ID BMAL1_MESAU Reviewed; 626 AA. AC O88529; DT 15-AUG-2003, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1998, sequence version 1. DT 24-JAN-2024, entry version 148. DE RecName: Full=Basic helix-loop-helix ARNT-like protein 1; DE AltName: Full=Aryl hydrocarbon receptor nuclear translocator-like protein 1; DE AltName: Full=Brain and muscle ARNT-like 1; GN Name=BMAL1; Synonyms=ARNTL; OS Mesocricetus auratus (Golden hamster). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; OC Cricetidae; Cricetinae; Mesocricetus. OX NCBI_TaxID=10036; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=9616112; DOI=10.1126/science.280.5369.1564; RA Gekakis N., Staknis D., Nguyen H.B., Davis F.C., Wilsbacher L.D., RA King D.P., Takahashi J.S., Weitz C.J.; RT "Role of the CLOCK protein in the mammalian circadian mechanism."; RL Science 280:1564-1569(1998). CC -!- FUNCTION: Transcriptional activator which forms a core component of the CC circadian clock. The circadian clock, an internal time-keeping system, CC regulates various physiological processes through the generation of CC approximately 24 hour circadian rhythms in gene expression, which are CC translated into rhythms in metabolism and behavior. It is derived from CC the Latin roots 'circa' (about) and 'diem' (day) and acts as an CC important regulator of a wide array of physiological functions CC including metabolism, sleep, body temperature, blood pressure, CC endocrine, immune, cardiovascular, and renal function. Consists of two CC major components: the central clock, residing in the suprachiasmatic CC nucleus (SCN) of the brain, and the peripheral clocks that are present CC in nearly every tissue and organ system. Both the central and CC peripheral clocks can be reset by environmental cues, also known as CC Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the CC central clock is light, which is sensed by retina and signals directly CC to the SCN. The central clock entrains the peripheral clocks through CC neuronal and hormonal signals, body temperature and feeding-related CC cues, aligning all clocks with the external light/dark cycle. Circadian CC rhythms allow an organism to achieve temporal homeostasis with its CC environment at the molecular level by regulating gene expression to CC create a peak of protein expression once every 24 hours to control when CC a particular physiological process is most active with respect to the CC solar day. Transcription and translation of core clock components CC (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a CC critical role in rhythm generation, whereas delays imposed by post- CC translational modifications (PTMs) are important for determining the CC period (tau) of the rhythms (tau refers to the period of a rhythm and CC is the length, in time, of one complete cycle). A diurnal rhythm is CC synchronized with the day/night cycle, while the ultradian and CC infradian rhythms have a period shorter and longer than 24 hours, CC respectively. Disruptions in the circadian rhythms contribute to the CC pathology of cardiovascular diseases, cancer, metabolic syndromes and CC aging. A transcription/translation feedback loop (TTFL) forms the core CC of the molecular circadian clock mechanism. Transcription factors, CC CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the CC feedback loop, act in the form of a heterodimer and activate the CC transcription of core clock genes and clock-controlled genes (involved CC in key metabolic processes), harboring E-box elements (5'-CACGTG-3') CC within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which CC are transcriptional repressors form the negative limb of the feedback CC loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer CC inhibiting its activity and thereby negatively regulating their own CC expression. This heterodimer also activates nuclear receptors NR1D1/2 CC and RORA/B/G, which form a second feedback loop and which activate and CC repress BMAL1 transcription, respectively. BMAL1 positively regulates CC myogenesis and negatively regulates adipogenesis via the CC transcriptional control of the genes of the canonical Wnt signaling CC pathway. Plays a role in normal pancreatic beta-cell function; CC regulates glucose-stimulated insulin secretion via the regulation of CC antioxidant genes NFE2L2/NRF2 and its targets SESN2, PRDX3, CCLC and CC CCLM. Negatively regulates the mTORC1 signaling pathway; regulates the CC expression of MTOR and DEPTOR. Controls diurnal oscillations of Ly6C CC inflammatory monocytes; rhythmic recruitment of the PRC2 complex CC imparts diurnal variation to chemokine expression that is necessary to CC sustain Ly6C monocyte rhythms. Regulates the expression of HSD3B2, CC STAR, PTGS2, CYP11A1, CYP19A1 and LHCGR in the ovary and also the genes CC involved in hair growth. Plays an important role in adult hippocampal CC neurogenesis by regulating the timely entry of neural stem/progenitor CC cells (NSPCs) into the cell cycle and the number of cell divisions that CC take place prior to cell-cycle exit. Regulates the circadian expression CC of CIART and KLF11. The CLOCK-BMAL1 heterodimer regulates the circadian CC expression of SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, CC PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4, CC MTA1, KLF10 and also genes implicated in glucose and lipid metabolism. CC Promotes rhythmic chromatin opening, regulating the DNA accessibility CC of other transcription factors. The NPAS2-BMAL1 heterodimer positively CC regulates the expression of MAOA, F7 and LDHA and modulates the CC circadian rhythm of daytime contrast sensitivity by regulating the CC rhythmic expression of adenylate cyclase type 1 (ADCY1) in the retina. CC The preferred binding motif for the CLOCK-BMAL1 heterodimer is 5'- CC CACGTGA-3', which contains a flanking adenine nucleotide at the 3-prime CC end of the canonical 6-nucleotide E-box sequence. CLOCK specifically CC binds to the half-site 5'-CAC-3', while BMAL1 binds to the half-site CC 5'-GTGA-3'. The CLOCK-BMAL1 heterodimer also recognizes the non- CC canonical E-box motifs 5'-AACGTGA-3' and 5'-CATGTGA-3'. Essential for CC the rhythmic interaction of CLOCK with ASS1 and plays a critical role CC in positively regulating CLOCK-mediated acetylation of ASS1. Plays a CC role in protecting against lethal sepsis by limiting the expression of CC immune checkpoint protein CD274 in macrophages in a PKM2-dependent CC manner (By similarity). Regulates the diurnal rhythms of skeletal CC muscle metabolism via transcriptional activation of genes promoting CC triglyceride synthesis (DGAT2) and metabolic efficiency (COQ10B) (By CC similarity). {ECO:0000250|UniProtKB:O00327, CC ECO:0000250|UniProtKB:Q9WTL8}. CC -!- SUBUNIT: Component of the circadian clock oscillator which includes the CC CRY1/2 proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, CC TIMELESS and the PER1/2/3 proteins (By similarity). Forms a heterodimer CC with CLOCK (By similarity). The CLOCK-BMAL1 heterodimer is required for CC E-box-dependent transactivation, for CLOCK nuclear translocation and CC degradation, and, for phosphorylation of both CLOCK and BMAL1 (By CC similarity). Part of a nuclear complex which also includes RACK1 and CC PRKCA; RACK1 and PRKCA are recruited to the complex in a circadian CC manner (By similarity). Interacts with NPAS2 (By similarity). Interacts CC with EZH2 (By similarity). Interacts with SUMO3 (By similarity). CC Interacts with SIRT1 (By similarity). Interacts with AHR (By CC similarity). Interacts with ID1, ID2 and ID3 (By similarity). Interacts CC with DDX4 (By similarity). Interacts with OGT (By similarity). CC Interacts with EED and SUZ12 (By similarity). Interacts with MTA1 (By CC similarity). Interacts with