InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: CLOCK

Summary

InnateDB Protein

IDBP-19415.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

CLOCK

Protein Name

clock homolog (mouse)

Synonyms

bHLHe8; KAT13D;

Species

Homo sapiens

Ensembl Protein

ENSP00000308741

InnateDB Gene

IDBG-19411 (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. The CLOCK-ARNTL2/BMAL2 heterodimer activates the transcription of SERPINE1/PAI1 and BHLHE40/DEC1. {ECO:0000269PubMed:14645221, ECO:0000269PubMed:18587630, ECO:0000269PubMed:21659603, ECO:0000269PubMed:21980503, ECO:0000269PubMed:22284746, ECO:0000269PubMed:23785138, ECO:0000269PubMed:24005054}.

Subcellular Localization

Nucleus. Chromosome. Cytoplasm {ECO:0000250}. Note=Shuffling between the cytoplasm and the nucleus is under circadian regulation and is ARNTL/BMAL1- dependent. Phosphorylated form located in the nucleus while the nonphosphorylated form found only in the cytoplasm. Sequestered to the cytoplasm in the presence of ID2 (By similarity). Localizes to sites of DNA damage in a H2AX-independent manner. {ECO:0000250}.

Disease Associations

Tissue Specificity

Hair follicles (at protein level). Expressed in all tissues examined including spleen, thymus, prostate, testis, ovary, small intestine, colon, leukocytes, heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Highest levels in testis and skeletal muscle. Low levels in thymus, lung and liver. Expressed in all brain regions with highest levels in cerebellum. Highly expressed in the suprachiasmatic nucleus (SCN). {ECO:0000269PubMed:10198158, ECO:0000269PubMed:24005054}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 24 experimentally validated interaction(s) in this database.
They are also associated with 25 interaction(s) predicted by orthology.

Experimentally validated
Total	24 [view]
Protein-Protein	18 [view]
Protein-DNA	0
Protein-RNA	0
DNA-DNA	6 [view]
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	25 [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: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: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:0006325	chromatin organization
GO:0006355	regulation of transcription, DNA-templated
GO:0006357	regulation of transcription from RNA polymerase II promoter
GO:0006366	transcription from RNA polymerase II promoter
GO:0007165	signal transduction
GO:0007283	spermatogenesis
GO:0007623	circadian rhythm
GO:0009648	photoperiodism
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: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: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

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
PF13426
PF00010
PF08447
PF00989

PRINTS

PR00785

PIRSF

SMART

SM00091
SM00086
SM00353

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt