4f3l

Structural highlights

Function

BMAL1_MOUSE Transcriptional activator which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress ARNTL/BMAL1 transcription, respectively. ARNTL/BMAL1 positively regulates myogenesis and negatively regulates adipogenesis via the transcriptional control of the genes of the canonical Wnt signaling pathway. Plays a role in normal pancreatic beta-cell function; regulates glucose-stimulated insulin secretion via the regulation of antioxidant genes NFE2L2/NRF2 and its targets SESN2, PRDX3, CCLC and CCLM. Negatively regulates the mTORC1 signaling pathway; regulates the expression of MTOR and DEPTOR. Controls diurnal oscillations of Ly6C inflammatory monocytes; rhythmic recruitment of the PRC2 complex imparts diurnal variation to chemokine expression that is necessary to sustain Ly6C monocyte rhythms. Regulates the expression of HSD3B2, STAR, PTGS2, CYP11A1, CYP19A1 and LHCGR in the ovary and also the genes involved in hair growth. Plays an important role in adult hippocampal neurogenesis by regulating the timely entry of neural stem/progenitor cells (NSPCs) into the cell cycle and the number of cell divisions that take place prior to cell-cycle exit. Regulates the circadian expression of CIART and KLF11. The CLOCK-ARNTL/BMAL1 heterodimer regulates the circadian expression of SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10 and also genes implicated in glucose and lipid metabolism. Promotes rhythmic chromatin opening, regulating the DNA accessibility of other transcription factors. May play a role in spermatogenesis; contributes to the chromatoid body assembly and physiology. The NPAS2-ARNTL/BMAL1 heterodimer positively regulates the expression of MAOA, F7 and LDHA and modulates the circadian rhythm of daytime contrast sensitivity by regulating the rhythmic expression of adenylate cyclase type 1 (ADCY1) in the retina. The preferred binding motif for the CLOCK-ARNTL/BMAL1 heterodimer is 5'-CACGTGA-3', which contains a flanking Ala residue in addition to the canonical 6-nucleotide E-box sequence (By similarity). CLOCK specifically binds to the half-site 5'-CAC-3', while ARNTL binds to the half-site 5'-GTGA-3' (By similarity). The CLOCK-ARNTL/BMAL1 heterodimer also recognizes the non-canonical E-box motifs 5'-AACGTGA-3' and 5'-CATGTGA-3' (By similarity). Essential for the rhythmic interaction of CLOCK with ASS1 and plays a critical role in positively regulating CLOCK-mediated acetylation of ASS1 (PubMed:28985504). Plays a role in protecting against lethal sepsis by limiting the expression of immune checkpoint protein CD274 in macrophages in a PKM2-dependent manner (PubMed:29996098). Regulates the diurnal rhythms of skeletal muscle metabolism via transcriptional activation of genes promoting triglyceride synthesis (DGAT2) and metabolic efficiency (COQ10B) (PubMed:30096135).[UniProtKB:O00327]^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41]}

References

