Clock
entrez
12753
canonical
uniprot
O08785
canonical
ensembl
ENSMUSG00000029238
resolver
ensp
ENSMUSP00000074656
resolver
ensp
ENSMUSP00000143939
resolver
ensp
ENSMUSP00000144022
resolver
ensp
ENSMUSP00000186202
resolver
ensp
ENSMUSP00000186204
resolver
ensp
ENSMUSP00000186205
resolver
ensp
ENSMUSP00000186206
resolver
ensp
ENSMUSP00000186207
resolver
ensp
ENSMUSP00000186210
resolver
ensp
ENSMUSP00000186222
resolver
enst
ENSMUST00000202122
resolver
genesymbol
Clock
resolver
genesymbol_syn
mKIAA0334
resolver
uniprot
A0A0J9YU61
resolver
uniprot
Q3UWG6
resolver
uniprot
Q6ZQD6
resolver
uniprot
Q8C9W6
resolver
uniprot_entry
A0A0J9YU61_MOUSE
resolver
uniprot_entry
CLOCK_MOUSE
resolver
uniprot_entry
Q3UWG6_MOUSE
resolver
uniprot_entry
Q6ZQD6_MOUSE
resolver
uniprot_entry
Q8C9W6_MOUSE
resolver
amino_acid_sequence
MVFTVSCSKMSSIVDRDDSSIFDGLVEEDDKDKAKRVSRNKSEKKRRDQFNVLIKELGSMLPGNARKMDKSTVLQKSIDFLRKHKETTAQSDASEIRQDWKPTFLSNEEFTQLMLEALDGFFLAIMTDGSIIYVSESVTSLLEHLPSDLVDQSIFNFIPEGEHSEVYKILSTHLLESDSLTPEYLKSKNQLEFCCHMLRGTIDPKEPSTYEYVRFIGNFKSLTSVSTSTHNGFEGTIQRTHRPSYEDRVCFVATVRLATPQFIKEMCTVEEPNEEFTSRHSLEWKFLFLDHRAPPIIGYLPFEVLGTSGYDYYHVDDLENLAKCHEHLMQYGKGKSCYYRFLTKGQQWIWLQTHYYITYHQWNSRPEFIVCTHTVVSYAEVRAERRRELGIEESLPETAADKSQDSGSDNRINTVSLKEALERFDHSPTPSASSRSSRKSSHTAVSDPSSTPTKIPTDTSTPPRQHLPAHEKMTQRRSSFSSQSINSQSVGPSLTQPAMSQAANLPIPQGMSQFQFSAQLGAMQHLKDQLEQRTRMIEANIHRQQEELRKIQEQLQMVHGQGLQMFLQQSNPGLNFGSVQLSSGNSNIQQLTPVNMQGQVVPANQVQSGHISTGQHMIQQQTLQSTSTQQSQQSVMSGHSQQTSLPSQTPSTLTAPLYNTMVISQPAAGSMVQIPSSMPQNSTQSATVTTFTQDRQIRFSQGQQLVTKLVTAPVACGAVMVPSTMLMGQVVTAYPTFATQQQQAQTLSVTQQQQQQQQQPPQQQQQQQQSSQEQQLPSVQQPAQAQLGQPPQQFLQTSRLLHGNPSTQLILSAAFPLQQSTFPPSHHQQHQPQQQQQLPRHRTDSLTDPSKVQPQ
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. May play a role in spermatogenesis; contributes to the chromatoid body assembly and physiology. 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 (By similarity). CLOCK specifically binds to the half-site 5'-CAC-3', while BMAL1 binds to the half-site 5'-GTGA-3' (By similarity). The CLOCK-BMAL1 heterodimer also recognizes the non-canonical E-box motifs 5'-AACGTGA-3' and 5'-CATGTGA-3'. 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. 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 (By similarity). 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 (PubMed:30012868). {ECO:0000250|UniProtKB:O15516, ECO:0000269|PubMed:12738229, ECO:0000269|PubMed:14672706, ECO:0000269|PubMed:16678094, ECO:0000269|PubMed:17417633, ECO:0000269|PubMed:18075593, ECO:0000269|PubMed:18316400, ECO:0000269|PubMed:19141540, ECO:0000269|PubMed:19286518, ECO:0000269|PubMed:19299583, ECO:0000269|PubMed:19605937, ECO:0000269|PubMed:20385766, ECO:0000269|PubMed:20430893, ECO:0000269|PubMed:20562852, ECO:0000269|PubMed:20658528, ECO:0000269|PubMed:20956306, ECO:0000269|PubMed:21768648, ECO:0000269|PubMed:22284746, ECO:0000269|PubMed:22653727, ECO:0000269|PubMed:22895791, ECO:0000269|PubMed:22900038, ECO:0000269|PubMed:22981862, ECO:0000269|PubMed:23291174, ECO:0000269|PubMed:23785138, ECO:0000269|PubMed:24089055, ECO:0000269|PubMed:24270424, ECO:0000269|PubMed:24333415, ECO:0000269|PubMed:24378737, ECO:0000269|PubMed:24385426, ECO:0000269|PubMed:24395244, ECO:0000269|PubMed:24442997, ECO:0000269|PubMed:28985504, ECO:0000269|PubMed:30012868}.
