5vji

Structural highlights

Function

[CLOCK_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. CLOCK has an intrinsic acetyltransferase activity, which enables circadian chromatin remodeling by acetylating histones and nonhistone proteins, including its own partner ARNTL/BMAL1. Regulates the circadian expression of ICAM1, VCAM1, CCL2, THPO and MPL and also acts as an enhancer of the transactivation potential of NF-kappaB. Plays an important role in the homeostatic regulation of sleep. 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. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by reducing the association of NR3C1/GR to glucocorticoid response elements (GREs) via the acetylation of multiple lysine residues located in its hinge region. 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 CLOCK-ARNTL2/BMAL2 heterodimer activates the transcription of SERPINE1/PAI1 and BHLHE40/DEC1.^{[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]} [CIPC_MOUSE] Transcriptional repressor which may act as a negative-feedback regulator of CLOCK-ARNTL/BMAL1 transcriptional activity in the circadian-clock mechanism. May stimulate ARNTL/BMAL1-dependent phosphorylation of CLOCK (PubMed:17310242, PubMed:19414601). However, the physiogical relevance of these observations is unsure, since experiments in knockout mice showed that CIPC is not critially required for basic circadian clock (PubMed:25862660).^{[31] [32] [33]}

References

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2. ↑ Kawamoto T, Noshiro M, Sato F, Maemura K, Takeda N, Nagai R, Iwata T, Fujimoto K, Furukawa M, Miyazaki K, Honma S, Honma Ki, Kato Y. A novel autofeedback loop of Dec1 transcription involved in circadian rhythm regulation. Biochem Biophys Res Commun. 2004 Jan 2;313(1):117-24. PMID:14672706
3. ↑ Doi M, Hirayama J, Sassone-Corsi P. Circadian regulator CLOCK is a histone acetyltransferase. Cell. 2006 May 5;125(3):497-508. PMID:16678094 doi:http://dx.doi.org/10.1016/j.cell.2006.03.033
4. ↑ DeBruyne JP, Weaver DR, Reppert SM. CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock. Nat Neurosci. 2007 May;10(5):543-5. Epub 2007 Apr 8. PMID:17417633 doi:http://dx.doi.org/10.1038/nn1884
5. ↑ Hirayama J, Sahar S, Grimaldi B, Tamaru T, Takamatsu K, Nakahata Y, Sassone-Corsi P. CLOCK-mediated acetylation of BMAL1 controls circadian function. Nature. 2007 Dec 13;450(7172):1086-90. PMID:18075593 doi:nature06394
6. ↑ 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
7. ↑ 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
8. ↑ 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
9. ↑ Ramsey KM, Yoshino J, Brace CS, Abrassart D, Kobayashi Y, Marcheva B, Hong HK, Chong JL, Buhr ED, Lee C, Takahashi JS, Imai S, Bass J. Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science. 2009 May 1;324(5927):651-4. doi: 10.1126/science.1171641. Epub 2009 Mar , 19. PMID:19299583 doi:http://dx.doi.org/10.1126/science.1171641
10. ↑ 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
11. ↑ Guillaumond F, Grechez-Cassiau A, Subramaniam M, Brangolo S, Peteri-Brunback B, Staels B, Fievet C, Spelsberg TC, Delaunay F, Teboul M. Kruppel-like factor KLF10 is a link between the circadian clock and metabolism in liver. Mol Cell Biol. 2010 Jun;30(12):3059-70. doi: 10.1128/MCB.01141-09. Epub 2010 Apr , 12. PMID:20385766 doi:http://dx.doi.org/10.1128/MCB.01141-09
12. ↑ Doi R, Oishi K, Ishida N. CLOCK regulates circadian rhythms of hepatic glycogen synthesis through transcriptional activation of Gys2. J Biol Chem. 2010 Jul 16;285(29):22114-21. doi: 10.1074/jbc.M110.110361. Epub, 2010 Apr 29. PMID:20430893 doi:http://dx.doi.org/10.1074/jbc.M110.110361
13. ↑ Marcheva B, Ramsey KM, Buhr ED, Kobayashi Y, Su H, Ko CH, Ivanova G, Omura C, Mo S, Vitaterna MH, Lopez JP, Philipson LH, Bradfield CA, Crosby SD, JeBailey L, Wang X, Takahashi JS, Bass J. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature. 2010 Jul 29;466(7306):627-31. PMID:20562852 doi:10.1038/nature09253