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3. ↑ Bertolucci C, Cavallari N, Colognesi I, Aguzzi J, Chen Z, Caruso P, Foa A, Tosini G, Bernardi F, Pinotti M. Evidence for an overlapping role of CLOCK and NPAS2 transcription factors in liver circadian oscillators. Mol Cell Biol. 2008 May;28(9):3070-5. doi: 10.1128/MCB.01931-07. Epub 2008 Mar 3. PMID:18316400 doi:http://dx.doi.org/10.1128/MCB.01931-07
4. ↑ Nader N, Chrousos GP, Kino T. Circadian rhythm transcription factor CLOCK regulates the transcriptional activity of the glucocorticoid receptor by acetylating its hinge region lysine cluster: potential physiological implications. FASEB J. 2009 May;23(5):1572-83. doi: 10.1096/fj.08-117697. Epub 2009 Jan 13. PMID:19141540 doi:http://dx.doi.org/10.1096/fj.08-117697
5. ↑ Nakahata Y, Sahar S, Astarita G, Kaluzova M, Sassone-Corsi P. Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. Science. 2009 May 1;324(5927):654-7. doi: 10.1126/science.1170803. Epub 2009 Mar , 12. PMID:19286518 doi:http://dx.doi.org/10.1126/science.1170803
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7. ↑ Sasaki M, Yoshitane H, Du NH, Okano T, Fukada Y. Preferential inhibition of BMAL2-CLOCK activity by PER2 reemphasizes its negative role and a positive role of BMAL2 in the circadian transcription. J Biol Chem. 2009 Sep 11;284(37):25149-59. doi: 10.1074/jbc.M109.040758. Epub, 2009 Jul 15. PMID:19605937 doi:http://dx.doi.org/10.1074/jbc.M109.040758
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13. ↑ Ozber N, Baris I, Tatlici G, Gur I, Kilinc S, Unal EB, Kavakli IH. Identification of two amino acids in the C-terminal domain of mouse CRY2 essential for PER2 interaction. BMC Mol Biol. 2010 Sep 14;11:69. doi: 10.1186/1471-2199-11-69. PMID:20840750 doi:http://dx.doi.org/10.1186/1471-2199-11-69
14. ↑ Andrews JL, Zhang X, McCarthy JJ, McDearmon EL, Hornberger TA, Russell B, Campbell KS, Arbogast S, Reid MB, Walker JR, Hogenesch JB, Takahashi JS, Esser KA. CLOCK and BMAL1 regulate MyoD and are necessary for maintenance of skeletal muscle phenotype and function. Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):19090-5. Epub 2010 Oct 18. PMID:20956306 doi:10.1073/pnas.1014523107
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17. ↑ Lee J, Kim MS, Li R, Liu VY, Fu L, Moore DD, Ma K, Yechoor VK. Loss of Bmal1 leads to uncoupling and impaired glucose-stimulated insulin secretion in beta-cells. Islets. 2011 Nov-Dec;3(6):381-8. doi: 10.4161/isl.3.6.18157. PMID:22045262 doi:http://dx.doi.org/10.4161/isl.3.6.18157
18. ↑ Khapre RV, Kondratova AA, Susova O, Kondratov RV. Circadian clock protein BMAL1 regulates cellular senescence in vivo. Cell Cycle. 2011 Dec 1;10(23):4162-9. doi: 10.4161/cc.10.23.18381. Epub 2011 Dec , 1. PMID:22101268 doi:http://dx.doi.org/10.4161/cc.10.23.18381
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20. ↑ Huang N, Chelliah Y, Shan Y, Taylor CA, Yoo SH, Partch C, Green CB, Zhang H, Takahashi JS. Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional activator complex. Science. 2012 Jul 13;337(6091):189-94. Epub 2012 May 31. PMID:22653727 doi:10.1126/science.1222804
21. ↑ Peruquetti RL, de Mateo S, Sassone-Corsi P. Circadian proteins CLOCK and BMAL1 in the chromatoid body, a RNA processing granule of male germ cells. PLoS One. 2012;7(8):e42695. doi: 10.1371/journal.pone.0042695. Epub 2012 Aug 10. PMID:22900038 doi:http://dx.doi.org/10.1371/journal.pone.0042695
