BMAL1_PONAB
ID BMAL1_PONAB Reviewed; 625 AA.
AC Q5R4T2;
DT 28-NOV-2006, integrated into UniProtKB/Swiss-Prot.
DT 21-DEC-2004, sequence version 1.
DT 03-AUG-2022, entry version 107.
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 Pongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pongo.
OX NCBI_TaxID=9601;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain cortex;
RG The German cDNA consortium;
RL Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases.
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-537 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-537 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; CR861161; CAH93234.1; -; mRNA.
DR RefSeq; NP_001126900.1; NM_001133428.1.
DR AlphaFoldDB; Q5R4T2; -.
DR SMR; Q5R4T2; -.
DR STRING; 9601.ENSPPYP00000003988; -.
DR GeneID; 100173916; -.
DR KEGG; pon:100173916; -.
DR CTD; 406; -.
DR eggNOG; KOG3561; Eukaryota.
DR InParanoid; Q5R4T2; -.
DR OrthoDB; 331262at2759; -.
DR Proteomes; UP000001595; Unplaced.
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 regulator complex; ISS:UniProtKB.
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: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: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:0045944; P:positive regulation of transcription by RNA polymerase II; IEA:UniProt.
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: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; 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; 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..625
FT /note="Aryl hydrocarbon receptor nuclear translocator-like
FT protein 1"
FT /id="PRO_0000263006"
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 325..395
FT /note="PAS 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140"
FT DOMAIN 400..443
FT /note="PAC"
FT REGION 1..60
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 454..491
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 507..587
FT /note="Interaction with CIART"
FT /evidence="ECO:0000250|UniProtKB:Q9WTL8"
FT REGION 510..594
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 360..368
FT /note="Nuclear export signal 2"
FT /evidence="ECO:0000250|UniProtKB:Q9WTL8"
FT COMPBIAS 1..37
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 38..60
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 511..531
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 547..573
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 537
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 625 AA; 68682 MW; 7AF05583E7A96912 CRC64;
MADQRMDISS TISDFMSPGP TDLLSSSLGT SGVDCNRKRK GSSTDYQESM DTDKDDPHGR
LEYTEHQGRI KNAREAHSQI EKRRRDKMNS FIDELASLVP TCNAMSRKLD KLTVLRMAVQ
HMKTLRGATN PYTEANYKPT FLSDDELKHL ILRAADGFLF VVGCDRGKIL FVSESAFKIL
NYSQNDLIGQ SLFDYLHPKD IAKVKEQLSS SDTAPRERLI DAKTGLPVKT DITPGPSRLC
SGARRSFFCR MKCNRPSVKV EDKDFPSTCS KKKDRKSFCT IHSTGYLKSW PPTKMGLDED
NEPDNEGCNL SCLVAIGRLH SHVVPQPVNG EIRVKSMEYV SRHAIDGKFV FVDQRATAIL
AYLPQELLGT SCYEYFHQDD IGHLAECHRQ VLQTREKITT NCYKFKIKDG SFITLRSRWF
SFMNPWTKEV EYIVSTNTVV LANVLEGGDP TFPQLTASPR SMDSMLPSGE GGPKRTHPTV
PGIPGGTRAG AGKIGRMIAE EIMEIHRIRG SSPSSCGSSP LNITSTPPPD ASSPGGKKIL
NGGTPDIPSS GLLSGQAQEN PGYPYSDSSS ILGENPHIGI DMIDNDQGSS SPSNDEAAMA
VIMSLLEADA GLGGPVDFSD LPWPL
