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 10-APR-2019, entry version 131. 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; OC Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; OC Muroidea; 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 CC of the circadian clock. The circadian clock, an internal time- CC keeping system, regulates various physiological processes through CC the generation of approximately 24 hour circadian rhythms in gene CC expression, which are translated into rhythms in metabolism and CC behavior. It is derived from the Latin roots 'circa' (about) and CC 'diem' (day) and acts as an important regulator of a wide array of CC physiological functions including metabolism, sleep, body CC temperature, blood pressure, endocrine, immune, cardiovascular, CC and renal function. Consists of two major components: the central CC clock, residing in the suprachiasmatic nucleus (SCN) of the brain, CC and the peripheral clocks that are present in nearly every tissue CC and organ system. Both the central and peripheral clocks can be CC reset by environmental cues, also known as Zeitgebers (German for CC 'timegivers'). The predominant Zeitgeber for the central clock is CC light, which is sensed by retina and signals directly to the SCN. CC The central clock entrains the peripheral clocks through neuronal CC and hormonal signals, body temperature and feeding-related cues, CC 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 CC to create a peak of protein expression once every 24 hours to CC control when a particular physiological process is most active CC with respect to the solar day. Transcription and translation of CC core clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, CC PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm CC generation, whereas delays imposed by post-translational CC modifications (PTMs) are important for determining the period CC (tau) of the rhythms (tau refers to the period of a rhythm and is CC 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 CC the pathology of cardiovascular diseases, cancer, metabolic CC syndromes and aging. A transcription/translation feedback loop CC (TTFL) forms the core of the molecular circadian clock mechanism. CC Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or CC ARNTL2/BMAL2, form the positive limb of the feedback loop, act in CC the form of a heterodimer and activate the transcription of core CC clock genes and clock-controlled genes (involved in key metabolic CC processes), harboring E-box elements (5'-CACGTG-3') within their CC promoters. The core clock genes: PER1/2/3 and CRY1/2 which are CC transcriptional repressors form the negative limb of the feedback CC loop and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 CC heterodimer inhibiting its activity and thereby negatively CC regulating their own expression. This heterodimer also activates CC nuclear receptors NR1D1/2 and RORA/B/G, which form a second CC feedback loop and which activate and repress ARNTL/BMAL1 CC transcription, respectively. ARNTL/BMAL1 positively regulates CC myogenesis and negatively regulates adipogenesis via the CC transcriptional control of the genes of the canonical Wnt CC signaling pathway. Plays a role in normal pancreatic beta-cell CC function; regulates glucose-stimulated insulin secretion via the CC regulation of antioxidant genes NFE2L2/NRF2 and its targets SESN2, CC PRDX3, CCLC and CCLM. Negatively regulates the mTORC1 signaling CC pathway; regulates the expression of MTOR and DEPTOR. Controls CC diurnal oscillations