22. ↑ Stratmann M, Suter DM, Molina N, Naef F, Schibler U. Circadian Dbp transcription relies on highly dynamic BMAL1-CLOCK interaction with E boxes and requires the proteasome. Mol Cell. 2012 Oct 26;48(2):277-87. doi: 10.1016/j.molcel.2012.08.012. Epub 2012 , Sep 13. PMID:22981862 doi:http://dx.doi.org/10.1016/j.molcel.2012.08.012
23. ↑ Oishi K, Koyanagi S, Ohkura N. The molecular clock regulates circadian transcription of tissue factor gene. Biochem Biophys Res Commun. 2013 Feb 8;431(2):332-5. doi:, 10.1016/j.bbrc.2012.12.098. Epub 2013 Jan 4. PMID:23291174 doi:http://dx.doi.org/10.1016/j.bbrc.2012.12.098
24. ↑ Chatterjee S, Nam D, Guo B, Kim JM, Winnier GE, Lee J, Berdeaux R, Yechoor VK, Ma K. Brain and muscle Arnt-like 1 is a key regulator of myogenesis. J Cell Sci. 2013 May 15;126(Pt 10):2213-24. doi: 10.1242/jcs.120519. Epub 2013, Mar 22. PMID:23525013 doi:http://dx.doi.org/10.1242/jcs.120519
25. ↑ Lee J, Moulik M, Fang Z, Saha P, Zou F, Xu Y, Nelson DL, Ma K, Moore DD, Yechoor VK. Bmal1 and beta-cell clock are required for adaptation to circadian disruption, and their loss of function leads to oxidative stress-induced beta-cell failure in mice. Mol Cell Biol. 2013 Jun;33(11):2327-38. doi: 10.1128/MCB.01421-12. Epub 2013 Apr , 1. PMID:23547261 doi:http://dx.doi.org/10.1128/MCB.01421-12
26. ↑ Kennaway DJ, Varcoe TJ, Voultsios A, Boden MJ. Global loss of bmal1 expression alters adipose tissue hormones, gene expression and glucose metabolism. PLoS One. 2013 Jun 4;8(6):e65255. doi: 10.1371/journal.pone.0065255. Print 2013. PMID:23750248 doi:http://dx.doi.org/10.1371/journal.pone.0065255
27. ↑ Watabe Y, Tomioka M, Watabe A, Aihara M, Shimba S, Inoue H. The clock gene brain and muscle Arnt-like protein-1 (BMAL1) is involved in hair growth. Arch Dermatol Res. 2013 Oct;305(8):755-61. doi: 10.1007/s00403-013-1403-0. Epub, 2013 Aug 18. PMID:23955654 doi:http://dx.doi.org/10.1007/s00403-013-1403-0
28. ↑ Nguyen KD, Fentress SJ, Qiu Y, Yun K, Cox JS, Chawla A. Circadian gene Bmal1 regulates diurnal oscillations of Ly6C(hi) inflammatory monocytes. Science. 2013 Sep 27;341(6153):1483-8. doi: 10.1126/science.1240636. Epub 2013, Aug 22. PMID:23970558 doi:http://dx.doi.org/10.1126/science.1240636
29. ↑ Hwang CK, Chaurasia SS, Jackson CR, Chan GC, Storm DR, Iuvone PM. Circadian rhythm of contrast sensitivity is regulated by a dopamine-neuronal PAS-domain protein 2-adenylyl cyclase 1 signaling pathway in retinal ganglion cells. J Neurosci. 2013 Sep 18;33(38):14989-97. doi: 10.1523/JNEUROSCI.2039-13.2013. PMID:24048828 doi:http://dx.doi.org/10.1523/JNEUROSCI.2039-13.2013
30. ↑ Li DQ, Pakala SB, Reddy SD, Peng S, Balasenthil S, Deng CX, Lee CC, Rea MA, Kumar R. Metastasis-associated protein 1 is an integral component of the circadian molecular machinery. Nat Commun. 2013;4:2545. doi: 10.1038/ncomms3545. PMID:24089055 doi:http://dx.doi.org/10.1038/ncomms3545