CIART (By similarity). Interacts with HSP90 CC (By similarity). Interacts with KAT2B and EP300 (By similarity). CC Interacts with BHLHE40/DEC1 and BHLHE41/DEC2 (By similarity). Interacts CC with RELB and the interaction is enhanced in the presence of CLOCK (By CC similarity). Interacts with PER1, PER2, CRY1 and CRY2 and this CC interaction requires a translocation to the nucleus (By similarity). CC Interaction of the CLOCK-BMAL1 heterodimer with PER or CRY inhibits CC transcription activation (By similarity). Interaction of the CLOCK- CC BMAL1 with CRY1 is independent of DNA but with PER2 is off DNA (By CC similarity). The CLOCK-BMAL1 heterodimer interacts with GSK3B (By CC similarity). Interacts with KDM5A (By similarity). Interacts with CC KMT2A; in a circadian manner (By similarity). Interacts with UBE3A (By CC similarity). Interacts with PRKCG (By similarity). Interacts with CC MAGEL2 (By similarity). Interacts with NCOA2 (By similarity). Interacts CC with THRAP3 (By similarity). The CLOCK-BMAL1 heterodimer interacts with CC PASD1 (By similarity). Interacts with PASD1 (By similarity). Interacts CC with USP9X (By similarity). Interacts with PIWIL2 (via PIWI domain) (By CC similarity). Interacts with HDAC3 (By similarity). Interacts with HNF4A CC (By similarity). {ECO:0000250|UniProtKB:O00327, CC ECO:0000250|UniProtKB:Q9WTL8}. CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00981}. CC Cytoplasm {ECO:0000250|UniProtKB:Q9WTL8}. Nucleus, PML body CC {ECO:0000250|UniProtKB:Q9WTL8}. Note=Shuttles between the nucleus and CC the cytoplasm and this nucleocytoplasmic shuttling is essential for the CC nuclear accumulation of CLOCK, target gene transcription and the CC degradation of the CLOCK-BMAL1 heterodimer. The sumoylated form CC localizes in the PML body. Sequestered to the cytoplasm in the presence CC of ID2. {ECO:0000250|UniProtKB:Q9WTL8}. CC -!- PTM: Ubiquitinated, leading to its proteasomal degradation. CC Deubiquitinated by USP9X. {ECO:0000250|UniProtKB:Q9WTL8}. CC -!- PTM: O-glycosylated; contains O-GlcNAc. O-glycosylation by OGT prevents CC protein degradation by inhibiting ubiquitination. It also stabilizes CC the CLOCK-BMAL1 heterodimer thereby increasing CLOCK-BMAL1-mediated CC transcription of genes in the negative loop of the circadian clock such CC as PER1/2/3 and CRY1/2. {ECO:0000250|UniProtKB:Q9WTL8}. CC -!- PTM: Acetylated on Lys-538 by CLOCK during the repression phase of the CC circadian cycle. Acetylation facilitates recruitment of CRY1 protein CC and initiates the repression phase of the circadian cycle. Acetylated CC at Lys-538 by KAT5 during the activation phase of the cycle, leading to CC recruitment of the positive transcription elongation factor b (P-TEFb) CC and BRD4, followed by productive elongation of circadian transcripts. CC Deacetylated by SIRT1, which may result in decreased protein stability. CC {ECO:0000250|UniProtKB:Q9WTL8}. CC -!- PTM: Phosphorylated upon dimerization with CLOCK. Phosphorylation CC enhances the transcriptional activity, alters the subcellular CC localization and decreases the stability of the CLOCK-BMAL1 heterodimer CC by promoting its degradation. Phosphorylation shows circadian CC variations in the liver with a peak between CT10 to CT14. CC Phosphorylation at Ser-90 by CK2 is essential for its nuclear CC localization, its interaction with CLOCK and controls CLOCK nuclear CC entry. Dephosphorylation at Ser-78 is important for dimerization with CC CLOCK and transcriptional activity. {ECO:0000250|UniProtKB:O00327, CC ECO:0000250|UniProtKB:Q9WTL8}. CC -!- PTM: Sumoylated on Lys-259 upon dimerization with CLOCK. Predominantly CC conjugated to poly-SUMO2/3 rather than SUMO1 and the level of these CC conjugates undergo rhythmic variation, peaking at CT9-CT12. Sumoylation CC localizes it exclusively to the PML body and promotes its CC ubiquitination in the PML body, ubiquitin-dependent proteasomal CC degradation and the transcriptional activity of the CLOCK-BMAL1 CC heterodimer. {ECO:0000250|UniProtKB:Q9WTL8}. CC -!