ComplexPortal; CPX-3229; CLOCK-BMAL1 transcription complex.
DR CORUM; O00327; -.
DR DIP; DIP-46008N; -.
DR IntAct; O00327; 24.
DR MINT; O00327; -.
DR STRING; 9606.ENSP00000384517; -.
DR GlyCosmos; O00327; 1 site, 1 glycan.
DR GlyGen; O00327; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; O00327; -.
DR PhosphoSitePlus; O00327; -.
DR BioMuta; ARNTL; -.
DR EPD; O00327; -.
DR jPOST; O00327; -.
DR MassIVE; O00327; -.
DR MaxQB; O00327; -.
DR PaxDb; O00327; -.
DR PeptideAtlas; O00327; -.
DR ProteomicsDB; 47841; -. [O00327-2]
DR ProteomicsDB; 47842; -. [O00327-1]
DR ProteomicsDB; 47843; -. [O00327-3]
DR ProteomicsDB; 47844; -. [O00327-4]
DR ProteomicsDB; 47845; -. [O00327-5]
DR ProteomicsDB; 47846; -. [O00327-6]
DR ProteomicsDB; 47847; -. [O00327-7]
DR ProteomicsDB; 47848; -. [O00327-8]
DR ProteomicsDB; 47849; -. [O00327-9]
DR Antibodypedia; 11861; 609 antibodies from 45 providers.
DR DNASU; 406; -.
DR Ensembl; ENST00000389707.8; ENSP00000374357.4; ENSG00000133794.20. [O00327-8]
DR Ensembl; ENST00000401424.6; ENSP00000385915.2; ENSG00000133794.20. [O00327-9]
DR Ensembl; ENST00000403290.6; ENSP00000384517.1; ENSG00000133794.20. [O00327-2]
DR Ensembl; ENST00000403482.7; ENSP00000385897.3; ENSG00000133794.20. [O00327-7]
DR Ensembl; ENST00000403510.8; ENSP00000385581.4; ENSG00000133794.20. [O00327-2]
DR Ensembl; ENST00000529388.6; ENSP00000433571.2; ENSG00000133794.20. [O00327-2]
DR GeneID; 406; -.
DR KEGG; hsa:406; -.
DR MANE-Select; ENST00000403290.6; ENSP00000384517.1; NM_001297719.2; NP_001284648.1.
DR UCSC; uc001mko.4; human. [O00327-2]
DR AGR; HGNC:701; -.
DR CTD; 406; -.
DR DisGeNET; 406; -.
DR GeneCards; BMAL1; -.
DR HGNC; HGNC:701; BMAL1.
DR HPA; ENSG00000133794; Low tissue specificity.
DR MIM; 602550; gene.
DR neXtProt; NX_O00327; -.
DR OpenTargets; ENSG00000133794; -.
DR PharmGKB; PA24996; -.
DR VEuPathDB; HostDB:ENSG00000133794; -.
DR eggNOG; KOG3561; Eukaryota.
DR GeneTree; ENSGT00940000157523; -.
DR HOGENOM; CLU_011864_2_2_1; -.
DR InParanoid; O00327; -.
DR OMA; YHHEDIP; -.
DR PhylomeDB; O00327; -.
DR TreeFam; TF319983; -.
DR PathwayCommons; O00327; -.
DR Reactome; R-HSA-1368108; BMAL1:CLOCK,NPAS2 activates circadian gene expression.
DR Reactome; R-HSA-1989781; PPARA activates gene expression.
DR Reactome; R-HSA-400253; Circadian Clock.
DR Reactome; R-HSA-9707616; Heme signaling.
DR Reactome; R-HSA-9768919; NPAS4 regulates expression of target genes.
DR SignaLink; O00327; -.
DR SIGNOR; O00327; -.
DR BioGRID-ORCS; 406; 10 hits in 1167 CRISPR screens.
DR ChiTaRS; ARNTL; human.
DR GeneWiki; ARNTL; -.
DR GenomeRNAi; 406; -.
DR Pharos; O00327; Tbio.
DR PRO; PR:O00327; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; O00327; protein.
DR Bgee; ENSG00000133794; Expressed in left ovary and 188 other tissues.
DR ExpressionAtlas; O00327; baseline and differential.
DR Genevisible; O00327; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0033391; C:chromatoid body; ISS:UniProtKB.
DR GO; GO:1990513; C:CLOCK-BMAL transcription complex; IPI:ComplexPortal.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0016605; C:PML body; IEA:UniProtKB-SubCell.
DR GO; GO:0017162; F:aryl hydrocarbon receptor binding; IPI:BHF-UCL.
DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISS:BHF-UCL.