uniprot
proteins
mass_dalton
96393
uniprot
proteins
mutagenesis
MUTAGEN 38; /note="S->D: Significant decrease in transcriptional activation by the CLOCK-BMAL1 heterodimer. Significant decrease in transcriptional activation by the CLOCK-BMAL1 heterodimer, reduced nuclear localization and DNA-binding; when associated with D-42."; /evidence="ECO:0000269|PubMed:19414601"; MUTAGEN 42; /note="S->D: Significant decrease in transcriptional activation by the CLOCK-BMAL1 heterodimer. Significant decrease in transcriptional activation by the CLOCK-BMAL1 heterodimer, reduced nuclear localization and DNA-binding; when associated with D-38."; /evidence="ECO:0000269|PubMed:19414601"; MUTAGEN 57; /note="L->E: Reduced BMAL1 binding. Abolishes transcriptional activation by the CLOCK-BMAL1 heterodimer. Abolishes regulation of circadian clock."; /evidence="ECO:0000269|PubMed:22653727"; MUTAGEN 67; /note="K->R: Decrease in sumoylation and its transcriptional activity. Abolishes sumoylation and interaction with ESR1 and decrease in its transcriptional activity; when associated with R-851."; /evidence="ECO:0000269|PubMed:23160374"; MUTAGEN 74; /note="L->E: Reduced BMAL1 binding. Abolishes transcriptional activation by the CLOCK-BMAL1 heterodimer."; /evidence="ECO:0000269|PubMed:22653727"; MUTAGEN 284; /note="W->A: Reduced BMAL1 binding. Slightly reduced transcriptional activation by the CLOCK-BMAL1 heterodimer."; /evidence="ECO:0000269|PubMed:22653727"; MUTAGEN 427; /note="S->A: Significant loss of phosphorylation."; /evidence="ECO:0000269|PubMed:19414601, ECO:0000269|PubMed:19946213"; MUTAGEN 431; /note="S->A: Significant loss of phosphorylation."; /evidence="ECO:0000269|PubMed:19946213"; MUTAGEN 656; /note="P->A: Reduces histone acetyltransferase activity; when associated with A-658 and A-659."; /evidence="ECO:0000269|PubMed:16678094"; MUTAGEN 658; /note="Y->A: Reduces histone acetyltransferase activity; when associated with A-656 and A-659."; /evidence="ECO:0000269|PubMed:16678094"; MUTAGEN 659; /note="N->A: Reduces histone acetyltransferase activity; when associated with A-656 and A-658."; /evidence="ECO:0000269|PubMed:16678094"; MUTAGEN 669; /note="G->A: Reduces histone acetyltransferase activity; when associated with A-670 and A-672."; /evidence="ECO:0000269|PubMed:16678094"; MUTAGEN 670; /note="S->A: Reduces histone acetyltransferase activity; when associated with A-669 and A-672."; /evidence="ECO:0000269|PubMed:16678094"; MUTAGEN 672; /note="V->A: Reduces histone acetyltransferase activity; when associated with A-669 and A-670."; /evidence="ECO:0000269|PubMed:16678094"; MUTAGEN 851; /note="K->R: Decrease in sumoylation and its transcriptional activity. Abolishes sumoylation and interaction with ESR1 and decrease in its transcriptional activity; when associated with R-67."; /evidence="ECO:0000269|PubMed:23160374
uniprot
proteins
post_translational_modification
PTM: Ubiquitinated, leading to its proteasomal degradation. {ECO:0000269|PubMed:16980631}.; 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:0000269|PubMed:23395175, ECO:0000269|PubMed:23395176}.; 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: the hyperphosphorylated form peaks at midnight (CT18), while the hypophosphorylated form is abundant throughout the day. May be phosphorylated by CSNK1D and CKSN1E. {ECO:0000269|PubMed:11779462, ECO:0000269|PubMed:12897057, ECO:0000269|PubMed:19414601, ECO:0000269|PubMed:19946213, ECO:0000269|PubMed:21930935, 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. {ECO:0000269|PubMed:23160374}.; PTM: Undergoes lysosome-mediated degradation in a time-dependent manner in the liver. {ECO:0000269|PubMed:29937374}.
