Bmal1
entrez
11865
canonical
uniprot
Q9WTL8
canonical
ensembl
ENSMUSG00000055116
resolver
ensp
ENSMUSP00000046235
resolver
ensp
ENSMUSP00000147764
resolver
ensp
ENSMUSP00000147823
resolver
ensp
ENSMUSP00000256789
resolver
ensp
ENSMUSP00000256791
resolver
ensp
ENSMUSP00000256799
resolver
ensp
ENSMUSP00000256800
resolver
ensp
ENSMUSP00000256807
resolver
ensp
ENSMUSP00000256808
resolver
ensp
ENSMUSP00000256814
resolver
ensp
ENSMUSP00000256818
resolver
ensp
ENSMUSP00000256822
resolver
ensp
ENSMUSP00000256825
resolver
ensp
ENSMUSP00000256829
resolver
ensp
ENSMUSP00000256840
resolver
ensp
ENSMUSP00000346792
resolver
enst
ENSMUST00000211770
resolver
genesymbol
Bmal1
resolver
genesymbol_syn
Arntl
resolver
uniprot
A0A1B0GS77
resolver
uniprot
O88295
resolver
uniprot
Q3UHZ2
resolver
uniprot
Q921S4
resolver
uniprot
Q9R0U2
resolver
uniprot
Q9WTL9
resolver
uniprot_entry
A0A1B0GS77_MOUSE
resolver
uniprot_entry
BMAL1_MOUSE
resolver
uniprot_entry
Q3UHZ2_MOUSE
resolver
uniprot_sec
O88295
resolver
uniprot_sec
Q921S4
resolver
uniprot_sec
Q9R0U2
resolver
uniprot_sec
Q9WTL9
resolver
activity_regulation
ACTIVITY REGULATION: The redox state of the cell can modulate the transcriptional activity of the CLOCK-BMAL1 and NPAS2-BMAL1 heterodimers; NADH and NADPH enhance the DNA-binding activity of the heterodimers. {ECO:0000250|UniProtKB:O00327}.
uniprot
proteins
amino_acid_sequence
MADQRMDISSTISDFMSPGPTDLLSGSLGTSGVDCNRKRKGSATDYQLDDFAFEESMDTDKDDPHGRLEYAEHQGRIKNAREAHSQIEKRRRDKMNSFIDELASLVPTCNAMSRKLDKLTVLRMAVQHMKTLRGATNPYTEANYKPTFLSDDELKHLILRAADGFLFVVGCDRGKILFVSESVFKILNYSQNDLIGQSLFDYLHPKDIAKVKEQLSSSDTAPRERLIDAKTGLPVKTDITPGPSRLCSGARRSFFCRMKCNRPSVKVEDKDFASTCSKKKDRKSFCTIHSTGYLKSWPPTKMGLDEDNEPDNEGCNLSCLVAIGRLHSHMVPQPANGEIRVKSMEYVSRHAIDGKFVFVDQRATAILAYLPQELLGTSCYEYFHQDDIGHLAECHRQVLQTREKITTNCYKFKIKDGSFITLRSRWFSFMNPWTKEVEYIVSTNTVVLANVLEGGDPTFPQLTAPPHSMDSMLPSGEGGPKRTHPTVPGIPGGTRAGAGKIGRMIAEEIMEIHRIRGSSPSSCGSSPLNITSTPPPDASSPGGKKILNGGTPDIPSTGLLPGQAQETPGYPYSDSSSILGENPHIGIDMIDNDQGSSSPSNDEAAMAVIMSLLEADAGLGGPVDFSDLPWPL
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. BMAL1 positively regulates myogenesis and negatively regulates adipogenesis via the transcriptional control of the genes of the canonical Wnt signaling pathway. Plays a role in normal pancreatic beta-cell function; regulates glucose-stimulated insulin secretion via the regulation of antioxidant genes NFE2L2/NRF2 and its targets SESN2, PRDX3, CCLC and CCLM. Negatively regulates the mTORC1 signaling pathway; regulates the expression of MTOR and DEPTOR. Controls diurnal oscillations of Ly6C inflammatory monocytes; rhythmic recruitment of the PRC2 complex imparts diurnal variation to chemokine expression that is necessary to sustain Ly6C monocyte rhythms. Regulates the expression of HSD3B2, STAR, PTGS2, CYP11A1, CYP19A1 and LHCGR in the ovary and also the genes involved in hair growth. Plays an important role in adult hippocampal neurogenesis by regulating the timely entry of neural stem/progenitor cells (NSPCs) into the cell cycle and the number of cell divisions that take place prior to cell-cycle exit. Regulates the circadian expression of CIART and KLF11. 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 NPAS2-BMAL1 heterodimer positively regulates the expression of MAOA, F7 and LDHA and modulates the circadian rhythm of daytime contrast sensitivity by regulating the rhythmic expression of adenylate cyclase type 1 (ADCY1) in the retina. 