DR GO; GO:0140297; F:DNA-binding transcription factor binding; IPI:GO_Central.
DR GO; GO:0070888; F:E-box binding; IDA:UniProtKB.
DR GO; GO:0051879; F:Hsp90 protein binding; IDA:BHF-UCL.
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; ISS:UniProtKB.
DR GO; GO:0043565; F:sequence-specific DNA binding; ISS:UniProtKB.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; ISS:UniProtKB.
DR GO; GO:0032922; P:circadian regulation of gene expression; IDA:UniProtKB.
DR GO; GO:0007623; P:circadian rhythm; IBA:GO_Central.
DR GO; GO:0120163; P:negative regulation of cold-induced thermogenesis; ISS:YuBioLab.
DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; ISS:UniProtKB.
DR GO; GO:0045599; P:negative regulation of fat cell differentiation; ISS:UniProtKB.
DR GO; GO:2000323; P:negative regulation of glucocorticoid receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0032007; P:negative regulation of TOR signaling; ISS:UniProtKB.
DR GO; GO:0090403; P:oxidative stress-induced premature senescence; ISS:UniProtKB.
DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; ISS:UniProtKB.
DR GO; GO:0042753; P:positive regulation of circadian rhythm; IDA:ComplexPortal.
DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB.
DR GO; GO:1901985; P:positive regulation of protein acetylation; IMP:UniProtKB.
DR GO; GO:2001016; P:positive regulation of skeletal muscle cell differentiation; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:BHF-UCL.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR GO; GO:0051726; P:regulation of cell cycle; ISS:UniProtKB.
DR GO; GO:2000772; P:regulation of cellular senescence; ISS:UniProtKB.
DR GO; GO:0006355; P:regulation of DNA-templated transcription; ISS:UniProtKB.
DR GO; GO:0042634; P:regulation of hair cycle; IMP:UniProtKB.
DR GO; GO:0050796; P:regulation of insulin secretion; ISS:UniProtKB.
DR GO; GO:0050767; P:regulation of neurogenesis; ISS:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:2000074; P:regulation of type B pancreatic cell development; ISS:UniProtKB.
DR GO; GO:0051775; P:response to redox state; IDA:UniProtKB.
DR GO; GO:0007283; P:spermatogenesis; ISS:UniProtKB.
DR CDD; cd11438; bHLH-PAS_ARNTL_PASD3; 1.
DR CDD; cd00130; PAS; 2.
DR Gene3D; 4.10.280.10; Helix-loop-helix DNA-binding domain; 1.
DR Gene3D; 3.30.450.20; PAS domain; 2.
DR IDEAL; IID00426; -.
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 PANTHER; PTHR23042:SF52; ARYL HYDROCARBON RECEPTOR NUCLEAR TRANSLOCATOR-LIKE PROTEIN 1; 1.
DR PANTHER; PTHR23042; CIRCADIAN PROTEIN CLOCK/ARNT/BMAL/PAS; 1.
DR Pfam; PF00010; HLH; 1.
DR Pfam; PF00989; PAS; 1.
DR Pfam; PF14598; PAS_11; 1.
DR PRINTS; PR00785; NCTRNSLOCATR.
DR SMART; SM00353; HLH; 1.
DR SMART; SM00086; PAC; 1.
DR SMART; SM00091; PAS; 2.
DR SUPFAM; SSF47459; HLH, helix-loop-helix DNA-binding domain; 1.
DR SUPFAM; SSF55785; PYP-like sensor domain (PAS domain); 2.
DR 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; Isopeptide bond; Nucleus;
KW Phosphoprotein; Reference proteome; Repeat; Transcription;
KW Transcription regulation; Ubl conjugation.
