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 12-OCT-2022, entry version 144. DE RecName: Full=Aryl hydrocarbon receptor nuclear translocator-like protein 1; DE AltName: Full=Brain and muscle ARNT-like 1; GN Name=ARNTL; Synonyms=BMAL1; 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, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and CC CRY2) plays a critical role in rhythm generation, whereas delays CC imposed by post-translational modifications (PTMs) are important for CC determining the period (tau) of the rhythms (tau refers to the period CC of a rhythm and is the length, in time, of one complete cycle). A CC diurnal rhythm is synchronized with the day/night cycle, while the CC ultradian and infradian rhythms have a period shorter and longer than CC 24 hours, respectively. Disruptions in the circadian rhythms contribute CC to the pathology of cardiovascular diseases, cancer, metabolic CC syndromes and aging. A transcription/translation feedback loop (TTFL) CC forms the core of the molecular circadian clock mechanism. CC Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2, CC form the positive limb of the feedback loop, act in the form of a CC heterodimer and activate the transcription of core clock genes and CC clock-controlled genes (involved in key metabolic processes), harboring CC E-box elements (5'-CACGTG-3') within their promoters. The core clock CC genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form CC the negative limb of the feedback loop and interact with the CC CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its CC activity and thereby negatively regulating their own expression. This CC heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, CC which form a second feedback loop and which activate and repress CC ARNTL/BMAL1 transcription, respectively. ARNTL/BMAL1 positively CC regulates 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-ARNTL/BMAL1 heterodimer regulates the CC circadian expression of SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, CC MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, CC ATF4, MTA1, KLF10 and also genes implicated in glucose and lipid CC metabolism. Promotes rhythmic chromatin opening, regulating the DNA CC accessibility of other transcription factors. The NPAS2-ARNTL/BMAL1 CC heterodimer positively regulates the expression of MAOA, F7 and LDHA CC and modulates the circadian rhythm of daytime contrast sensitivity by CC regulating the rhythmic expression of adenylate cyclase type 1 (ADCY1) CC in the retina. The preferred binding motif for the CLOCK-ARNTL/BMAL1 CC heterodimer is 5'-CACGTGA-3', which contains a flanking Ala residue in CC addition to the canonical 6-nucleotide E-box sequence. CLOCK CC specifically binds to the half-site 5'-CAC-3', while ARNTL binds to the CC half-site 5'-GTGA-3'. The CLOCK-ARNTL/BMAL1 heterodimer also recognizes CC the non-canonical E-box motifs 5'-AACGTGA-3' and 5'-CATGTGA-3'. CC Essential for the rhythmic interaction of CLOCK with ASS1 and plays a CC critical role in positively regulating CLOCK-mediated acetylation of CC ASS1. Plays a role in protecting against lethal sepsis by limiting the CC expression of immune checkpoint protein CD274 in macrophages in a PKM2- CC dependent manner (By similarity). Regulates the diurnal rhythms of CC skeletal muscle metabolism via transcriptional activation of genes CC promoting triglyceride synthesis (DGAT2) and metabolic efficiency CC (COQ10B) (By 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, ARNTL/BMAL1 or ARNTL2/BMAL2, CSNK1D CC and/or CSNK1E, TIMELESS and the PER1/2/3 proteins (By similarity). CC Forms a heterodimer with CLOCK (By similarity). The CLOCK-ARNTL/BMAL1 CC heterodimer is required for E-box-dependent transactivation, for CLOCK CC nuclear translocation and degradation, and, for phosphorylation of both CC CLOCK and ARNTL/BMAL1 (By similarity). Part of a nuclear complex which CC also includes RACK1 and PRKCA; RACK1 and PRKCA are recruited to the CC complex in a circadian manner (By similarity). Interacts with NPAS2 (By CC similarity). Interacts with EZH2 (By similarity). Interacts with SUMO3 CC (By similarity). Interacts with SIRT1 (By similarity). Interacts with CC AHR (By similarity). Interacts with ID1, ID2 and ID3 (By similarity). CC Interacts with DDX4 (By similarity). Interacts with OGT (By CC similarity). Interacts with EED and SUZ12 (By similarity). Interacts CC with MTA1 (By similarity). Interacts with CIART (By similarity). CC Interacts with HSP90 (By similarity). Interacts with KAT2B and EP300 CC (By similarity). Interacts with BHLHE40/DEC1 and BHLHE41/DEC2 (By CC similarity). Interacts with RELB and the interaction is enhanced in the CC presence of CLOCK (By similarity). Interacts with PER1, PER2, CRY1 and CC CRY2 and this interaction requires a translocation to the nucleus (By CC similarity). Interaction of the CLOCK-ARNTL/BMAL1 heterodimer with PER CC or CRY inhibits transcription activation (By similarity). Interaction CC of the CLOCK-ARNTL/BMAL1 with CRY1 is independent of DNA but with PER2 CC is off DNA (By similarity). The CLOCK-ARNTL/BMAL1 heterodimer interacts CC with GSK3B (By similarity). Interacts with KDM5A (By similarity). CC Interacts with KMT2A; in a circadian manner (By similarity). Interacts CC with UBE3A (By similarity). Interacts with PRKCG (By similarity). CC Interacts with MAGEL2 (By similarity). Interacts with NCOA2 (By CC similarity). Interacts with THRAP3 (By similarity). The CLOCK- CC ARNTL/BMAL1 heterodimer interacts with PASD1 (By similarity). Interacts CC with PASD1 (By similarity). Interacts with USP9X (By similarity). CC Interacts with PIWIL2 (via PIWI domain) (By similarity). Interacts with CC HDAC3 (By similarity). Interacts with HNF4A (By similarity). CC {ECO:0000250|UniProtKB:O00327, 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-ARNTL/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-ARNTL/BMAL1 heterodimer thereby increasing CLOCK-ARNTL/BMAL1- CC mediated transcription of genes in the negative loop of the circadian CC clock such 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-ARNTL/BMAL1 CC heterodimer by promoting its degradation. Phosphorylation shows CC circadian 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-ARNTL/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.XP_005075715.1; -. DR GeneID; 101835598; -. DR CTD; 406; -. DR eggNOG; KOG3561; Eukaryota. DR OrthoDB; 331262at2759; -. 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; cd00130; PAS; 2. DR Gene3D; 4.10.280.10; -; 1. 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 Pfam; PF00010; HLH; 1. DR Pfam; PF00989; PAS; 1. DR PRINTS; PR00785; NCTRNSLOCATR. DR SMART; SM00353; HLH; 1. DR SMART; SM00086; PAC; 1. DR SMART; SM00091; PAS; 2. DR SUPFAM; SSF47459; SSF47459; 1. DR SUPFAM; SSF55785; SSF55785; 2. DR TIGRFAMs; TIGR00229; sensory_box; 1. 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="Aryl hydrocarbon receptor nuclear translocator-like FT 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 //