of Ly6C inflammatory monocytes; rhythmic CC recruitment of the PRC2 complex imparts diurnal variation to CC chemokine expression that is necessary to sustain Ly6C monocyte CC rhythms. Regulates the expression of HSD3B2, STAR, PTGS2, CYP11A1, CC CYP19A1 and LHCGR in the ovary and also the genes involved in hair CC growth. Plays an important role in adult hippocampal neurogenesis CC by regulating the timely entry of neural stem/progenitor cells CC (NSPCs) into the cell cycle and the number of cell divisions that CC take place prior to cell-cycle exit. Regulates the circadian CC expression of CIART and KLF11. The CLOCK-ARNTL/BMAL1 heterodimer CC regulates the circadian expression of SERPINE1/PAI1, VWF, B3, CC CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2, CC F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10 and also genes CC implicated in glucose and lipid metabolism. Promotes rhythmic CC chromatin opening, regulating the DNA accessibility of other CC transcription factors. The NPAS2-ARNTL/BMAL1 heterodimer CC positively regulates the expression of MAOA, F7 and LDHA and CC modulates the circadian rhythm of daytime contrast sensitivity by CC regulating the rhythmic expression of adenylate cyclase type 1 CC (ADCY1) in the retina. The preferred binding motif for the CLOCK- CC ARNTL/BMAL1 heterodimer is 5'-CACGTGA-3', which contains a CC flanking Ala residue in addition to the canonical 6-nucleotide E- CC box sequence. CLOCK specifically binds to the half-site 5'-CAC-3', CC while ARNTL binds to the half-site 5'-GTGA-3'. The CLOCK- CC ARNTL/BMAL1 heterodimer also recognizes the non-canonical E-box CC motifs 5'-AACGTGA-3' and 5'-CATGTGA-3'. Essential for the rhythmic CC interaction of CLOCK with ASS1 and plays a critical role in CC positively regulating CLOCK-mediated acetylation of ASS1. Plays a CC role in protecting against lethal sepsis by limiting the CC expression of immune checkpoint protein CD274 in macrophages in a CC PKM2-dependent manner (By similarity). CC {ECO:0000250|UniProtKB:O00327, ECO:0000250|UniProtKB:Q9WTL8}. CC -!- SUBUNIT: Component of the circadian clock oscillator which CC includes the CRY1/2 proteins, CLOCK or NPAS2, ARNTL/BMAL1 or CC ARNTL2/BMAL2, CSNK1D and/or CSNK1E, TIMELESS and the PER1/2/3 CC proteins (By similarity). Forms a heterodimer with CLOCK (By CC similarity). The CLOCK-ARNTL/BMAL1 heterodimer is required for E- CC box-dependent transactivation, for CLOCK nuclear translocation and CC degradation, and, for phosphorylation of both CLOCK and CC ARNTL/BMAL1 (By similarity). Part of a nuclear complex which also CC includes RACK1 and PRKCA; RACK1 and PRKCA are recruited to the CC complex in a circadian manner (By similarity). Interacts with CC NPAS2 (By similarity). Interacts with EZH2 (By similarity). CC Interacts with SUMO3 (By similarity). Interacts with SIRT1 (By CC similarity). Interacts with AHR (By similarity). Interacts with CC ID1, ID2 and ID3 (By similarity). Interacts with DDX4 (By CC similarity). Interacts with OGT (By similarity). Interacts with CC EED and SUZ12 (By similarity). Interacts with MTA1 (By CC similarity). Interacts with CIART (By similarity). Interacts with CC HSP90 (By similarity). Interacts with KAT2B and EP300 (By CC similarity). Interacts with BHLHE40/DEC1 and BHLHE41/DEC2 (By CC similarity). Interacts with RELB and the interaction is enhanced CC in the presence of CLOCK (By similarity). Interacts with PER1, CC PER2, CRY1 and CRY2 and this interaction requires a translocation CC to the nucleus (By similarity). Interaction of the CLOCK- CC