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Protein

Aryl hydrocarbon receptor nuclear translocator-like protein 1

Gene

Arntl

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at transcript leveli

Functioni

Transcriptional activator which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress ARNTL/BMAL1 transcription, respectively. ARNTL/BMAL1 positively regulates myogenesis and negatively regulates adipogenesis via the transcriptional control of the genes of the canonical Wnt signaling pathway. Plays a role in normal pancreatic beta-cell function; regulates glucose-stimulated insulin secretion via the regulation of antioxidant genes NFE2L2/NRF2 and its targets SESN2, PRDX3, CCLC and CCLM. Negatively regulates the mTORC1 signaling pathway; regulates the expression of MTOR and DEPTOR. Controls diurnal oscillations of Ly6C inflammatory monocytes; rhythmic recruitment of the PRC2 complex imparts diurnal variation to chemokine expression that is necessary to sustain Ly6C monocyte rhythms. Regulates the expression of HSD3B2, STAR, PTGS2, CYP11A1, CYP19A1 and LHCGR in the ovary and also the genes involved in hair growth. Plays an important role in adult hippocampal neurogenesis by regulating the timely entry of neural stem/progenitor cells (NSPCs) into the cell cycle and the number of cell divisions that take place prior to cell-cycle exit. Regulates the circadian expression of CIART and KLF11. The CLOCK-ARNTL/BMAL1 heterodimer regulates the circadian expression of SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10 and also genes implicated in glucose and lipid metabolism. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by reducing the association of NR3C1/GR to glucocorticoid response elements (GREs) via the acetylation of multiple lysine residues located in its hinge region. Promotes rhythmic chromatin opening, regulating the DNA accessibility of other transcription factors. May play a role in spermatogenesis; contributes to the chromatoid body assembly and physiology. The NPAS2-ARNTL/BMAL1 heterodimer positively regulates the expression of MAOA, F7 and LDHA and modulates the circadian rhythm of daytime contrast sensitivity by regulating the rhythmic expression of adenylate cyclase type 1 (ADCY1) in the retina.2 Publications

Enzyme regulationi

The redox state of the cell can modulate the transcriptional activity of the CLOCK-ARNTL/BMAL1 and NPAS2-ARNTL/BMAL1 heterodimers; NADH and NADPH enhance the DNA-binding activity of the heterodimers.By similarity

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Activator

Keywords - Biological processi

Biological rhythms, Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Aryl hydrocarbon receptor nuclear translocator-like protein 1
Alternative name(s):
Brain and muscle ARNT-like 1
Tic
Gene namesi
Name:Arntl
Synonyms:Bmal1, Tic
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi62003. Arntl.

Subcellular locationi

  • Nucleus PROSITE-ProRule annotation1 Publication
  • Cytoplasm By similarity
  • NucleusPML body By similarity

  • Note: Shuttles between the nucleus and the cytoplasm and this nucleocytoplasmic shuttling is essential for the nuclear accumulation of CLOCK, target gene transcription and the degradation of the CLOCK-ARNTL/BMAL1 heterodimer. The sumoylated form localizes in the PML body. Sequestered to the cytoplasm in the presence of ID2.By similarity

GO - Cellular componenti

  • chromatoid body Source: UniProtKB
  • nucleus Source: UniProtKB
  • PML body Source: UniProtKB-SubCell
  • transcription factor complex Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 626626Aryl hydrocarbon receptor nuclear translocator-like protein 1PRO_0000127159Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei17 – 171Phosphoserine; by GSK3-betaBy similarity
Modified residuei21 – 211Phosphothreonine; by GSK3-betaBy similarity
Modified residuei90 – 901Phosphoserine; by CK2By similarity
Cross-linki252 – 252Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2 and SUMO3)By similarity
Cross-linki259 – 259Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)By similarity
Modified residuei538 – 5381N6-acetyllysineBy similarity

