CLOCK
entrez
9575
canonical
uniprot
O15516
canonical
ensembl
ENSG00000134852
resolver
ensp
ENSP00000308741
resolver
ensp
ENSP00000370723
resolver
ensp
ENSP00000426983
resolver
ensp
ENSP00000552428
resolver
ensp
ENSP00000552429
resolver
ensp
ENSP00000552430
resolver
ensp
ENSP00000552432
resolver
ensp
ENSP00000552433
resolver
ensp
ENSP00000596643
resolver
ensp
ENSP00000596644
resolver
ensp
ENSP00000596645
resolver
ensp
ENSP00000632834
resolver
enst
ENST00000309964
resolver
enst
ENST00000381322
resolver
enst
ENST00000513440
resolver
enst
ENST00000882369
resolver
enst
ENST00000882370
resolver
enst
ENST00000882371
resolver
enst
ENST00000882373
resolver
enst
ENST00000882374
resolver
enst
ENST00000926584
resolver
enst
ENST00000926585
resolver
enst
ENST00000926586
resolver
enst
ENST00000962775
resolver
genesymbol
CLOCK
resolver
genesymbol_syn
BHLHE8
resolver
genesymbol_syn
KIAA0334
resolver
hgnc
HGNC:2082
resolver
uniprot
A0AV01
resolver
uniprot
A2I2N9
resolver
uniprot
O14516
resolver
uniprot
Q3ZCT4
resolver
uniprot
Q53EU0
resolver
uniprot
Q9UIT8
resolver
uniprot_entry
CLOCK_HUMAN
resolver
uniprot_entry
Q3ZCT4_HUMAN
resolver
uniprot_entry
Q53EU0_HUMAN
resolver
uniprot_sec
A0AV01
resolver
uniprot_sec
A2I2N9
resolver
uniprot_sec
O14516
resolver
uniprot_sec
Q9UIT8
resolver
activity_regulation
ACTIVITY REGULATION: There is conflicting data about the effect of NAD cofactors on activity. PubMed:11441146 suggests that the redox state of the cell can modulate the transcriptional activity of the CLOCK-BMAL1 heterodimer; NADH and NADPH enhance the DNA-binding activity of the heterodimer. PubMed:23229515 reports that NADH and NADPH have no significant effect on DNA-binding activity of the CLOCK-BMAL1 heterodimer. {ECO:0000269|PubMed:11441146, ECO:0000269|PubMed:23229515}.
uniprot
proteins
amino_acid_sequence
MLFTVSCSKMSSIVDRDDSSIFDGLVEEDDKDKAKRVSRNKSEKKRRDQFNVLIKELGSMLPGNARKMDKSTVLQKSIDFLRKHKEITAQSDASEIRQDWKPTFLSNEEFTQLMLEALDGFFLAIMTDGSIIYVSESVTSLLEHLPSDLVDQSIFNFIPEGEHSEVYKILSTHLLESDSLTPEYLKSKNQLEFCCHMLRGTIDPKEPSTYEYVKFIGNFKSLNSVSSSAHNGFEGTIQRTHRPSYEDRVCFVATVRLATPQFIKEMCTVEEPNEEFTSRHSLEWKFLFLDHRAPPIIGYLPFEVLGTSGYDYYHVDDLENLAKCHEHLMQYGKGKSCYYRFLTKGQQWIWLQTHYYITYHQWNSRPEFIVCTHTVVSYAEVRAERRRELGIEESLPETAADKSQDSGSDNRINTVSLKEALERFDHSPTPSASSRSSRKSSHTAVSDPSSTPTKIPTDTSTPPRQHLPAHEKMVQRRSSFSSQSINSQSVGSSLTQPVMSQATNLPIPQGMSQFQFSAQLGAMQHLKDQLEQRTRMIEANIHRQQEELRKIQEQLQMVHGQGLQMFLQQSNPGLNFGSVQLSSGNSSNIQQLAPINMQGQVVPTNQIQSGMNTGHIGTTQHMIQQQTLQSTSTQSQQNVLSGHSQQTSLPSQTQSTLTAPLYNTMVISQPAAGSMVQIPSSMPQNSTQSAAVTTFTQDRQIRFSQGQQLVTKLVTAPVACGAVMVPSTMLMGQVVTAYPTFATQQQQSQTLSVTQQQQQQSSQEQQLTSVQQPSQAQLTQPPQQFLQTSRLLHGNPSTQLILSAAFPLQQSTFPQSHHQQHQSQQQQQLSRHRTDSLPDPSKVQPQ
uniprot
proteins
ec_number
2.3.1.48
uniprot
proteins
function