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' (By similarity). Essential for the rhythmic interaction of CLOCK with ASS1 and plays a critical role in positively regulating CLOCK-mediated acetylation of ASS1 (PubMed:28985504). Plays a role in protecting against lethal sepsis by limiting the expression of immune checkpoint protein CD274 in macrophages in a PKM2-dependent manner (PubMed:29996098). Regulates the diurnal rhythms of skeletal muscle metabolism via transcriptional activation of genes promoting triglyceride synthesis (DGAT2) and metabolic efficiency (COQ10B) (PubMed:30096135). {ECO:0000250|UniProtKB:O00327, ECO:0000269|PubMed:14672706, ECO:0000269|PubMed:18258755, ECO:0000269|PubMed:18316400, ECO:0000269|PubMed:19141540, ECO:0000269|PubMed:19286518, ECO:0000269|PubMed:19299583, ECO:0000269|PubMed:19605937, ECO:0000269|PubMed:20153195, ECO:0000269|PubMed:20385766, ECO:0000269|PubMed:20430893, ECO:0000269|PubMed:20562852, ECO:0000269|PubMed:20658528, ECO:0000269|PubMed:20840750, ECO:0000269|PubMed:20956306, ECO:0000269|PubMed:21768648, ECO:0000269|PubMed:21966465, ECO:0000269|PubMed:22045262, ECO:0000269|PubMed:22101268, ECO:0000269|PubMed:22611086, ECO:0000269|PubMed:22653727, ECO:0000269|PubMed:22900038, ECO:0000269|PubMed:22981862, ECO:0000269|PubMed:23291174, ECO:0000269|PubMed:23525013, ECO:0000269|PubMed:23547261, ECO:0000269|PubMed:23750248, ECO:0000269|PubMed:23955654, ECO:0000269|PubMed:23970558, ECO:0000269|PubMed:24048828, ECO:0000269|PubMed:24089055, ECO:0000269|PubMed:24268780, ECO:0000269|PubMed:24270424, ECO:0000269|PubMed:24378737, ECO:0000269|PubMed:24385426, ECO:0000269|PubMed:24395244, ECO:0000269|PubMed:24442997, ECO:0000269|PubMed:24481314, ECO:0000269|PubMed:24736997, ECO:0000269|PubMed:28985504, ECO:0000269|PubMed:29996098, ECO:0000269|PubMed:30096135}.
uniprot
proteins
mass_dalton
69452
uniprot
proteins
mutagenesis
MUTAGEN 38..39; /note="KR->AA: Loss of nuclear localization."; /evidence="ECO:0000269|PubMed:16980631"; MUTAGEN 97; /note="S->A: Impaired nuclear accumulation, decreased interaction with CLOCK and disruption of circadian clock function."; /evidence="ECO:0000269|PubMed:19330005"; MUTAGEN 102; /note="L->E: Reduced CLOCK binding. Abolishes transcriptional activation by the CLOCK-BMAL1 heterodimer."; /evidence="ECO:0000269|PubMed:22653727"; MUTAGEN 122; /note="L->E: Reduced CLOCK binding. Abolishes transcriptional activation by the CLOCK-BMAL1 heterodimer."; /evidence="ECO:0000269|PubMed:22653727"; MUTAGEN 154; /note="L->A: Significant reduction in nucleocytoplasmic shuttling; when associated with A-157."; /evidence="ECO:0000269|PubMed:16980631"; MUTAGEN 157; /note="L->A: Significant reduction in nucleocytoplasmic shuttling; when associated with A-154."; /evidence="ECO:0000269|PubMed:16980631"; MUTAGEN 230; /note="K->R: No effect on sumoylation."; /evidence="ECO:0000269|PubMed:16109848"; MUTAGEN 236; /note="K->R: No effect on sumoylation."; /evidence="ECO:0000269|PubMed:16109848"; MUTAGEN 259; /note="K->R: Significant decrease in; transcriptional activity, localization in PML body, ubiquitination and proteasome-mediated proteolysis."; /evidence="ECO:0000269|PubMed:18644859"; MUTAGEN 266; /note="K->R: Abolishes sumoylation."; /evidence="ECO:0000269|PubMed:16109848"; MUTAGEN 279; /note="K->R: No effect on sumoylation."; /evidence="ECO:0000269|PubMed:16109848"; MUTAGEN 323; /note="I->D: Reduced CLOCK binding. Slightly reduced transcriptional activation by the CLOCK-BMAL1 heterodimer. Impairs regulation of circadian clock. Loss of ability to inhibit the expression of CD274 in macrophages."; /evidence="ECO:0000269|PubMed:22653727, ECO:0000269|PubMed:29996098"; MUTAGEN 370; /note="L->A: Significant reduction in nucleocytoplasmic shuttling; when associated with A-374."; /evidence="ECO:0000269|PubMed:16980631"; MUTAGEN 374; /note="L->A: Significant reduction in nucleocytoplasmic shuttling; when associated with A-370."; /evidence="ECO:0000269|PubMed:16980631"; MUTAGEN 418; /note="S->A: Decreases without abolishing O-GlcNAcylation."; /evidence="ECO:0000269|PubMed:23395176"; MUTAGEN 544; /note="K->R: Decreased acetylation, leading to decreased transcription elongation during the activation phase of the circadian cycle."; /evidence="ECO:0000269|PubMed:31294688
uniprot
proteins
post_translational_modification
PTM: Ubiquitinated, leading to its proteasomal degradation (PubMed:16980631, PubMed:18644859, PubMed:23185022, PubMed:26776516). Deubiquitinated by USP9X (PubMed:29626158). {ECO:0000269|PubMed:16980631, ECO:0000269|PubMed:18644859, ECO:0000269|PubMed:23185022, ECO:0000269|PubMed:26776516, ECO:0000269|PubMed:29626158}.; 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 transcription of genes in the negative loop of the circadian clock such as PER1/2/3 and CRY1/2. {ECO:0000269|PubMed:23337503, ECO:0000269|PubMed:23395176}.; PTM: Acetylated on Lys-544 by CLOCK during the repression phase of the circadian cycle (PubMed:18075593, PubMed:31294688). Acetylation facilitates recruitment of CRY1 protein and initiates the repression phase of the circadian cycle (PubMed:18075593). Acetylated at Lys-544 by KAT5 during the activation phase of the cycle, leading to recruitment of the positive transcription elongation factor b (P-TEFb) and BRD4, followed by productive elongation of circadian transcripts (PubMed:31294688). Deacetylated by SIRT1, which may result in decreased protein stability (PubMed:18662547). {ECO:0000269|PubMed:18075593, ECO:0000269|PubMed:18662547, ECO:0000269|PubMed:31294688}.; PTM: Phosphorylated upon dimerization with CLOCK. Phosphorylation enhances the transcriptional activity, alters the subcellular localization and decreases the stability of the CLOCK-BMAL1 heterodimer by promoting its degradation. Phosphorylation shows circadian variations in the liver with a peak between CT10 to CT14. Phosphorylation at Ser-97 by CK2 is essential for its nuclear localization, its interaction with CLOCK and controls CLOCK nuclear entry. Dephosphorylation at Ser-85 is important for dimerization with CLOCK and transcriptional activity (By similarity). {ECO:0000250|UniProtKB:O00327, ECO:0000269|PubMed:11779462, ECO:0000269|PubMed:12897057, ECO:0000269|PubMed:19330005, ECO:0000269|PubMed:19414601, ECO:0000269|PubMed:19946213, ECO:0000269|PubMed:20049328}.; PTM: Sumoylated on Lys-266 upon dimerization with CLOCK. Predominantly conjugated to poly-SUMO2/3 rather than SUMO1 and the level of these conjugates undergo rhythmic variation, peaking at CT9-CT12. Sumoylation localizes it exclusively to the PML body and promotes its ubiquitination in the PML body, ubiquitin-dependent proteasomal degradation and the transcriptional activity of the CLOCK-BMAL1 heterodimer. {ECO:0000269|PubMed:16109848, ECO:0000269|PubMed:18644859}.; PTM: Undergoes lysosome-mediated degradation in a time-dependent manner in the liver. {ECO:0000269|PubMed:29937374}.
