BMAL1_TYTAL
ID BMAL1_TYTAL Reviewed; 633 AA.
AC Q6YGZ5;
DT 28-NOV-2006, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 90.
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 Tyto alba (Barn owl).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Archelosauria; Archosauria; Dinosauria; Saurischia; Theropoda;
OC Coelurosauria; Aves; Neognathae; Strigiformes; Tytonidae; Tyto.
OX NCBI_TaxID=56313;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=14662308; DOI=10.1016/s1096-4959(03)00276-8;
RA Fidler A.E., Gwinner E.;
RT "Comparative analysis of avian BMAL1 and CLOCK protein sequences: a search
RT for features associated with owl nocturnal behaviour.";
RL Comp. Biochem. Physiol. 136B:861-874(2003).
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. The preferred binding motif
CC for the CLOCK-ARNTL/BMAL1 heterodimer is 5'-CACGTGA-3', which contains
CC a flanking Ala residue in addition to the canonical 6-nucleotide E-box
CC sequence. CLOCK specifically binds to the half-site 5'-CAC-3', while
CC ARNTL binds to the half-site 5'-GTGA-3'. Essential for the rhythmic
CC interaction of CLOCK with ASS1 and plays a critical role in positively
CC regulating CLOCK-mediated acetylation of ASS1. Plays a role in
CC protecting against lethal sepsis by limiting the expression of immune
CC checkpoint protein CD274 in macrophages in a PKM2-dependent manner (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, 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). Interacts with PER1, PER2, CRY1
CC and CRY2 and this interaction requires a translocation to the nucleus
CC (By similarity). Interaction of the CLOCK-ARNTL/BMAL1 heterodimer with
CC PER or CRY inhibits transcription activation (By similarity).
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-ARNTL/BMAL1 heterodimer. The sumoylated form
CC localizes in the PML body. {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-545 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-545 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-97 by CK2 is essential for its nuclear
CC localization, its interaction with CLOCK and controls CLOCK nuclear
CC entry. Dephosphorylation at Ser-85 is important for dimerization with
CC CLOCK and transcriptional activity. {ECO:0000250|UniProtKB:O00327,
CC ECO:0000250|UniProtKB:Q9WTL8}.
CC -!- PTM: Sumoylated on Lys-266 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}.
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DR EMBL; AY150849; AAO06118.1; -; mRNA.
DR RefSeq; XP_009971016.1; XM_009972714.1.
DR AlphaFoldDB; Q6YGZ5; -.
DR SMR; Q6YGZ5; -.
DR GeneID; 104365864; -.
DR KEGG; tala:104365864; -.
DR CTD; 406; -.
DR OrthoDB; 331262at2759; -.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0016605; C:PML body; IEA:UniProtKB-SubCell.
DR GO; GO:0005667; C:transcription regulator complex; IEA:InterPro.
DR GO; GO:0003677; F:DNA binding; ISS:UniProtKB.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; IEA:InterPro.
DR GO; GO:0046983; F:protein dimerization activity; IEA:InterPro.
DR GO; GO:1901985; P:positive regulation of protein acetylation; ISS:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0051775; P:response to redox state; ISS:UniProtKB.
DR GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW.
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; Repeat; Transcription;
KW Transcription regulation; Ubl conjugation.
FT CHAIN 1..633
FT /note="Aryl hydrocarbon receptor nuclear translocator-like
FT protein 1"
FT /id="PRO_0000262646"
FT DOMAIN 79..132
FT /note="bHLH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981"
FT DOMAIN 150..222
FT /note="PAS 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140"
FT DOMAIN 333..403
FT /note="PAS 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140"
FT DOMAIN 408..451
FT /note="PAC"
FT REGION 1..65
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 472..499
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 518..555
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 149..159
FT /note="Nuclear export signal 1"
FT /evidence="ECO:0000250|UniProtKB:Q9WTL8"
FT MOTIF 368..376
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 519..540
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 84
FT /note="Interaction with E-box DNA"
FT /evidence="ECO:0000250|UniProtKB:O00327"
FT SITE 87
FT /note="Interaction with E-box DNA"
FT /evidence="ECO:0000250|UniProtKB:O00327"
FT SITE 88
FT /note="Interaction with E-box DNA"
FT /evidence="ECO:0000250|UniProtKB:O00327"
FT SITE 92
FT /note="Interaction with E-box DNA"
FT /evidence="ECO:0000250|UniProtKB:O00327"
FT SITE 132
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 85
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O00327"
FT MOD_RES 97
FT /note="Phosphoserine; by CK2"
FT /evidence="ECO:0000250|UniProtKB:Q9WTL8"
FT MOD_RES 545
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9WTL8"
FT CROSSLNK 259
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2 and SUMO3)"
FT /evidence="ECO:0000250|UniProtKB:Q9WTL8"
FT CROSSLNK 266
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000250|UniProtKB:Q9WTL8"
SQ SEQUENCE 633 AA; 69551 MW; 11167B3263E49518 CRC64;
MADQRMDISS TISDFMSPDP ADLISSSLST SGMDCNRKRK GSSTDYQLDG FPFEEGMDTD
KDDQHGRLEY TDQQGRIKNA REAHSQIEKR RRDKMNSFID ELASLVPTCN AMSRKLDKLT
VLRMAVQHMK TLRGATNPYT EANYKPAFLS DDELKHLILR AADGFLFVVG CDRGKILFVS
ESVFKILNYS QNDLIGQSLF DYLHPKDIAK VKEQLSSSDT APRERLIDAK TGLPVKTDIT
PGPSRLCSGA RRSFFCRMKC NRPSVKVEDK DFPSTCSKKK ADRKSFCTIH STGYLKSWPP
TKMGLDEDNE PDNEGCNLSC LVAIGRLHPH VVPQPVNGEI RVKPTEYVSR HAIDGKFVFV
DQRATAILAY LPQELLGTSC YEYFHQDDIG HLAECHRQVL QTREKITTNC YKFKIKDGSF
ITLRSRWFSF MNPWTKEVEY IVSTNTVVST NVLDSGDAAF PQLAASPHSM DSVLQAGEGG
PKRTHPTVPG IPGGTRAGAG KIGRMIAEEI MEIHRIRGSS PSSCGSSPLN ITSTPPPDTS
SPGGKKILNG GTPDISSAGL LSGQIQDNSG YPYSDNSSIL GENSHIGIDM IDNDQGSSSP
SNDEAAMAVI MSLLEADAGL GGPVDFSDLP WPL