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, BMAL1, 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 BMAL1 or 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-BMAL1|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 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-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-BMAL2 heterodimer activates the transcription of SERPINE1/PAI1 and BHLHE40/DEC1. The preferred binding motif for the CLOCK-BMAL1 heterodimer is 5'-CACGTGA-3', which contains a flanking adenine nucleotide at the 3-prime end of the canonical 6-nucleotide E-box sequence (PubMed:23229515). CLOCK specifically binds to the half-site 5'-CAC-3', while BMAL1 binds to the half-site 5'-GTGA-3' (PubMed:23229515). The CLOCK-BMAL1 heterodimer also recognizes the non-canonical E-box motifs 5'-AACGTGA-3' and 5'-CATGTGA-3' (PubMed:23229515). CLOCK has an intrinsic acetyltransferase activity, which enables circadian chromatin remodeling by acetylating histones and nonhistone proteins, including its own partner BMAL1. 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 (PubMed:21980503). The acetyltransferase activity of CLOCK is as important as its transcription activity in circadian control. Acetylates metabolic enzymes IMPDH2 and NDUFA9 in a circadian manner. Facilitated by BMAL1, rhythmically interacts and acetylates argininosuccinate synthase 1 (ASS1) leading to enzymatic inhibition of ASS1 as well as the circadian oscillation of arginine biosynthesis and subsequent ureagenesis (PubMed:28985504). Drives the circadian rhythm of blood pressure through transcriptional activation of ATP1B1 (By similarity). {ECO:0000250|UniProtKB:O08785, ECO:0000269|PubMed:14645221, ECO:0000269|PubMed:18587630, ECO:0000269|PubMed:21659603, ECO:0000269|PubMed:21980503, ECO:0000269|PubMed:22284746, ECO:0000269|PubMed:23229515, ECO:0000269|PubMed:23785138, ECO:0000269|PubMed:24005054, ECO:0000269|PubMed:28985504}.
uniprot
proteins
mass_dalton
95304
uniprot
proteins
mutagenesis
MUTAGEN 38; /note="S->E: Phosphomimetic mutant with no effect on DNA binding or CLOCK-BMAL1 transcriptional activity."; /evidence="ECO:0000269|PubMed:23229515"; MUTAGEN 42; /note="S->E: Phosphomimetic mutant with no effect on DNA binding or CLOCK-BMAL1 transcriptional activity."; /evidence="ECO:0000269|PubMed:23229515"; MUTAGEN 50; /note="F->M: No effect on BMAL1 binding."; /evidence="ECO:0000269|PubMed:23229515"; MUTAGEN 84; /note="H->L: Impaired BMAL1 binding."; /evidence="ECO:0000269|PubMed:23229515"; MUTAGEN 116; /note="E->K: 3-fold increase in PER1 reporter activity by CLOCK-BMAL1. Some reduction of CRY1 inhibition of CLOCK-BMAL1 transcriptional activity; when associated with K-367 and L-601."; /evidence="ECO:0000269|PubMed:16474406"; MUTAGEN 332; /note="G->E: 3-fold increase in PER1 reporter activity by CLOCK-BMAL1. Some reduction of CRY1 inhibition of CLOCK-BMAL1 transcriptional activity; when associated with L-840."; /evidence="ECO:0000269|PubMed:16474406"; MUTAGEN 360; /note="H->Y: 3-fold increase in PER1 reporter activity by CLOCK-BMAL1. Some reduction of CRY1 inhibition of CLOCK-BMAL1 transcriptional activity."; /evidence="ECO:0000269|PubMed:16474406"; MUTAGEN 367; /note="E->K: 3-fold increase in PER1 reporter activity by CLOCK-BMAL1. Some reduction of CRY1 inhibition of CLOCK-BMAL1 transcriptional activity; when associated with E-116 and L-601."; /evidence="ECO:0000269|PubMed:16474406"; MUTAGEN 451; /note="T->F: Significant loss in phosphorylation."; /evidence="ECO:0000269|PubMed:24235147"; MUTAGEN 461; /note="T->F: Significant loss