31. ↑ Bouchard-Cannon P, Mendoza-Viveros L, Yuen A, Kaern M, Cheng HY. The circadian molecular clock regulates adult hippocampal neurogenesis by controlling the timing of cell-cycle entry and exit. Cell Rep. 2013 Nov 27;5(4):961-73. doi: 10.1016/j.celrep.2013.10.037. Epub 2013, Nov 21. PMID:24268780 doi:http://dx.doi.org/10.1016/j.celrep.2013.10.037
32. ↑ Musiek ES, Lim MM, Yang G, Bauer AQ, Qi L, Lee Y, Roh JH, Ortiz-Gonzalez X, Dearborn JT, Culver JP, Herzog ED, Hogenesch JB, Wozniak DF, Dikranian K, Giasson BI, Weaver DR, Holtzman DM, Fitzgerald GA. Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration. J Clin Invest. 2013 Dec;123(12):5389-400. doi: 10.1172/JCI70317. Epub 2013 Nov, 25. PMID:24270424 doi:http://dx.doi.org/10.1172/JCI70317
33. ↑ Han DH, Lee YJ, Kim K, Kim CJ, Cho S. Modulation of glucocorticoid receptor induction properties by core circadian clock proteins. Mol Cell Endocrinol. 2014 Mar 5;383(1-2):170-80. doi: 10.1016/j.mce.2013.12.013. , Epub 2013 Dec 27. PMID:24378737 doi:http://dx.doi.org/10.1016/j.mce.2013.12.013
34. ↑ Annayev Y, Adar S, Chiou YY, Lieb JD, Sancar A, Ye R. Gene model 129 (Gm129) encodes a novel transcriptional repressor that modulates circadian gene expression. J Biol Chem. 2014 Feb 21;289(8):5013-24. doi: 10.1074/jbc.M113.534651. Epub 2014 , Jan 2. PMID:24385426 doi:http://dx.doi.org/10.1074/jbc.M113.534651
35. ↑ Menet JS, Pescatore S, Rosbash M. CLOCK:BMAL1 is a pioneer-like transcription factor. Genes Dev. 2014 Jan 1;28(1):8-13. doi: 10.1101/gad.228536.113. PMID:24395244 doi:http://dx.doi.org/10.1101/gad.228536.113
36. ↑ Zhou B, Zhang Y, Zhang F, Xia Y, Liu J, Huang R, Wang Y, Hu Y, Wu J, Dai C, Wang H, Tu Y, Peng X, Wang Y, Zhai Q. CLOCK/BMAL1 regulates circadian change of mouse hepatic insulin sensitivity by SIRT1. Hepatology. 2014 Jun;59(6):2196-206. doi: 10.1002/hep.26992. Epub 2014 Apr 25. PMID:24442997 doi:http://dx.doi.org/10.1002/hep.26992
37. ↑ Khapre RV, Kondratova AA, Patel S, Dubrovsky Y, Wrobel M, Antoch MP, Kondratov RV. BMAL1-dependent regulation of the mTOR signaling pathway delays aging. Aging (Albany NY). 2014 Jan;6(1):48-57. doi: 10.18632/aging.100633. PMID:24481314 doi:http://dx.doi.org/10.18632/aging.100633
38. ↑ Goriki A, Hatanaka F, Myung J, Kim JK, Yoritaka T, Tanoue S, Abe T, Kiyonari H, Fujimoto K, Kato Y, Todo T, Matsubara A, Forger D, Takumi T. A novel protein, CHRONO, functions as a core component of the mammalian circadian clock. PLoS Biol. 2014 Apr 15;12(4):e1001839. doi: 10.1371/journal.pbio.1001839., eCollection 2014 Apr. PMID:24736997 doi:http://dx.doi.org/10.1371/journal.pbio.1001839
39. ↑ Lin R, Mo Y, Zha H, Qu Z, Xie P, Zhu ZJ, Xu Y, Xiong Y, Guan KL. CLOCK Acetylates ASS1 to Drive Circadian Rhythm of Ureagenesis. Mol Cell. 2017 Oct 5;68(1):198-209.e6. doi: 10.1016/j.molcel.2017.09.008. PMID:28985504 doi:http://dx.doi.org/10.1016/j.molcel.2017.09.008
40. ↑ Deng W, Zhu S, Zeng L, Liu J, Kang R, Yang M, Cao L, Wang H, Billiar TR, Jiang J, Xie M, Tang D. The Circadian Clock Controls Immune Checkpoint Pathway in Sepsis. Cell Rep. 2018 Jul 10;24(2):366-378. doi: 10.1016/j.celrep.2018.06.026. PMID:29996098 doi:http://dx.doi.org/10.1016/j.celrep.2018.06.026
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