ARNTL/BMAL1 heterodimer with PER or CRY inhibits transcription CC activation (By similarity). Interaction of the CLOCK-ARNTL/BMAL1 CC with CRY1 is independent of DNA but with PER2 is off DNA (By CC similarity). The CLOCK-ARNTL/BMAL1 heterodimer interacts with CC GSK3B (By similarity). Interacts with KDM5A (By similarity). CC Interacts with KMT2A; in a circadian manner (By similarity). CC Interacts with UBE3A (By similarity). Interacts with PRKCG (By CC similarity). Interacts with MAGEL2 (By similarity). Interacts with CC NCOA2 (By similarity). Interacts with THRAP3 (By similarity). The CC CLOCK-ARNTL/BMAL1 heterodimer interacts with PASD1 (By CC similarity). Interacts with PASD1 (By similarity). Interacts with CC USP9X (By similarity). Interacts with PIWIL2 (via PIWI domain) (By CC similarity). Interacts with HDAC3 (By similarity). CC {ECO:0000250|UniProtKB:O00327, ECO:0000250|UniProtKB:Q9WTL8}. CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE- CC ProRule:PRU00981}. Cytoplasm {ECO:0000250|UniProtKB:Q9WTL8}. CC Nucleus, PML body {ECO:0000250|UniProtKB:Q9WTL8}. Note=Shuttles CC between the nucleus and the cytoplasm and this nucleocytoplasmic CC shuttling is essential for the nuclear accumulation of CLOCK, CC target gene transcription and the degradation of the CLOCK- CC ARNTL/BMAL1 heterodimer. The sumoylated form localizes in the PML CC body. Sequestered to the cytoplasm in the presence of ID2. CC {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 CC prevents protein degradation by inhibiting ubiquitination. It also CC stabilizes the CLOCK-ARNTL/BMAL1 heterodimer thereby increasing CC CLOCK-ARNTL/BMAL1-mediated transcription of genes in the negative CC loop of the circadian clock such as PER1/2/3 and CRY1/2. CC {ECO:0000250|UniProtKB:Q9WTL8}. CC -!- PTM: Acetylated on Lys-538 upon dimerization with CLOCK. CC Acetylation facilitates CRY1-mediated repression. Deacetylated by CC 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 CC CT14. Phosphorylation at Ser-90 by CK2 is essential for its CC nuclear localization, its interaction with CLOCK and controls CC CLOCK nuclear entry. Dephosphorylation at Ser-78 is important for CC dimerization with CLOCK and transcriptional activity. CC {ECO:0000250|UniProtKB:O00327, ECO:0000250|UniProtKB:Q9WTL8}. CC -!- PTM: Sumoylated on Lys-259 upon dimerization with CLOCK. CC Predominantly conjugated to poly-SUMO2/3 rather than SUMO1 and the CC level of these conjugates undergo rhythmic variation, peaking at CC CT9-CT12. Sumoylation localizes it exclusively to the PML body and CC promotes its ubiquitination in the PML body, ubiquitin-dependent CC proteasomal degradation and the transcriptional activity of the CC CLOCK-ARNTL/BMAL1 heterodimer. {ECO:0000250|UniProtKB:Q9WTL8}. CC -!- PTM: Undergoes lysosome-mediated degradation in a time-dependent CC manner 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 ProteinModelPortal; O88529; -. DR SMR; O88529; -. DR IntAct; O88529; 1. DR STRING; 10036.XP_005075715.1; -. DR PRIDE; O88529; -. DR Ensembl; ENSMAUT00000011481; ENSMAUP00000007669; ENSMAUG00000009271. DR GeneID; 101835598; -. DR CTD; 406; -. DR HOVERGEN; HBG107503; -. DR Proteomes; UP000189706; Genome assembly. DR GO; GO:0033391; C:chromatoid body; ISS:UniProtKB. DR GO; GO:0005634; C:nucleus; ISS:UniProtKB. DR GO; GO:0016605; C:PML body; IEA:UniProtKB-SubCell. DR GO; GO:0005667; C:transcription factor complex; ISS:UniProtKB. DR GO; GO:0017162; F:aryl hydrocarbon receptor binding; IEA:Ensembl. DR GO; GO:0043425; F:bHLH transcription factor binding; IEA:Ensembl. DR