- PTM: Undergoes lysosome-mediated degradation in a time-dependent manner CC in the liver. {ECO:0000250|UniProtKB:Q9WTL8}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF070917; AAC23606.1; -; mRNA. DR RefSeq; NP_001268496.1; NM_001281567.1. DR RefSeq; XP_012972924.1; XM_013117470.1. DR RefSeq; XP_012972925.1; XM_013117471.1. DR RefSeq; XP_012972926.1; XM_013117472.1. DR RefSeq; XP_012972927.1; XM_013117473.1. DR AlphaFoldDB; O88529; -. DR SMR; O88529; -. DR IntAct; O88529; 1. DR STRING; 10036.ENSMAUP00000007669; -. DR GeneID; 101835598; -. DR KEGG; maua:101835598; -. DR CTD; 406; -. DR eggNOG; KOG3561; Eukaryota. DR OrthoDB; 2872674at2759; -. DR Proteomes; UP000189706; Unplaced. DR GO; GO:0033391; C:chromatoid body; ISS:UniProtKB. DR GO; GO:1990513; C:CLOCK-BMAL transcription complex; IEA:Ensembl. DR GO; GO:0005634; C:nucleus; ISS:UniProtKB. DR GO; GO:0016605; C:PML body; IEA:UniProtKB-SubCell. DR GO; GO:0005667; C:transcription regulator complex; ISS:UniProtKB. DR GO; GO:0017162; F:aryl hydrocarbon receptor binding; IEA:Ensembl. DR GO; GO:0003677; F:DNA binding; ISS:UniProtKB. DR GO; GO:0003700; F:DNA-binding transcription factor activity; IEA:InterPro. DR GO; GO:0070888; F:E-box binding; ISS:UniProtKB. DR GO; GO:0051879; F:Hsp90 protein binding; IEA:Ensembl. DR GO; GO:0046983; F:protein dimerization activity; IEA:InterPro. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; ISS:UniProtKB. DR GO; GO:0043565; F:sequence-specific DNA binding; ISS:UniProtKB. DR GO; GO:0000976; F:transcription cis-regulatory region binding; ISS:UniProtKB. DR GO; GO:0032922; P:circadian regulation of gene expression; ISS:UniProtKB. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; ISS:UniProtKB. DR GO; GO:0045599; P:negative regulation of fat cell differentiation; ISS:UniProtKB. DR GO; GO:2000323; P:negative regulation of glucocorticoid receptor signaling pathway; ISS:UniProtKB. DR GO; GO:0032007; P:negative regulation of TOR signaling; ISS:UniProtKB. DR GO; GO:0090403; P:oxidative stress-induced premature senescence; ISS:UniProtKB. DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; ISS:UniProtKB. DR GO; GO:0042753; P:positive regulation of circadian rhythm; ISS:UniProtKB. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; ISS:UniProtKB. DR GO; GO:1901985; P:positive regulation of protein acetylation; ISS:UniProtKB. DR GO; GO:2001016; P:positive regulation of skeletal muscle cell differentiation; ISS:UniProtKB. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; ISS:UniProtKB. DR GO; GO:0051726; P:regulation of cell cycle; ISS:UniProtKB. DR GO; GO:2000772; P:regulation of cellular senescence; ISS:UniProtKB. DR GO; GO:0006355; P:regulation of DNA-templated transcription; ISS:UniProtKB. DR GO; GO:0042634; P:regulation of hair cycle; ISS:UniProtKB. DR GO; GO:0050796; P:regulation of insulin secretion; ISS:UniProtKB. DR GO; GO:0050767; P:regulation of neurogenesis; ISS:UniProtKB. DR GO; GO:2000074; P:regulation of type B pancreatic cell development; ISS:UniProtKB. DR GO; GO:0051775; P:response to redox state; ISS:UniProtKB. DR GO; GO:0007283; P:spermatogenesis; ISS:UniProtKB. DR CDD; cd11438; bHLH-PAS_ARNTL_PASD3; 1. DR CDD; cd00130; PAS; 2. DR Gene3D; 4.10.280.10; Helix-loop-helix DNA-binding domain; 1. DR Gene3D; 3.30.450.20; PAS domain; 2. DR InterPro; IPR011598; bHLH_dom. DR InterPro; IPR036638; HLH_DNA-bd_sf. DR InterPro; IPR001067; Nuc_translocat. DR InterPro; IPR001610; PAC. DR InterPro; IPR000014; PAS. DR InterPro; IPR035965; PAS-like_dom_sf. DR InterPro; IPR013767; PAS_fold. DR NCBIfam; TIGR00229; sensory_box; 1. DR PANTHER; PTHR23042:SF52; ARYL HYDROCARBON RECEPTOR NUCLEAR TRANSLOCATOR-LIKE PROTEIN 1; 1. DR PANTHER; PTHR23042; CIRCADIAN PROTEIN CLOCK/ARNT/BMAL/PAS; 1. DR