14. ↑ Somanath PR, Podrez EA, Chen J, Ma Y, Marchant K, Antoch M, Byzova TV. Deficiency in core circadian protein Bmal1 is associated with a prothrombotic and vascular phenotype. J Cell Physiol. 2011 Jan;226(1):132-40. doi: 10.1002/jcp.22314. PMID:20658528 doi:http://dx.doi.org/10.1002/jcp.22314
15. ↑ 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
16. ↑ Koyanagi S, Hamdan AM, Horiguchi M, Kusunose N, Okamoto A, Matsunaga N, Ohdo S. cAMP-response element (CRE)-mediated transcription by activating transcription factor-4 (ATF4) is essential for circadian expression of the Period2 gene. J Biol Chem. 2011 Sep 16;286(37):32416-23. doi: 10.1074/jbc.M111.258970. Epub, 2011 Jul 18. PMID:21768648 doi:http://dx.doi.org/10.1074/jbc.M111.258970
17. ↑ Tracey CJ, Pan X, Catterson JH, Harmar AJ, Hussain MM, Hartley PS. Diurnal expression of the thrombopoietin gene is regulated by CLOCK. J Thromb Haemost. 2012 Apr;10(4):662-9. doi: 10.1111/j.1538-7836.2012.04643.x. PMID:22284746 doi:http://dx.doi.org/10.1111/j.1538-7836.2012.04643.x
18. ↑ 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
19. ↑ Spengler ML, Kuropatwinski KK, Comas M, Gasparian AV, Fedtsova N, Gleiberman AS, Gitlin II, Artemicheva NM, Deluca KA, Gudkov AV, Antoch MP. Core circadian protein CLOCK is a positive regulator of NF-kappaB-mediated transcription. Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):E2457-65. doi:, 10.1073/pnas.1206274109. Epub 2012 Aug 15. PMID:22895791 doi:http://dx.doi.org/10.1073/pnas.1206274109
20. ↑ 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
21. ↑ 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
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23. ↑ Baeza-Raja B, Eckel-Mahan K, Zhang L, Vagena E, Tsigelny IF, Sassone-Corsi P, Ptacek LJ, Akassoglou K. p75 neurotrophin receptor is a clock gene that regulates oscillatory components of circadian and metabolic networks. J Neurosci. 2013 Jun 19;33(25):10221-34. doi: 10.1523/JNEUROSCI.2757-12.2013. PMID:23785138 doi:http://dx.doi.org/10.1523/JNEUROSCI.2757-12.2013
24. ↑ 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
25. ↑ 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
26. ↑ Gao Y, Meng D, Sun N, Zhu Z, Zhao R, Lu C, Chen S, Hua L, Qian R. Clock upregulates intercellular adhesion molecule-1 expression and promotes mononuclear cells adhesion to endothelial cells. Biochem Biophys Res Commun. 2014 Jan 10;443(2):586-91. doi:, 10.1016/j.bbrc.2013.12.022. Epub 2013 Dec 11. PMID:24333415 doi:http://dx.doi.org/10.1016/j.bbrc.2013.12.022
27. ↑ 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
28. ↑ 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
29. ↑ 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
30. ↑ 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
31. ↑ Zhao WN, Malinin N, Yang FC, Staknis D, Gekakis N, Maier B, Reischl S, Kramer A, Weitz CJ. CIPC is a mammalian circadian clock protein without invertebrate homologues. Nat Cell Biol. 2007 Mar;9(3):268-75. Epub 2007 Feb 18. PMID:17310242 doi:http://dx.doi.org/10.1038/ncb1539
32. ↑ Yoshitane H, Takao T, Satomi Y, Du NH, Okano T, Fukada Y. Roles of CLOCK phosphorylation in suppression of E-box-dependent transcription. Mol Cell Biol. 2009 Jul;29(13):3675-86. doi: 10.1128/MCB.01864-08. Epub 2009 May , 4. PMID:19414601 doi:http://dx.doi.org/10.1128/MCB.01864-08
33. ↑ Qu Z, Wang X, Liu D, Gao X, Xu Y. Inactivation of Cipc alters the expression of Per1 but not circadian rhythms in mice. Sci China Life Sci. 2015 Apr;58(4):368-72. doi: 10.1007/s11427-015-4828-1. Epub, 2015 Apr 11. PMID:25862660 doi:http://dx.doi.org/10.1007/s11427-015-4828-1
34. ↑ Hou Z, Su L, Pei J, Grishin NV, Zhang H. Crystal Structure of the CLOCK Transactivation Domain Exon19 in Complex with a Repressor. Structure. 2017 Aug 1;25(8):1187-1194.e3. doi: 10.1016/j.str.2017.05.023. Epub, 2017 Jun 29. PMID:28669630 doi:http://dx.doi.org/10.1016/j.str.2017.05.023