GO; GO:0003677; F:DNA binding; ISS:UniProtKB. DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IEA:Ensembl. DR GO; GO:0070888; F:E-box binding; ISS:UniProtKB. DR GO; GO:0051879; F:Hsp90 protein binding; IEA:Ensembl. DR GO; GO:0046982; F:protein heterodimerization activity; IEA:Ensembl. DR GO; GO:0070491; F:repressing transcription factor binding; IEA:Ensembl. DR GO; GO:0000980; F:RNA polymerase II distal enhancer sequence-specific DNA binding; ISS:UniProtKB. DR GO; GO:0043565; F:sequence-specific DNA binding; ISS:UniProtKB. DR GO; GO:0000976; F:transcription regulatory region sequence-specific DNA binding; ISS:UniProtKB. DR GO; GO:0032922; P:circadian regulation of gene expression; ISS:UniProtKB. DR GO; GO:0060137; P:maternal process involved in parturition; IEA:Ensembl. DR GO; GO:0120163; P:negative regulation of cold-induced thermogenesis; IEA:Ensembl. 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:0045892; P:negative regulation of transcription, DNA-templated; 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: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:0045893; P:positive regulation of transcription, DNA-templated; ISS:UniProtKB. 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: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:0042176; P:regulation of protein catabolic process; IEA:Ensembl. DR GO; GO:0006355; P:regulation of transcription, DNA-templated; 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; cd00083; HLH; 1. 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; Complete proteome; KW Cytoplasm; DNA-binding; Isopeptide bond; Nucleus; Phosphoprotein; KW Reference proteome; Repeat; Transcription; Transcription regulation; KW Ubl conjugation. FT CHAIN 1 626 Aryl hydrocarbon receptor nuclear FT translocator-like protein 1. FT /FTId=PRO_0000127157. FT DOMAIN 72 125 bHLH. {ECO:0000255|PROSITE- FT ProRule:PRU00981}. FT DOMAIN 143 215 PAS 1. {ECO:0000255|PROSITE- FT ProRule:PRU00140}. FT DOMAIN 326 396 PAS 2. {ECO:0000255|PROSITE- FT ProRule:PRU00140}. FT DOMAIN 401 444 PAC. FT REGION 508 588 Interaction with CIART. FT {ECO:0000250|UniProtKB:Q9WTL8}. FT MOTIF 36 41 Nuclear localization signal. FT {ECO:0000250|UniProtKB:Q9WTL8}. FT MOTIF 142 152 Nuclear export signal 1. FT {ECO:0000250|UniProtKB:Q9WTL8}. FT MOTIF 361 369 Nuclear export signal 2. FT {ECO:0000250|UniProtKB:Q9WTL8}. FT SITE 77 77 Interaction with E-box DNA. FT {ECO:0000250|UniProtKB:O00327}. FT SITE 80 80 Interaction with E-box DNA. FT {ECO:0000250|UniProtKB:O00327}. FT SITE 81 81 Interaction with E-box DNA. FT {ECO:0000250|UniProtKB:O00327}. FT SITE 85 85 Interaction with E-box DNA. FT {ECO:0000250|UniProtKB:O00327}. FT SITE 125 125 Important for interaction with CLOCK. FT {ECO:0000250|UniProtKB:O00327}. FT MOD_RES 17 17 Phosphoserine; by GSK3-beta. FT {ECO:0000250|UniProtKB:Q9WTL8}. FT MOD_RES 21 21 Phosphothreonine; by GSK3-beta. FT {ECO:0000250|UniProtKB:Q9WTL8}. FT MOD_RES 78 78 Phosphoserine. FT {ECO:0000250|UniProtKB:O00327}. FT MOD_RES 90 90 Phosphoserine; by CK2. FT {ECO:0000250|UniProtKB:Q9WTL8}. FT MOD_RES 538 538 N6-acetyllysine. FT {ECO:0000250|UniProtKB:Q9WTL8}. FT CROSSLNK 252 252 Glycyl lysine isopeptide (Lys-Gly) FT (interchain with G-Cter in SUMO2 and FT SUMO3). {ECO:0000250|UniProtKB:Q9WTL8}. FT CROSSLNK 259 259 Glycyl lysine isopeptide (Lys-Gly) FT (interchain with G-Cter in SUMO); FT alternate. FT {ECO:0000250|UniProtKB:Q9WTL8}. FT CROSSLNK 259 259 Glycyl lysine isopeptide (Lys-Gly) FT (interchain with G-Cter in SUMO2); FT alternate. FT {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 //