in phosphorylation."; /evidence="ECO:0000269|PubMed:24235147"; MUTAGEN 601; /note="V->L: 3-fold increase in PER1 reporter activity by CLOCK-BMAL1. Some reduction of CRY1 inhibition of CLOCK-BMAL1 transcriptional activity; when associated with K-116 and K-367."; /evidence="ECO:0000269|PubMed:16474406"; MUTAGEN 840; /note="P->L: 3-fold increase in PER1 reporter activity by CLOCK-BMAL1. Some reduction of CRY1 inhibition of CLOCK-BMAL1 transcriptional activity; when associated with E-332."; /evidence="ECO:0000269|PubMed:16474406
uniprot
proteins
post_translational_modification
PTM: Ubiquitinated, leading to its proteasomal degradation. {ECO:0000250|UniProtKB:O08785}.; PTM: O-glycosylated; contains O-GlcNAc. O-glycosylation by OGT prevents protein degradation by inhibiting ubiquitination. It also stabilizes the CLOCK-BMAL1 heterodimer thereby increasing CLOCK-BMAL1-mediated transcriptional activation of PER1/2/3 and CRY1/2. {ECO:0000250|UniProtKB:O08785}.; PTM: Phosphorylation is dependent on the CLOCK-BMAL1 heterodimer formation. Phosphorylation enhances the transcriptional activity, alters the subcellular localization and decreases the stability of the heterodimer by promoting its degradation. Phosphorylation shows circadian variations in the liver. May be phosphorylated by CSNK1D and CKSN1E. {ECO:0000269|PubMed:24235147}.; PTM: Sumoylation enhances its transcriptional activity and interaction with ESR1, resulting in up-regulation of ESR1 activity. Estrogen stimulates sumoylation. Desumoylation by SENP1 negatively regulates its transcriptional activity. Sumoylation stimulates cell proliferation and increases the proportion of S phase cells in breast cancer cell lines. {ECO:0000269|PubMed:23160374}.; PTM: Undergoes lysosome-mediated degradation in a time-dependent manner in the liver. {ECO:0000250|UniProtKB:O08785}.
uniprot
proteins
pubmed
10198158
uniprot
proteins
pubmed
11441146
uniprot
proteins
pubmed
14645221
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16474406
uniprot
proteins
pubmed
18587630
uniprot
proteins
pubmed
20861012
uniprot
proteins
pubmed
21613214
uniprot
proteins
pubmed
21659603
uniprot
proteins
pubmed
21960634
uniprot
proteins
pubmed
21980503
uniprot
proteins
pubmed
22284746
uniprot
proteins
pubmed
23160374
uniprot
proteins
pubmed
23229515
uniprot
proteins
pubmed
23303907
uniprot
proteins
pubmed
23576606
uniprot
proteins
pubmed
23785138
uniprot
proteins
pubmed
23916625
uniprot
proteins
pubmed
24005054
uniprot
proteins
pubmed
24235147
uniprot
proteins
pubmed
24275569
uniprot
proteins
pubmed
25936801
uniprot
proteins
pubmed
28903391
uniprot
proteins
pubmed
28985504
uniprot
proteins
pubmed
30530698
uniprot
proteins
pubmed
9205841
uniprot
proteins
sequence_length
846
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:14645221, ECO:0000269|PubMed:23160374, ECO:0000269|PubMed:28985504}. Cytoplasm {ECO:0000250|UniProtKB:O08785}. Cytoplasm, cytosol {ECO:0000269|PubMed:28985504}. Note=Shuttling between the cytoplasm and the nucleus is under circadian regulation and is 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|UniProtKB:O08785, ECO:0000269|PubMed:21659603}.
uniprot
proteins