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O00327

- BMAL1_HUMAN

UniProt

O00327 - BMAL1_HUMAN

Protein

Aryl hydrocarbon receptor nuclear translocator-like protein 1

Gene

ARNTL

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 153 (01 Oct 2014)
      Sequence version 2 (15 Aug 2003)
      Previous versions | rss
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    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, NR1D2, RORA, RORB and RORG, 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. 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 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. 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.6 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.

    GO - Molecular functioni

    1. aryl hydrocarbon receptor binding Source: BHF-UCL
    2. core promoter binding Source: UniProtKB
    3. DNA binding Source: UniProtKB
    4. E-box binding Source: UniProtKB
    5. Hsp90 protein binding Source: BHF-UCL
    6. protein binding Source: UniProtKB
    7. RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity Source: BHF-UCL
    8. RNA polymerase II transcription factor binding transcription factor activity involved in positive regulation of transcription Source: Ensembl
    9. sequence-specific DNA binding Source: UniProtKB
    10. signal transducer activity Source: InterPro
    11. transcription regulatory region sequence-specific DNA binding Source: UniProtKB

    GO - Biological processi

    1. circadian regulation of gene expression Source: UniProtKB
    2. circadian rhythm Source: ProtInc
    3. negative regulation of fat cell differentiation Source: UniProtKB
    4. negative regulation of glucocorticoid receptor signaling pathway Source: UniProtKB
    5. negative regulation of TOR signaling Source: UniProtKB
    6. negative regulation of transcription, DNA-templated Source: UniProtKB
    7. oxidative stress-induced premature senescence Source: UniProtKB
    8. positive regulation of canonical Wnt signaling pathway Source: UniProtKB
    9. positive regulation of circadian rhythm Source: UniProtKB
    10. positive regulation of skeletal muscle cell differentiation Source: UniProtKB
    11. positive regulation of transcription, DNA-templated Source: UniProtKB
    12. positive regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
    13. proteasome-mediated ubiquitin-dependent protein catabolic process Source: UniProtKB
    14. protein import into nucleus, translocation Source: Ensembl
    15. regulation of cell cycle Source: UniProtKB
    16. regulation of cellular senescence Source: UniProtKB
    17. regulation of hair cycle Source: UniProtKB
    18. regulation of insulin secretion Source: UniProtKB
    19. regulation of neurogenesis Source: UniProtKB
    20. regulation of protein catabolic process Source: Ensembl
    21. regulation of transcription, DNA-templated Source: UniProtKB
    22. regulation of type B pancreatic cell development Source: UniProtKB
    23. response to redox state Source: UniProtKB
    24. spermatogenesis Source: UniProtKB
    25. transcription from RNA polymerase II promoter Source: GOC

    Keywords - Molecular functioni

    Activator

    Keywords - Biological processi

    Biological rhythms, Transcription, Transcription regulation

    Keywords - Ligandi

    DNA-binding

    Enzyme and pathway databases

    ReactomeiREACT_111118. BMAL1:CLOCK,NPAS2 activates circadian gene expression.
    REACT_116145. PPARA activates gene expression.
    REACT_118659. RORA activates circadian gene expression.
    REACT_118789. REV-ERBA represses gene expression.
    REACT_24941. Circadian Clock.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Aryl hydrocarbon receptor nuclear translocator-like protein 1
    Alternative name(s):
    Basic-helix-loop-helix-PAS protein MOP3
    Brain and muscle ARNT-like 1
    Class E basic helix-loop-helix protein 5
    Short name:
    bHLHe5
    Member of PAS protein 3
    PAS domain-containing protein 3
    bHLH-PAS protein JAP3
    Gene namesi
    Name:ARNTL
    Synonyms:BHLHE5, BMAL1, MOP3, PASD3
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 11

    Organism-specific databases

    HGNCiHGNC:701. ARNTL.

    Subcellular locationi

    Nucleus 1 PublicationPROSITE-ProRule annotation. 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.By similarity

    GO - Cellular componenti

    1. chromatoid body Source: UniProtKB
    2. nucleus Source: UniProtKB
    3. PML body Source: UniProtKB-SubCell
    4. transcription factor complex Source: MGI

    Keywords - Cellular componenti

    Cytoplasm, Nucleus

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi9 – 91S → A or E: Enhanced PER1 reporter activity by CLOCK-ARNTL/BMAL1. 1 Publication
    Mutagenesisi9 – 91S → F: 2-2.5-fold increase in CLOCK-BMAL1 transcriptional activity in the absence of CRY1. No change in repression activity in the presence of CRY1. 1 Publication
    Mutagenesisi10 – 101S → A or E: Enhanced PER1 reporter activity by CLOCK-ARNTL/BMAL1. 1 Publication
    Mutagenesisi10 – 101S → L: 2-2.5-fold increase in CLOCK-ARNTL/BMAL1 transcriptional activity in the absence of CRY1. No change in repression activity in the presence of CRY1. 1 Publication
    Mutagenesisi611 – 6111A → S or T: Increased desensitization to CRY1, in the presence of CLOCK. Approximately 2-fold increase in CLOCK-ARNTL/BMAL1 transcriptional activity in the absence of CRY1; when associated with E-407. 1 Publication
    Mutagenesisi612 – 6121G → E: Increased desensitization to CRY1, in the presence of CLOCK. Approximately 2-fold increase in CLOCK-ARNTL/BMAL1 transcriptional activity in the absence of CRY1. 1 Publication