FT CHAIN 1..626
FT /note="Basic helix-loop-helix ARNT-like protein 1"
FT /id="PRO_0000127156"
FT DOMAIN 72..125
FT /note="bHLH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981"
FT DOMAIN 143..215
FT /note="PAS 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140"
FT DOMAIN 326..396
FT /note="PAS 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140"
FT DOMAIN 401..444
FT /note="PAC"
FT REGION 1..60
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 458..493
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 508..588
FT /note="Interaction with CIART"
FT /evidence="ECO:0000250|UniProtKB:Q9WTL8"
FT REGION 511..595
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 36..41
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250|UniProtKB:Q9WTL8"
FT MOTIF 142..152
FT /note="Nuclear export signal 1"
FT /evidence="ECO:0000250|UniProtKB:Q9WTL8"
FT MOTIF 361..369
FT /note="Nuclear export signal 2"
FT /evidence="ECO:0000250|UniProtKB:Q9WTL8"
FT COMPBIAS 1..37
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 38..60
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 512..532
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 548..574
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 77
FT /note="Interaction with E-box DNA"
FT /evidence="ECO:0000269|PubMed:23229515"
FT SITE 80
FT /note="Interaction with E-box DNA"
FT /evidence="ECO:0000269|PubMed:23229515"
FT SITE 81
FT /note="Interaction with E-box DNA"
FT /evidence="ECO:0000269|PubMed:23229515"
FT SITE 85
FT /note="Interaction with E-box DNA"
FT /evidence="ECO:0000269|PubMed:23229515"
FT SITE 125
FT /note="Important for interaction with CLOCK"
FT /evidence="ECO:0000269|PubMed:23229515"
FT MOD_RES 17
FT /note="Phosphoserine; by GSK3-beta"
FT /evidence="ECO:0000250|UniProtKB:Q9WTL8"
FT MOD_RES 21
FT /note="Phosphothreonine; by GSK3-beta"
FT /evidence="ECO:0000250|UniProtKB:Q9WTL8"
FT MOD_RES 78
FT /note="Phosphoserine"
FT /evidence="ECO:0000305|PubMed:23229515"
FT MOD_RES 90
FT /note="Phosphoserine; by CK2"
FT /evidence="ECO:0000250|UniProtKB:Q9WTL8"
FT MOD_RES 538
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9WTL8"
FT CROSSLNK 252
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2 and SUMO3)"
FT /evidence="ECO:0000250|UniProtKB:Q9WTL8"
FT CROSSLNK 259
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:28112733"
FT VAR_SEQ 1..59
FT /note="MADQRMDISSTISDFMSPGPTDLLSSSLGTSGVDCNRKRKGSSTDYQESMDT
FT DKDDPHG -> MSKEAVSLWALTVSLQPPVPLCVCREMTGSGRRKQQCVTLPFISRELC
FT FYLLLFPPP (in isoform MOP3)"
FT /evidence="ECO:0000303|PubMed:9079689"
FT /id="VSP_002095"
FT VAR_SEQ 1..47
FT /note="MADQRMDISSTISDFMSPGPTDLLSSSLGTSGVDCNRKRKGSSTDYQ -> M
FT INI (in isoform BMAL1A and isoform 9)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_002094"
FT VAR_SEQ 224
FT /note="T -> R (in isoform BMAL1C)"
FT /evidence="ECO:0000305"
FT /id="VSP_002096"
FT VAR_SEQ 225..626
FT /note="Missing (in isoform BMAL1C)"
FT /evidence="ECO:0000305"
FT /id="VSP_002097"
FT VAR_SEQ 274..391
FT /note="Missing (in isoform BMAL1D)"
FT /evidence="ECO:0000305"
FT /id="VSP_002098"
FT VAR_SEQ 274
FT /note="Missing (in isoform 8 and isoform 9)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_035457"
FT VAR_SEQ 278..301
FT /note="SFCTIHSTGYLKSWPPTKMGLDED -> AFCTIHSTGYFGIFTTRTSRHIVL
FT (in isoform BMAL1E)"
FT /evidence="ECO:0000305"
FT /id="VSP_002099"
FT VAR_SEQ 302..626
FT /note="Missing (in isoform BMAL1E)"
FT /evidence="ECO:0000305"
FT /id="VSP_002100"
FT VAR_SEQ 443..526
FT /note="ANVLEGGDPTFPQLTASPHSMDSMLPSGEGGPKRTHPTVPGIPGGTRAGAGK
FT IGRMIAEEIMEIHRIRGSSPSSCGSSPLNITS -> SRVDTGHLGQVERCTVLSRPNSR
FT FLIAGMFTEPTSWKAGTQPSHSSQHPPTAWTACCPLEKVAQRGPTPLFQGFQGEPGLGQ
FT EK (in isoform BMAL1F)"
FT /evidence="ECO:0000305"
FT /id="VSP_002101"
FT VAR_SEQ 527..626
FT /note="Missing (in isoform BMAL1F)"
FT /evidence="ECO:0000305"
FT /id="VSP_002102"
FT MUTAGEN 9
FT /note="S->A,E: Enhanced PER1 reporter activity by CLOCK-
FT BMAL1."
FT /evidence="ECO:0000269|PubMed:16474406"
FT MUTAGEN 9
FT /note="S->F: 2-2.5-fold increase in CLOCK-BMAL1
FT transcriptional activity in the absence of CRY1. No change
FT in repression activity in the presence of CRY1."
FT /evidence="ECO:0000269|PubMed:16474406"
FT MUTAGEN 10
FT /note="S->A,E: Enhanced PER1 reporter activity by CLOCK-
FT BMAL1."
FT /evidence="ECO:0000269|PubMed:16474406"
FT MUTAGEN 10
FT /note="S->L: 2-2.5-fold increase in CLOCK-BMAL1
FT transcriptional activity in the absence of CRY1. No change
FT in repression activity in the presence of CRY1."
FT /evidence="ECO:0000269|PubMed:16474406"
FT MUTAGEN 78
FT /note="S->E: Phosphomimetic mutant which severely impairs
FT DNA binding and CLOCK-BMAL1 transcriptional activity."
FT /evidence="ECO:0000269|PubMed:23229515"
FT MUTAGEN 88
FT /note="M->F: No effect on CLOCK binding."
FT /evidence="ECO:0000269|PubMed:23229515"
FT MUTAGEN 90
FT /note="S->E: Phosphomimetic mutant with no effect on DNA
FT binding or CLOCK-BMAL1 transcriptional activity."
FT /evidence="ECO:0000269|PubMed:23229515"
FT MUTAGEN 125
FT /note="L->H: Impaired CLOCK binding."
FT /evidence="ECO:0000269|PubMed:23229515"
FT MUTAGEN 611
FT /note="A->S,T: Increased desensitization to CRY1, in the
FT presence of CLOCK. Approximately 2-fold increase in CLOCK-
FT BMAL1 transcriptional activity in the absence of CRY1; when
FT associated with E-407."
FT /evidence="ECO:0000269|PubMed:16474406"
FT MUTAGEN 612
FT /note="G->E: Increased desensitization to CRY1, in the
FT presence of CLOCK. Approximately 2-fold increase in CLOCK-
FT BMAL1 transcriptional activity in the absence of CRY1."
FT /evidence="ECO:0000269|PubMed:16474406"
FT CONFLICT 69
FT /note="R -> G (in Ref. 2; AAC51213)"
FT /evidence="ECO:0000305"
FT CONFLICT 123
FT /note="K -> R (in Ref. 1; BAA19935)"
FT /evidence="ECO:0000305"
FT CONFLICT 173
FT /note="S -> P (in Ref. 1; BAA19939)"
FT /evidence="ECO:0000305"
FT CONFLICT 259
FT /note="K -> N (in Ref. 1; BAA19938)"
FT /evidence="ECO:0000305"
FT CONFLICT 264
FT /note="D -> N (in Ref. 1; BAA19938)"
FT /evidence="ECO:0000305"
FT CONFLICT 418
FT /note="S -> N (in Ref. 1; BAA19937)"
FT /evidence="ECO:0000305"
FT CONFLICT 513..514
FT /note="SP -> LR (in Ref. 2; AAC51213)"
FT /evidence="ECO:0000305"
FT HELIX 71..98
FT /evidence="ECO:0007829|PDB:4H10"
FT HELIX 100..103
FT /evidence="ECO:0007829|PDB:4H10"
FT HELIX 111..125
FT /evidence="ECO:0007829|PDB:4H10"
SQ SEQUENCE 626 AA; 68762 MW; 820F0E07DC6265A6 CRC64;
MADQRMDISS TISDFMSPGP TDLLSSSLGT SGVDCNRKRK GSSTDYQESM DTDKDDPHGR
LEYTEHQGRI KNAREAHSQI EKRRRDKMNS FIDELASLVP TCNAMSRKLD KLTVLRMAVQ
HMKTLRGATN PYTEANYKPT FLSDDELKHL ILRAADGFLF VVGCDRGKIL FVSESVFKIL
NYSQNDLIGQ SLFDYLHPKD IAKVKEQLSS SDTAPRERLI DAKTGLPVKT DITPGPSRLC
SGARRSFFCR MKCNRPSVKV EDKDFPSTCS KKKADRKSFC TIHSTGYLKS WPPTKMGLDE
DNEPDNEGCN LSCLVAIGRL HSHVVPQPVN GEIRVKSMEY VSRHAIDGKF VFVDQRATAI
LAYLPQELLG TSCYEYFHQD DIGHLAECHR QVLQTREKIT TNCYKFKIKD GSFITLRSRW
FSFMNPWTKE VEYIVSTNTV VLANVLEGGD PTFPQLTASP HSMDSMLPSG EGGPKRTHPT
VPGIPGGTRA GAGKIGRMIA EEIMEIHRIR GSSPSSCGSS PLNITSTPPP DASSPGGKKI
LNGGTPDIPS SGLLSGQAQE NPGYPYSDSS SILGENPHIG IDMIDNDQGS SSPSNDEAAM
AVIMSLLEAD AGLGGPVDFS DLPWPL
//