uniprot
proteins
pubmed
11116088
uniprot
proteins
pubmed
11779462
uniprot
proteins
pubmed
12738229
uniprot
proteins
pubmed
12897057
uniprot
proteins
pubmed
14645221
uniprot
proteins
pubmed
14672706
uniprot
proteins
pubmed
16678094
uniprot
proteins
pubmed
16717091
uniprot
proteins
pubmed
16980631
uniprot
proteins
pubmed
17242355
uniprot
proteins
pubmed
17310242
uniprot
proteins
pubmed
17417633
uniprot
proteins
pubmed
18075593
uniprot
proteins
pubmed
18316400
uniprot
proteins
pubmed
18430226
uniprot
proteins
pubmed
18662546
uniprot
proteins
pubmed
18662547
uniprot
proteins
pubmed
19129230
uniprot
proteins
pubmed
19141540
uniprot
proteins
pubmed
19286518
uniprot
proteins
pubmed
19299583
uniprot
proteins
pubmed
19414601
uniprot
proteins
pubmed
19605937
uniprot
proteins
pubmed
19946213
uniprot
proteins
pubmed
20385766
uniprot
proteins
pubmed
20430893
uniprot
proteins
pubmed
20562852
uniprot
proteins
pubmed
20658528
uniprot
proteins
pubmed
20861012
uniprot
proteins
pubmed
20956306
uniprot
proteins
pubmed
21113167
uniprot
proteins
pubmed
21768648
uniprot
proteins
pubmed
21930935
uniprot
proteins
pubmed
21960634
uniprot
proteins
pubmed
22284746
uniprot
proteins
pubmed
22653727
uniprot
proteins
pubmed
22895791
uniprot
proteins
pubmed
22900038
uniprot
proteins
pubmed
22981862
uniprot
proteins
pubmed
23160374
uniprot
proteins
pubmed
23291174
uniprot
proteins
pubmed
23303907
uniprot
proteins
pubmed
23395175
uniprot
proteins
pubmed
23395176
uniprot
proteins
pubmed
23576606
uniprot
proteins
pubmed
23756047
uniprot
proteins
pubmed
23785138
uniprot
proteins
pubmed
23916625
uniprot
proteins
pubmed
24043798
uniprot
proteins
pubmed
24089055
uniprot
proteins
pubmed
24154698
uniprot
proteins
pubmed
24235147
uniprot
proteins
pubmed
24270424
uniprot
proteins
pubmed
24333415
uniprot
proteins
pubmed
24378737
uniprot
proteins
pubmed
24385426
uniprot
proteins
pubmed
24395244
uniprot
proteins
pubmed
24442997
uniprot
proteins
pubmed
24529706
uniprot
proteins
pubmed
28903391
uniprot
proteins
pubmed
28985504
uniprot
proteins
pubmed
29937374
uniprot
proteins
pubmed
30012868
uniprot
proteins
pubmed
9160755
uniprot
proteins
pubmed
9160756
uniprot
proteins
pubmed
9616112
uniprot
proteins
sequence_length
855
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:11779462, ECO:0000269|PubMed:12897057, ECO:0000269|PubMed:16980631, ECO:0000269|PubMed:17310242, ECO:0000269|PubMed:18662546, ECO:0000269|PubMed:19414601}. Cytoplasm {ECO:0000269|PubMed:12897057, ECO:0000269|PubMed:16980631}. Cytoplasm, cytosol {ECO:0000250|UniProtKB:O15516}. Note=Localizes to sites of DNA damage in a H2AX-independent manner (By similarity). Shuttling between the cytoplasm and the nucleus is under circadian regulation and is BMAL1-dependent. Phosphorylated form located in the nucleus predominantly between CT12 and CT21. Nonphosphorylated form found only in the cytoplasm. Sequestered to the cytoplasm in the presence of ID2. {ECO:0000250|UniProtKB:O15516, ECO:0000269|PubMed:11779462, ECO:0000269|PubMed:16980631, ECO:0000269|PubMed:20861012}.
uniprot
proteins