Pfam; PF00010; HLH; 1. DR Pfam; PF00989; PAS; 1. DR Pfam; PF14598; PAS_11; 1. DR PRINTS; PR00785; NCTRNSLOCATR. DR SMART; SM00353; HLH; 1. DR SMART; SM00086; PAC; 1. DR SMART; SM00091; PAS; 2. DR SUPFAM; SSF47459; HLH, helix-loop-helix DNA-binding domain; 1. DR SUPFAM; SSF55785; PYP-like sensor domain (PAS domain); 2. DR PROSITE; PS50888; BHLH; 1. DR PROSITE; PS50112; PAS; 2. PE 2: Evidence at transcript level; KW Acetylation; Activator; Biological rhythms; Cytoplasm; DNA-binding; KW Isopeptide bond; Nucleus; Phosphoprotein; Reference proteome; Repeat; KW Transcription; Transcription regulation; Ubl conjugation. FT CHAIN 1..626 FT /note="Basic helix-loop-helix ARNT-like protein 1" FT /id="PRO_0000127157" FT DOMAIN 72..125 FT /note="bHLH" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981" FT DOMAIN 143..215 FT /note="PAS 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140" FT DOMAIN 326..396 FT /note="PAS 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140" FT DOMAIN 401..444 FT /note="PAC" FT REGION 1..58 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 459..492 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 508..588 FT /note="Interaction with CIART" FT /evidence="ECO:0000250|UniProtKB:Q9WTL8" FT REGION 511..595 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 36..41 FT /note="Nuclear localization signal" FT /evidence="ECO:0000250|UniProtKB:Q9WTL8" FT MOTIF 142..152 FT /note="Nuclear export signal 1" FT /evidence="ECO:0000250|UniProtKB:Q9WTL8" FT MOTIF 361..369 FT /note="Nuclear export signal 2" FT /evidence="ECO:0000250|UniProtKB:Q9WTL8" FT COMPBIAS 1..33 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 38..58 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 512..532 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 552..574 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT SITE 77 FT /note="Interaction with E-box DNA" FT /evidence="ECO:0000250|UniProtKB:O00327" FT SITE 80 FT /note="Interaction with E-box DNA" FT /evidence="ECO:0000250|UniProtKB:O00327" FT SITE 81 FT /note="Interaction with E-box DNA" FT /evidence="ECO:0000250|UniProtKB:O00327" FT SITE 85 FT /note="Interaction with E-box DNA" FT /evidence="ECO:0000250|UniProtKB:O00327" FT SITE 125 FT /note="Important for interaction with CLOCK" FT /evidence="ECO:0000250|UniProtKB:O00327" FT MOD_RES 17 FT /note="Phosphoserine; by GSK3-beta" FT /evidence="ECO:0000250|UniProtKB:Q9WTL8" FT MOD_RES 21 FT /note="Phosphothreonine; by GSK3-beta" FT /evidence="ECO:0000250|UniProtKB:Q9WTL8" FT MOD_RES 78 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O00327" FT MOD_RES 90 FT /note="Phosphoserine; by CK2" FT /evidence="ECO:0000250|UniProtKB:Q9WTL8" FT MOD_RES 538 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q9WTL8" FT CROSSLNK 252 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2 and SUMO3)" FT /evidence="ECO:0000250|UniProtKB:Q9WTL8" FT CROSSLNK 259 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO); alternate" FT /evidence="ECO:0000250|UniProtKB:Q9WTL8" FT CROSSLNK 259 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2); alternate" FT /evidence="ECO:0000250|UniProtKB:O00327" SQ SEQUENCE 626 AA; 68701 MW; 65FDD28B38F1E016 CRC64; MADQRMDISS TISDFMSPGP TDLLSSSLGT SGVDCNRKRK GSATDYQESM DTDKDDPHGR LEYAEHQGRI KNAREAHSQI EKRRRDKMNS FIDELASLVP TCNAMSRKLD KLTVLRMAVQ HMKTLRGATN PYTEANYKPT FLSDDELKHL ILRAADGFLF VVGCDRGKIL FVSESVFKIL NYSQNDLIGQ SLFDYLHPKD IAKVKEQLSS SDTAPRERLI DAKTGLPVKT DITPGPSRLC SGARRSFFCR MKCNRPSVKV EDKDFASTCS KKKADRKSFC TIHSTGYLKS WPPTKMGLDE DNEPDNEGCN LSCLVAIGRL HSHVVPQPVN GEIRVKSMEY VSRHAIDGKF VFVDQRATAI LAYLPQELLG TSCYEYFHQD DIGHLAECHR QVLQTREKIT TNCYKFKIKD GSFITLRSRW FSFMNPWTKE VEYIVSTNTV VLANVLEGGD PTFPQLTASP HSMDSMLPSG EGGPKRTHPT VPGIPGGTRA GAGKIGRMIA EEIMEIHRIR GSSPSSCGSS PLNITSTPPP DASSPGGKKI LNGGTPDIPS TGLLPGQAQE TPGYPYSDSS SILGENPHIG IDMIDNDQGS SSPSNDEAAM AVIMSLLEAD AGLGGPVDFS DLPWPL //