Mus musculus Protein: Clock
InnateDB Protein IDBP-172860.6
Last Modified 2014-10-13 [Report errors or provide feedback]
Gene Symbol Clock
Protein Name circadian locomotor output cycles kaput
Synonyms 5330400M04Rik; bHLHe8; KAT13D; mKIAA0334;
Species Mus musculus
Ensembl Protein ENSMUSP00000074656
InnateDB Gene IDBG-172856 (Clock)
Protein Structure
UniProt Annotation
Function 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 CLOCKNPAS2-ARNTL/BMAL1ARNTL2/BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1, NR1D2, RORA, RORB and RORG, 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 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. {ECO:0000269PubMed:12738229, ECO:0000269PubMed:14672706, ECO:0000269PubMed:16678094, ECO:0000269PubMed:17417633, ECO:0000269PubMed:18075593, ECO:0000269PubMed:18316400, ECO:0000269PubMed:19141540, ECO:0000269PubMed:19286518, ECO:0000269PubMed:19605937, ECO:0000269PubMed:20430893, ECO:0000269PubMed:20562852, ECO:0000269PubMed:20658528, ECO:0000269PubMed:20956306, ECO:0000269PubMed:21768648, ECO:0000269PubMed:22284746, ECO:0000269PubMed:22653727, ECO:0000269PubMed:22895791, ECO:0000269PubMed:22900038, ECO:0000269PubMed:22981862, ECO:0000269PubMed:23291174, ECO:0000269PubMed:23785138, ECO:0000269PubMed:24089055, ECO:0000269PubMed:24270424, ECO:0000269PubMed:24333415, ECO:0000269PubMed:24378737, ECO:0000269PubMed:24385426, ECO:0000269PubMed:24395244, ECO:0000269PubMed:24442997}.
Subcellular Localization Nucleus. Chromosome. Cytoplasm. Note=Localizes to sites of DNA damage in a H2AX-independent manner (By similarity). Shuffling between the cytoplasm and the nucleus is under circadian regulation and is ARNTL/BMAL1-dependent. Phosphorylated form located in the nucleus predominantly between C12 and C21. Nonphosphorylated form found only in the cytoplasm. Sequestered to the cytoplasm in the presence of ID2. {ECO:0000250}.
Disease Associations
Tissue Specificity Expressed equally in brain, eye, testes, ovaries, liver, heart, lung, kidney. In the brain, expression is abundant in the suprachiasmatic nuclei (SCN), in the pyriform cortex, and in the hippocampus. Low expression throughout the rest of the brain. Expression does not appear to undergo circadian oscillations. {ECO:0000269PubMed:22900038, ECO:0000269PubMed:24154698, ECO:0000269PubMed:9160755}.
Number of Interactions This gene and/or its encoded proteins are associated with 52 experimentally validated interaction(s) in this database.
They are also associated with 14 interaction(s) predicted by orthology.
Experimentally validated
Total 52 [view]
Protein-Protein 47 [view]
Protein-DNA 3 [view]
Protein-RNA 0
DNA-DNA 2 [view]
Predicted by orthology
Total 14 [view]
Gene Ontology

Molecular Function
Accession GO Term
GO:0000978 RNA polymerase II core promoter proximal region sequence-specific DNA binding
GO:0000982 RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity
GO:0001047 core promoter binding
GO:0001077 RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription
GO:0001190 RNA polymerase II transcription factor binding transcription factor activity involved in positive regulation of transcription
GO:0003677 DNA binding
GO:0003700 sequence-specific DNA binding transcription factor activity
GO:0004402 histone acetyltransferase activity
GO:0004871 signal transducer activity
GO:0005515 protein binding
GO:0008134 transcription factor binding
GO:0031490 chromatin DNA binding
GO:0043565 sequence-specific DNA binding
GO:0046983 protein dimerization activity
GO:0070888 E-box binding
Biological Process
GO:0000077 DNA damage checkpoint
GO:0006355 regulation of transcription, DNA-templated
GO:0006366 transcription from RNA polymerase II promoter
GO:0007165 signal transduction
GO:0007283 spermatogenesis
GO:0007623 circadian rhythm
GO:0016573 histone acetylation
GO:0032922 circadian regulation of gene expression
GO:0042634 regulation of hair cycle
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process
GO:0045087 innate immune response
GO:0045892 negative regulation of transcription, DNA-templated
GO:0045893 positive regulation of transcription, DNA-templated
GO:0045944 positive regulation of transcription from RNA polymerase II promoter
GO:0050796 regulation of insulin secretion
GO:0051092 positive regulation of NF-kappaB transcription factor activity
GO:0051775 response to redox state
GO:0071479 cellular response to ionizing radiation
GO:2000074 regulation of type B pancreatic cell development
GO:2000323 negative regulation of glucocorticoid receptor signaling pathway
Cellular Component
GO:0005634 nucleus
GO:0005654 nucleoplasm
GO:0005667 transcription factor complex
GO:0005694 chromosome
GO:0005737 cytoplasm
GO:0005829 cytosol
GO:0033391 chromatoid body
GO:0043231 intracellular membrane-bounded organelle
Protein Structure and Domains
PDB ID MGI:99698
InterPro IPR000014 PAS domain
IPR001067 Nuclear translocator
IPR001610 PAC motif
IPR011598 Myc-type, basic helix-loop-helix (bHLH) domain
IPR013655 PAS fold-3
IPR013767 PAS fold
PFAM PF13188
Post-translational Modifications
SwissProt O08785
PhosphoSite PhosphoSite-O08785
UniProt Splice Variant
Entrez Gene 12753
UniGene Mm.470874
RefSeq NP_031741
MGI Symbol Clock
EMBL AF000998 AF146793 AK040337 AK129118
GenPept AAC53200 AAD30565 BAC30568 BAC97928