Post-translational modificationi

Ubiquitinated, leading to its proteasomal degradation.By similarity
O-glycosylated; contains O-GlcNAc. O-glycosylation by OGT prevents protein degradation by inhibiting ubiquitination. It also stabilizes the CLOCK-ARNTL/BMAL1 heterodimer thereby increasing CLOCK-ARNTL/BMAL1-mediated transcription of genes in the negative loop of the circadian clock such as PER1/2/3 and CRY1/2.By similarity
Acetylated on Lys-538 upon dimerization with CLOCK. Acetylation facilitates CRY1-mediated repression. Deacetylated by SIRT1, which may result in decreased protein stability.By similarity
Phosphorylated upon dimerization with CLOCK. Phosphorylation enhances the transcriptional activity, alters the subcellular localization and decreases the stability of the CLOCK-ARNTL/BMAL1 heterodimer by promoting its degradation. Phosphorylation shows circadian variations in the liver with a peak between CT10 to CT14. Phosphorylation at Ser-90 by CK2 is essential for its nuclear localization, its interaction with CLOCK and controls CLOCK nuclear entry.By similarity
Sumoylated on Lys-259 upon dimerization with CLOCK. Predominantly conjugated to poly-SUMO2/3 rather than SUMO1 and the level of these conjugates undergo rhythmic variation, peaking at CT9-CT12. Sumoylation localizes it exclusively to the PML body and promotes its ubiquitination in the PML body, ubiquitin-dependent proteasomal degradation and the transcriptional activity of the CLOCK-ARNTL/BMAL1 heterodimer.By similarity

Keywords - PTMi

Acetylation, Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

PRIDEiQ9EPW1.

PTM databases

PhosphoSiteiQ9EPW1.

Interactioni

Subunit structurei

Component of the circadian clock oscillator which includes the CRY1/2 proteins, CLOCK or NPAS2, ARNTL/BMAL1 or ARNTL2/BMAL2, CSNK1D and/or CSNK1E, TIMELESS and the PER1/2/3 proteins. Efficient DNA binding requires dimerization with another bHLH protein. Heterodimerization with CLOCK is required for E-box-dependent transactivation, for CLOCK nuclear translocation and degradation, and, for phosphorylation of both CLOCK and ARNTL/BMAL1. Part of a nuclear complex which also includes RACK1 and PRKCA; RACK1 and PRKCA are recruited to the complex in a circadian manner. Interacts with NPAS2, HSP90, AHR, CIART, DDX4, SUMO3, OGT, EED, EZH2, SUZ12, KAT2B, EP300, BHLHE40/DEC1, BHLHE41/DEC2, ID1, ID2, ID3, MTA1 and SIRT1. Interacts with RELB and the interaction is enhanced in the presence of CLOCK. Interacts with PER1, PER2, CRY1 and CRY2 and this interaction requires a translocation to the nucleus. Interaction of the CLOCK-ARNTL/BMAL1 heterodimer with PER or CRY inhibits transcription activation. Interaction of the CLOCK-ARNTL/BMAL1 with CRY1 is independent of DNA but with PER2 is off DNA. The CLOCK-ARNTL/BMAL1 heterodimer interacts with GSK3B. Interacts with KDM5A. Interacts with KMT2A in a circadian manner. Interacts with UBE3A and PRKCG. Interacts with MAGEL2. Interacts with NCOA2. Interacts with THRAP3. The CLOCK-ARNTL/BMAL1 heterodimer interacts with PASD1. Interacts with PASD1.By similarity

Structurei

3D structure databases

ProteinModelPortaliQ9EPW1.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini72 – 12554bHLHPROSITE-ProRule annotationAdd
BLAST
Domaini143 – 21573PAS 1PROSITE-ProRule annotationAdd
BLAST
Domaini326 – 39671PAS 2PROSITE-ProRule annotationAdd
BLAST
Domaini401 – 44444PACAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni508 – 58881Interaction with CIARTBy similarityAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi36 – 416Nuclear localization signalBy similarity
Motifi142 – 15211Nuclear export signal 1By similarityAdd
BLAST
Motifi361 – 3699Nuclear export signal 2By similarity

Sequence similaritiesi

Contains 1 bHLH (basic helix-loop-helix) domain.PROSITE-ProRule annotation
Contains 2 PAS (PER-ARNT-SIM) domains.PROSITE-ProRule annotation

Keywords - Domaini

Repeat

Phylogenomic databases

HOGENOMiHOG000234379.
HOVERGENiHBG107503.
InParanoidiQ9EPW1.
KOiK02296.
PhylomeDBiQ9EPW1.

