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CLOCK (O15516) - Overview - Molecular Target Synopsis

Protein


CLOCK, Circadian locomoter output cycles protein kaput
Enzyme Classification 2.3.1.48
UniProt O15516

Also Known as CLOCK_HUMAN, CLOCK, BHLHE8, KIAA0334

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. 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. 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. 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 (PubMed:23229515). CLOCK specifically binds to the h Component of the circadian clock oscillator which includes the CRY proteins, CLOCK or NPAS2, ARNTL/BMAL1 or ARNTL2/BMAL2, CSNK1D and/or CSNK1E, TIMELESS and the PER proteins (By similarity). Interacts with KMT2A; in a circadian manner (By similarity). Forms a heterodimer with ARNTL/BMAL1 (PubMed:21613214, PubMed:23229515). The CLOCK-ARNTL/BMAL1 heterodimer is required for E-box-dependent transactivation, for CLOCK nuclear translocation and degradation, and for phosphorylation of both CLOCK and ARNTL/BMAL1 (By similarity). Interacts with NR3C1 in a ligand-dependent fashion (PubMed:21980503). Interacts with ESR1 and estrogen stimulates this interaction (PubMed:23160374). Interacts with the complex p35/CDK5 (PubMed:24235147). Interacts with RELA/p65 (By similarity). Interacts with KAT2B, CREBBP, EP300 (PubMed:14645221). Interacts with ID1 and ID3 (By similarity). Interacts with ID2 (PubMed:20861012). Interacts with MTA1 (By similarity). Interacts with OGA (By similarity). Interacts with SIRT1 (By similarity). Interacts with CIPC (By similarity). Interacts with EZH2 (By similarity). Interacts with EIF4E, PIWIL1 and DDX4 (By similarity). Interacts with PER2 and CRY1 and the interaction with PER and CRY proteins requires translocation to the nucleus. Interacts with PER1 and CRY2 (By similarity). Interaction of the CLOCK-ARNTL/BMAL1 heterodimer with PER or CRY inhibits transcription activation (PubMed:21613214). Interaction of the CLOCK-ARNTL/BMAL1 with CRY1 is independent of DNA but with PER2 is off DNA (PubMed:21613214). The CLOCK-ARNTL/BMAL1 heterodimer interacts with GSK3B. Interacts with KDM5A (PubMed:21960634). Interacts with MYBBP1A (By similarity). Interacts with THRAP3 (By similarity). Interacts with MED1; this interaction requires the presence of THRAP3 (By similarity). Interacts with NCOA2 (By similarity). The CLOCK-ARNTL/BMAL1 heterodimer interacts with PASD1 (PubMed:25936801). Interacts with ASS1 and IMPDH2; in a circadian manner (PubMed:28985504). Interacts with NDUFA9 (PubMed:28985504).

4H10
INTERMOLECULAR RECOGNITION REVEALED BY THE COMPLEX STRUCTURE OF HUMAN CLOCK-BMAL1 BASIC HELIX-LOOP-HELIX DOMAINS WITH E-BOX DNA
RCSB/PDB
Inspect Structure
See all 3D Structures for CLOCK

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


UniProt: CLOCK is active in the following subcellular-locations: cytoplasm, cytosol, nucleus.
GO terms: CLOCK is active in the following subcellular-locations: chromatoid body, chromosome, cytosol, intracellular membrane-bounded organelle, nucleoplasm, nucleus, transcription factor complex.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project CLOCK has gain in 3 cell-lines, loss in 4 cell-lines and no signal in 998 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: SNB_19, SK_OV_3, HS578T

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: Caov-3, Panc 04.03, CL-11

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: NHLF, HSMM, HMEC

(see details)

3D Structures


For CLOCK there are:
1 structures (1 chains) solved
0 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis