O88529 · BMAL1_MESAU

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. 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. CLOCK specifically binds to the half-site 5'-CAC-3', while BMAL1 binds to the half-site 5'-GTGA-3'. The CLOCK-BMAL1 heterodimer also recognizes the non-canonical E-box motifs 5'-AACGTGA-3' and 5'-CATGTGA-3'. Essential for the rhythmic interaction of CLOCK with ASS1 and plays a critical role in positively regulating CLOCK-mediated acetylation of ASS1. Plays a role in protecting against lethal sepsis by limiting the expression of immune checkpoint protein CD274 in macrophages in a PKM2-dependent manner (By similarity).
Regulates the diurnal rhythms of skeletal muscle metabolism via transcriptional activation of genes promoting triglyceride synthesis (DGAT2) and metabolic efficiency (COQ10B) (By similarity).

Features

Showing features for site.

TypeIDPosition(s)Description
Site77Interaction with E-box DNA
Site80Interaction with E-box DNA
Site81Interaction with E-box DNA
Site85Interaction with E-box DNA
Site125Important for interaction with CLOCK

GO annotations

AspectTerm
Cellular Componentaryl hydrocarbon receptor complex
Cellular Componentchromatoid body
Cellular ComponentCLOCK-BMAL transcription complex
Cellular Componentnucleus
Cellular ComponentPML body
Cellular Componenttranscription regulator complex
Molecular Functionaryl hydrocarbon receptor binding
Molecular FunctionDNA binding
Molecular FunctionDNA-binding transcription factor activity, RNA polymerase II-specific
Molecular FunctionE-box binding
Molecular FunctionHsp90 protein binding
Molecular Functionprotein dimerization activity
Molecular FunctionRNA polymerase II cis-regulatory region sequence-specific DNA binding
Molecular Functionsequence-specific DNA binding
Molecular Functiontranscription cis-regulatory region binding
Biological Processcircadian regulation of gene expression
Biological Processnegative regulation of DNA-templated transcription
Biological Processnegative regulation of fat cell differentiation
Biological Processnegative regulation of glucocorticoid receptor signaling pathway
Biological Processnegative regulation of TOR signaling
Biological Processoxidative stress-induced premature senescence
Biological Processpositive regulation of canonical Wnt signaling pathway
Biological Processpositive regulation of circadian rhythm
Biological Processpositive regulation of DNA-templated transcription
Biological Processpositive regulation of protein acetylation
Biological Processpositive regulation of skeletal muscle cell differentiation
Biological Processpositive regulation of transcription by RNA polymerase II
Biological Processproteasome-mediated ubiquitin-dependent protein catabolic process
Biological Processregulation of cell cycle
Biological Processregulation of cellular senescence
Biological Processregulation of DNA-templated transcription
Biological Processregulation of hair cycle
Biological Processregulation of insulin secretion
Biological Processregulation of neurogenesis
Biological Processregulation of type B pancreatic cell development
Biological Processresponse to redox state
Biological Processspermatogenesis

Keywords

Names & Taxonomy

Protein names

  • Recommended name
    Basic helix-loop-helix ARNT-like protein 1
  • Alternative names
    • Aryl hydrocarbon receptor nuclear translocator-like protein 1
    • Brain and muscle ARNT-like 1

Gene names

    • Name
      BMAL1
    • Synonyms
      ARNTL

Organism names

  • Taxonomic identifier
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Cricetidae > Cricetinae > Mesocricetus

Accessions

  • Primary accession
    O88529

Proteomes

Subcellular Location

Nucleus
Cytoplasm
Nucleus, PML body
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.

Keywords

PTM/Processing

Features

Showing features for chain, modified residue, cross-link.

TypeIDPosition(s)Description
ChainPRO_00001271571-626Basic helix-loop-helix ARNT-like protein 1
Modified residue17Phosphoserine; by GSK3-beta
Modified residue21Phosphothreonine; by GSK3-beta
Modified residue78Phosphoserine
Modified residue90Phosphoserine; by CK2
Cross-link252Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2 and SUMO3)
Cross-link259Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO); alternate
Cross-link259Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2); alternate
Modified residue538N6-acetyllysine

Post-translational modification

Ubiquitinated, leading to its proteasomal degradation. Deubiquitinated by USP9X.
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.
Acetylated on Lys-538 by CLOCK during the repression phase of the circadian cycle. Acetylation facilitates recruitment of CRY1 protein and initiates the repression phase of the circadian cycle. Acetylated at Lys-538 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. Deacetylated by SIRT1, which may result in decreased protein stability.
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-90 by CK2 is essential for its nuclear localization, its interaction with CLOCK and controls CLOCK nuclear entry. Dephosphorylation at Ser-78 is important for dimerization with CLOCK and transcriptional activity.
Sumoylated on Lys-259 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.
Undergoes lysosome-mediated degradation in a time-dependent manner in the liver.

Keywords

Interaction

Subunit

Component of the circadian clock oscillator which includes the CRY1/2 proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, TIMELESS and the PER1/2/3 proteins (By similarity).
Forms a heterodimer with CLOCK (By similarity).
The CLOCK-BMAL1 heterodimer is required for E-box-dependent transactivation, for CLOCK nuclear translocation and degradation, and, for phosphorylation of both CLOCK and BMAL1 (By similarity).
Part of a nuclear complex which also includes RACK1 and PRKCA; RACK1 and PRKCA are recruited to the complex in a circadian manner (By similarity).
Interacts with NPAS2 (By similarity).
Interacts with EZH2 (By similarity).
Interacts with SUMO3 (By similarity).
Interacts with SIRT1 (By similarity).
Interacts with AHR (By similarity).
Interacts with ID1, ID2 and ID3 (By similarity).
Interacts with DDX4 (By similarity).
Interacts with OGT (By similarity).
Interacts with EED and SUZ12 (By similarity).
Interacts with MTA1 (By similarity).
Interacts with CIART (By similarity).
Interacts with HSP90 (By similarity).
Interacts with KAT2B and EP300 (By similarity).
Interacts with BHLHE40/DEC1 and BHLHE41/DEC2 (By similarity).
Interacts with RELB and the interaction is enhanced in the presence of CLOCK (By similarity).
Interacts with PER1, PER2, CRY1 and CRY2 and this interaction requires a translocation to the nucleus (By similarity).
Interaction of the CLOCK-BMAL1 heterodimer with PER or CRY inhibits transcription activation (By similarity).
Interaction of the CLOCK-BMAL1 with CRY1 is independent of DNA but with PER2 is off DNA (By similarity).
The CLOCK-BMAL1 heterodimer interacts with GSK3B (By similarity).
Interacts with KDM5A (By similarity).
Interacts with KMT2A; in a circadian manner (By similarity).
Interacts with UBE3A (By similarity).
Interacts with PRKCG (By similarity).
Interacts with MAGEL2 (By similarity).
Interacts with NCOA2 (By similarity).
Interacts with THRAP3 (By similarity).
The CLOCK-BMAL1 heterodimer interacts with PASD1 (By similarity).
Interacts with PASD1 (By similarity).
Interacts with USP9X (By similarity).
Interacts with PIWIL2 (via PIWI domain) (By similarity).
Interacts with HDAC3 (By similarity).
Interacts with HNF4A (By similarity).

Protein-protein interaction databases

Structure

Family & Domains

Features

Showing features for compositional bias, region, motif, domain.

TypeIDPosition(s)Description
Compositional bias1-33Polar residues
Region1-58Disordered
Motif36-41Nuclear localization signal
Compositional bias38-58Basic and acidic residues
Domain72-125bHLH
Motif142-152Nuclear export signal 1
Domain143-215PAS 1
Domain326-396PAS 2
Motif361-369Nuclear export signal 2
Domain401-444PAC
Region459-492Disordered
Region508-588Interaction with CIART
Region511-595Disordered
Compositional bias512-532Polar residues
Compositional bias552-574Polar residues

Keywords

Phylogenomic databases

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Length
    626
  • Mass (Da)
    68,701
  • Last updated
    1998-11-01 v1
  • Checksum
    65FDD28B38F1E016
MADQRMDISSTISDFMSPGPTDLLSSSLGTSGVDCNRKRKGSATDYQESMDTDKDDPHGRLEYAEHQGRIKNAREAHSQIEKRRRDKMNSFIDELASLVPTCNAMSRKLDKLTVLRMAVQHMKTLRGATNPYTEANYKPTFLSDDELKHLILRAADGFLFVVGCDRGKILFVSESVFKILNYSQNDLIGQSLFDYLHPKDIAKVKEQLSSSDTAPRERLIDAKTGLPVKTDITPGPSRLCSGARRSFFCRMKCNRPSVKVEDKDFASTCSKKKADRKSFCTIHSTGYLKSWPPTKMGLDEDNEPDNEGCNLSCLVAIGRLHSHVVPQPVNGEIRVKSMEYVSRHAIDGKFVFVDQRATAILAYLPQELLGTSCYEYFHQDDIGHLAECHRQVLQTREKITTNCYKFKIKDGSFITLRSRWFSFMNPWTKEVEYIVSTNTVVLANVLEGGDPTFPQLTASPHSMDSMLPSGEGGPKRTHPTVPGIPGGTRAGAGKIGRMIAEEIMEIHRIRGSSPSSCGSSPLNITSTPPPDASSPGGKKILNGGTPDIPSTGLLPGQAQETPGYPYSDSSSILGENPHIGIDMIDNDQGSSSPSNDEAAMAVIMSLLEADAGLGGPVDFSDLPWPL

Features

Showing features for compositional bias.

TypeIDPosition(s)Description
Compositional bias1-33Polar residues
Compositional bias38-58Basic and acidic residues
Compositional bias512-532Polar residues
Compositional bias552-574Polar residues

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
AF070917
EMBL· GenBank· DDBJ
AAC23606.1
EMBL· GenBank· DDBJ
mRNA

Genome annotation databases

Similar Proteins

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