Family and domain databases

Gene3Di4.10.280.10. 1 hit.
InterProiIPR011598. bHLH_dom.
IPR001067. Nuc_translocat.
IPR001610. PAC.
IPR000014. PAS.
IPR013767. PAS_fold.
[Graphical view]
PfamiPF00010. HLH. 1 hit.
PF00989. PAS. 1 hit.
[Graphical view]
PRINTSiPR00785. NCTRNSLOCATR.
SMARTiSM00353. HLH. 1 hit.
SM00086. PAC. 1 hit.
SM00091. PAS. 2 hits.
[Graphical view]
SUPFAMiSSF47459. SSF47459. 1 hit.
SSF55785. SSF55785. 3 hits.
TIGRFAMsiTIGR00229. sensory_box. 1 hit.
PROSITEiPS50888. BHLH. 1 hit.
PS50112. PAS. 2 hits.
[Graphical view]

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9EPW1-1) [UniParc]FASTAAdd to basket

Also known as: b

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MADQRMDISS TISDFMSPGP TDLLSGSLST SGVDCNRKRK GSATDYQESM
60 70 80 90 100
DTDKDDPHGR LEYAEHQGRI KNAREAHSQI EKRRRDKMNS FIDELASLVP
110 120 130 140 150
TCNAMSRKLD KLTVLRMAVQ HMKTLRGATN PYTEANYKPT SLSDDELKHL
160 170 180 190 200
ILRAADGFLF VVGCDRGKIL FVSESVFKIL NYSQNDLIGQ SLFDYLHPKD
210 220 230 240 250
IAKVKEQLSS SDTAPRERLI DAKTGLPVKT DITPGPSRLC SGARRSFFCR
260 270 280 290 300
MKCNRPSVKV EDKDFASTCS KKKADRKSFC TIHSTGYLKS WPPTKMGLDE
310 320 330 340 350
DSEPDNEGCN LSCLVAIGRL HSHMVPQPVN GEIRVKSMEY VSRHAIDGKF
360 370 380 390 400
VFVDQRATAI LAYLPQELLG TSCYEYFHQD DIGHLAECHR QVLQTREKIT
410 420 430 440 450
TNCYKFKIKD GSFITLRSRW FSFMNPWTKE VEYIVSTNTV VLANVLEGGD
460 470 480 490 500
PTFPQLTASP HSMDSMLPSG EGGPKRTHPT VPGIPGGTRA GAGKIGRMIA
510 520 530 540 550
EEIMEIHRIR GSSPSSCGSS PLNITSTPPP DASSPGGKKI LNGGTPDIPS
560 570 580 590 600
AGLLPGQAQE TPGYPYSDSS SILGENPHIG IDMIDNDQGS SSPSNDEAAM
610 620
AVIMSLLEAD AGLGGPVDFS DLPWPL
Length:626
Mass (Da):68,616
Last modified:May 1, 2007 - v4
Checksum:i512746E8F87659F5
GO
Isoform 2 (identifier: Q9EPW1-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     154-184: Missing.

Show »
Length:595
Mass (Da):65,210
Checksum:i3C820D257896234D
GO
Isoform 3 (identifier: Q9EPW1-3) [UniParc]FASTAAdd to basket

Also known as: g'

The sequence of this isoform differs from the canonical sequence as follows:
     154-263: AADGFLFVVG...NRPSVKVEDK → DVTEGRSSLS...RRLDFRLKRI
     264-626: Missing.

Show »
Length:263
Mass (Da):29,671
Checksum:i94B364DA512C43B5
GO

Sequence cautioni

The sequence AAC21449.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti141 – 1411S → F in AAC21449 (PubMed:9585435).Curated
Sequence conflicti141 – 1411S → F in AAG34180 (Ref. 3) Curated
Sequence conflicti141 – 1411S → F in AAH99833 (PubMed:15489334).Curated
Sequence conflicti505 – 5051E → G in BAA33450 (PubMed:9735336).Curated
Sequence conflicti603 – 6031I → T in BAA33450 (PubMed:9735336).Curated

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei154 – 263110AADGF…KVEDK → DVTEGRSSLSPNLSSRSSII ARMTLLARVCSTTCIQKILP KLRNSYLPRTLHLGSSRSSI IARMTLLARVCSTTCIQKIL PKLRNSYLPRTLHLGSDSSM RRLDFRLKRI in isoform 3. 1 PublicationVSP_007998Add
BLAST
Alternative sequencei154 – 18431Missing in isoform 2. 1 PublicationVSP_007997Add
BLAST
Alternative sequencei264 – 626363Missing in isoform 3. 1 PublicationVSP_007999Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB012600 mRNA. Translation: BAA33450.1.
AF015953 mRNA. Translation: AAC21449.1. Different initiation.
AF317669 mRNA. Translation: AAG34180.2.
BC099833 mRNA. Translation: AAH99833.1.
RefSeqiNP_077338.2. NM_024362.2.
XP_006230091.1. XM_006230029.2.
XP_008757938.1. XM_008759716.1.
UniGeneiRn.14532.

