CLOCK - Circadian locomoter output cycles protein kaput - human protein (Function)
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CLOCK »  Circadian locomoter output cycles protein kaput   [ EC ]
Protein also known as:  Class E basic helix-loop-helix protein 8 (bHLHe8).
Gene name:  CLOCK
Entry whose protein(s) existence is based on evidence at protein level
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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. The CLOCK-ARNTL2/BMAL2 heterodimer activates the transcription of SERPINE1/PAI1 and BHLHE40/DEC1.  
  • UniProtKB
GO molecular function 
Protein bindingdefinition[GO:0005515]  
  • UniProtKB
Protein dimerization activitydefinition[GO:0046983] silver  
  • InterPro 2 GO
Signal transducer activitydefinition[GO:0004871] silver  
  • InterPro 2 GO
GO biological process 
Circadian rhythmdefinition[GO:0007623]  
  • PINC
  • PINC
Positive regulation of transcription from RNA polymerase II promoterdefinition[GO:0045944]  
  • MGI
Regulation of transcription from RNA polymerase II promoterdefinition[GO:0006357]  
  • PINC
Signal transductiondefinition[GO:0007165] silver  
  • InterPro 2 GO
Transcription from RNA polymerase II promoterdefinition[GO:0006366] silver  
  • Ortholog Compara
Enzymatic activity 
This protein acts as an enzyme. It is known to catalyze the following reaction
EC Acetyl-CoA + [histone] CoA + acetyl-[histone].  
  • UniProtKB
It is regulated in the following manner
The redox state of the cell can modulate the transcriptional activity of the CLOCK-ARNTL/BMAL1 heterodimer; NADH and NADPH enhance the DNA-binding activity of the heterodimer.  
  • UniProtKB
According to KEGG, this protein belongs to the following pathways:
Circadian rhythm - mammal  hsa04710+9575  
Dopaminergic synapse  hsa04728+9575  
Herpes simplex infection  hsa05168+9575  
According to Reactome, this protein belongs to the following pathways:
BMAL1:CLOCK,NPAS2 activates circadian gene expression  REACT_111118  
Circadian Clock  REACT_24941  
HATs acetylate histones  REACT_172610  
PPARA activates gene expression  REACT_116145  
REV-ERBA represses gene expression  REACT_118789  
RORA activates circadian gene expression  REACT_118659  
CLOCK-ARNTL/BMAL1 double mutations within the PAS domains result in syngernistic desensitization to high levels of CRY on repression of CLOCK-ARNTL/BMAl1 transcriptional activity of PER1 and disrupt circadian rhythmicity.  
  • UniProtKB


Biological process 
Biological rhythms  definition   [KW-0090]
DNA damage  definition   [KW-0227]
Transcription  definition   [KW-0804]
Transcription regulation  definition   [KW-0805]
Molecular function 
Activator  definition   [KW-0010]
Acyltransferase  definition   [KW-0012]
Transferase  definition   [KW-0808]
Technical term 
Reference proteome  definition   [KW-1185]

Further external links

GeneWiki: CLOCK
GenomeRNAi: 9575
PRO: PR:O15516