uniprot
proteins
pubmed
10403839
uniprot
proteins
pubmed
11779462
uniprot
proteins
pubmed
12397359
uniprot
proteins
pubmed
12897057
uniprot
proteins
pubmed
14672706
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16109848
uniprot
proteins
pubmed
16628007
uniprot
proteins
pubmed
16717091
uniprot
proteins
pubmed
16790549
uniprot
proteins
pubmed
16980631
uniprot
proteins
pubmed
18075593
uniprot
proteins
pubmed
18258755
uniprot
proteins
pubmed
18316400
uniprot
proteins
pubmed
18430226
uniprot
proteins
pubmed
18644859
uniprot
proteins
pubmed
18662546
uniprot
proteins
pubmed
18662547
uniprot
proteins
pubmed
19141540
uniprot
proteins
pubmed
19286518
uniprot
proteins
pubmed
19299583
uniprot
proteins
pubmed
19330005
uniprot
proteins
pubmed
19414601
uniprot
proteins
pubmed
19605937
uniprot
proteins
pubmed
19946213
uniprot
proteins
pubmed
20049328
uniprot
proteins
pubmed
20093473
uniprot
proteins
pubmed
20106950
uniprot
proteins
pubmed
20153195
uniprot
proteins
pubmed
20385766
uniprot
proteins
pubmed
20430893
uniprot
proteins
pubmed
20562852
uniprot
proteins
pubmed
20658528
uniprot
proteins
pubmed
20840750
uniprot
proteins
pubmed
20861012
uniprot
proteins
pubmed
20956306
uniprot
proteins
pubmed
21113167
uniprot
proteins
pubmed
21613214
uniprot
proteins
pubmed
21768648
uniprot
proteins
pubmed
21960634
uniprot
proteins
pubmed
21966465
uniprot
proteins
pubmed
22045262
uniprot
proteins
pubmed
22101268
uniprot
proteins
pubmed
22208286
uniprot
proteins
pubmed
22611086
uniprot
proteins
pubmed
22653727
uniprot
proteins
pubmed
22894897
uniprot
proteins
pubmed
22900038
uniprot
proteins
pubmed
22981862
uniprot
proteins
pubmed
23185022
uniprot
proteins
pubmed
23291174
uniprot
proteins
pubmed
23303907
uniprot
proteins
pubmed
23337503
uniprot
proteins
pubmed
23395176
uniprot
proteins
pubmed
23525013
uniprot
proteins
pubmed
23531614
uniprot
proteins
pubmed
23547261
uniprot
proteins
pubmed
23576606
uniprot
proteins
pubmed
23750248
uniprot
proteins
pubmed
23831463
uniprot
proteins
pubmed
23916625
uniprot
proteins
pubmed
23955654
uniprot
proteins
pubmed
23970558
uniprot
proteins
pubmed
24043798
uniprot
proteins
pubmed
24048828
uniprot
proteins
pubmed
24089055
uniprot
proteins
pubmed
24154698
uniprot
proteins
pubmed
24268780
uniprot
proteins
pubmed
24270424
uniprot
proteins
pubmed
24378737
uniprot
proteins
pubmed
24385426
uniprot
proteins
pubmed
24395244
uniprot
proteins
pubmed
24442997
uniprot
proteins
pubmed
24481314
uniprot
proteins
pubmed
24529706
uniprot
proteins
pubmed
24603368
uniprot
proteins
pubmed
24736997
uniprot
proteins
pubmed
26776516
uniprot
proteins
pubmed
28903391
uniprot
proteins
pubmed
28985504
uniprot
proteins
pubmed
29138967
uniprot
proteins
pubmed
29626158
uniprot
proteins
pubmed
29937374
uniprot
proteins
pubmed
29996098
uniprot
proteins
pubmed
30096135
uniprot
proteins
pubmed
31294688
uniprot
proteins
pubmed
9616112
uniprot
proteins
pubmed
9704006
uniprot
proteins
sequence_length
632
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16980631, ECO:0000269|PubMed:22208286, ECO:0000269|PubMed:26776516}. Cytoplasm {ECO:0000269|PubMed:16980631}. Nucleus, PML body {ECO:0000269|PubMed:18644859}. Note=Shuttles between the nucleus and the cytoplasm and this nucleocytoplasmic shuttling is essential for the nuclear accumulation of CLOCK, target gene transcription and the degradation of the CLOCK-BMAL1 heterodimer. The sumoylated form localizes in the PML body. Sequestered to the cytoplasm in the presence of ID2. {ECO:0000269|PubMed:16980631, ECO:0000269|PubMed:18644859, ECO:0000269|PubMed:20861012}.
uniprot
proteins