Genome annotation databases

GeneIDi29657.
KEGGirno:29657.
UCSCiRGD:62003. rat. [Q9EPW1-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB012600 mRNA. Translation: BAA33450.1.
AF015953 mRNA. Translation: AAC21449.1. Different initiation.
AF317669 mRNA. Translation: AAG34180.2.
BC099833 mRNA. Translation: AAH99833.1.
RefSeqiNP_077338.2. NM_024362.2.
XP_006230091.1. XM_006230029.2.
XP_008757938.1. XM_008759716.1.
UniGeneiRn.14532.

3D structure databases

ProteinModelPortaliQ9EPW1.
ModBaseiSearch...
MobiDBiSearch...

PTM databases

PhosphoSiteiQ9EPW1.

Proteomic databases

PRIDEiQ9EPW1.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi29657.
KEGGirno:29657.
UCSCiRGD:62003. rat. [Q9EPW1-1]

Organism-specific databases

CTDi406.
RGDi62003. Arntl.

Phylogenomic databases

HOGENOMiHOG000234379.
HOVERGENiHBG107503.
InParanoidiQ9EPW1.
KOiK02296.
PhylomeDBiQ9EPW1.

Miscellaneous databases

PROiQ9EPW1.

Family and domain databases

Gene3Di4.10.280.10. 1 hit.
InterProiIPR011598. bHLH_dom.
IPR001067. Nuc_translocat.
IPR001610. PAC.
IPR000014. PAS.
IPR013767. PAS_fold.
[Graphical view]
PfamiPF00010. HLH. 1 hit.
PF00989. PAS. 1 hit.
[Graphical view]
PRINTSiPR00785. NCTRNSLOCATR.
SMARTiSM00353. HLH. 1 hit.
SM00086. PAC. 1 hit.
SM00091. PAS. 2 hits.
[Graphical view]
SUPFAMiSSF47459. SSF47459. 1 hit.
SSF55785. SSF55785. 3 hits.
TIGRFAMsiTIGR00229. sensory_box. 1 hit.
PROSITEiPS50888. BHLH. 1 hit.
PS50112. PAS. 2 hits.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Circadian oscillation of BMAL1, a partner of a mammalian clock gene clock, in rat suprachiasmatic nucleus."
    Honma S., Ikeda M., Abe H., Tanahashi Y., Namihira M., Honma K., Nomura M.
    Biochem. Biophys. Res. Commun. 250:83-87(1998) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
    Tissue: Brain.
  2. "Cloning and chromosomal localization of a new member of the bHLH/PAS transcription factor family."
    Wolting C.D., McGlade C.J.
    Mamm. Genome 9:463-468(1998) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
    Tissue: Brain.
  3. "Sequence of Rat BMAL1g' cDNA."
    Jac M., Sladek M., Sauman I.
    Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
    Strain: Wistar.
    Tissue: Brain.
  4. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
    Tissue: Prostate.
  5. "Thyroid transcription factor 1, a homeodomain containing transcription factor, contributes to regulating periodic oscillations in GnRH gene expression."
    Matagne V., Kim J.G., Ryu B.J., Hur M.K., Kim M.S., Kim K., Park B.S., Damante G., Smiley G., Lee B.J., Ojeda S.R.
    J. Neuroendocrinol. 24:916-929(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, SUBCELLULAR LOCATION.
  6. "Downregulation of core clock gene Bmal1 attenuates expression of progesterone and prostaglandin biosynthesis-related genes in rat luteinizing granulosa cells."
    Chen H., Zhao L., Kumazawa M., Yamauchi N., Shigeyoshi Y., Hashimoto S., Hattori M.A.
    Am. J. Physiol. 304:C1131-C1140(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.

Entry informationi

Entry nameiBMAL1_RAT
AccessioniPrimary (citable) accession number: Q9EPW1
Secondary accession number(s): O88337, O88810, Q499M8
Entry historyi
Integrated into UniProtKB/Swiss-Prot: August 15, 2003
Last sequence update: May 1, 2007
Last modified: June 8, 2016
This is version 128 of the entry and version 4 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.