    Organism-specific databases

    PharmGKBiPA24996.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 626626Aryl hydrocarbon receptor nuclear translocator-like protein 1PRO_0000127156Add
    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.By similarity
    Acetylated on Lys-538 upon dimerization with CLOCK. Acetylation facilitates CRY1-mediated repression By similarity.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.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.By similarity

    Keywords - PTMi

    Acetylation, Isopeptide bond, Phosphoprotein, Ubl conjugation

    Proteomic databases

    MaxQBiO00327.
    PaxDbiO00327.
    PRIDEiO00327.

    PTM databases

    PhosphoSiteiO00327.

    Expressioni

    Tissue specificityi

    Hair follicles (at protein level). Highly expressed in the adult brain, skeletal muscle and heart.1 Publication

    Gene expression databases

    ArrayExpressiO00327.
    BgeeiO00327.
    GenevestigatoriO00327.

    Organism-specific databases

    HPAiCAB045962.
    HPA050938.
    HPA054172.

    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. Interacts with HSP90; with AHR in vitro, but not in vivo. Part of a nuclear complex which also includes GNB2L1/RACK1 and PRKCA; GNB2L1 and PRKCA are recruited to the complex in a circadian manner. Interacts with PER2, CRY1 and CRY2. Interaction with PER and CRY proteins requires 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. Interacts with CIART. Interacts with DDX4, SUMO3, OGT, EED, EZH2 and SUZ12. The CLOCK-ARNTL/BMAL1 heterodimer interacts with GSK3B. Interacts with KAT2B AND EP300. Interacts with BHLHE40/DEC1 and BHLHE41/DEC2. Interacts with ID1, ID2 and ID3. Interacts with AHR. Interacts with RELB and the interaction is enhanced in the presence of CLOCK. Interacts with MTA1.4 Publications

    Protein-protein interaction databases

    BioGridi106899. 25 interactions.
    DIPiDIP-46008N.
    IntActiO00327. 3 interactions.

    Structurei

    Secondary structure

    1
    626
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Helixi71 – 9828
    Helixi100 – 1034
    Helixi111 – 12515

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    4H10X-ray2.40A66-128[»]
    ProteinModelPortaliO00327.
    SMRiO00327. Positions 69-442.
    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

    eggNOGiNOG293303.
    HOGENOMiHOG000234379.
    HOVERGENiHBG107503.
    InParanoidiO00327.
    KOiK02296.
    OMAiEKINTNC.
    OrthoDBiEOG7V1FQ8.
    PhylomeDBiO00327.
    TreeFamiTF319983.

    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 (9)i

    Sequence statusi: Complete.

    This entry describes 9 isoformsi produced by alternative splicing. Align

    Note: Additional isoforms seem to exist.

    Isoform BMAL1B (identifier: O00327-2) [UniParc]FASTAAdd to Basket

    Also known as: JAP3

    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

    MADQRMDISS TISDFMSPGP TDLLSSSLGT SGVDCNRKRK GSSTDYQESM    50
    DTDKDDPHGR LEYTEHQGRI KNAREAHSQI EKRRRDKMNS FIDELASLVP 100
    TCNAMSRKLD KLTVLRMAVQ HMKTLRGATN PYTEANYKPT FLSDDELKHL 150
    ILRAADGFLF VVGCDRGKIL FVSESVFKIL NYSQNDLIGQ SLFDYLHPKD 200
    IAKVKEQLSS SDTAPRERLI DAKTGLPVKT DITPGPSRLC SGARRSFFCR 250
    MKCNRPSVKV EDKDFPSTCS KKKADRKSFC TIHSTGYLKS WPPTKMGLDE 300
    DNEPDNEGCN LSCLVAIGRL HSHVVPQPVN GEIRVKSMEY VSRHAIDGKF 350
    VFVDQRATAI LAYLPQELLG TSCYEYFHQD DIGHLAECHR QVLQTREKIT 400
    TNCYKFKIKD GSFITLRSRW FSFMNPWTKE VEYIVSTNTV VLANVLEGGD 450
    PTFPQLTASP HSMDSMLPSG EGGPKRTHPT VPGIPGGTRA GAGKIGRMIA 500
    EEIMEIHRIR GSSPSSCGSS PLNITSTPPP DASSPGGKKI LNGGTPDIPS 550
    SGLLSGQAQE NPGYPYSDSS SILGENPHIG IDMIDNDQGS SSPSNDEAAM 600
    AVIMSLLEAD AGLGGPVDFS DLPWPL 626
    Length:626
    Mass (Da):68,762
    Last modified:August 15, 2003 - v2
    Checksum:i820F0E07DC6265A6
    GO
    Isoform BMAL1A (identifier: O00327-1) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-47: MADQRMDISSTISDFMSPGPTDLLSSSLGTSGVDCNRKRKGSSTDYQ → MINI

    Show »
    Length:583
    Mass (Da):64,207
    Checksum:i2AA8E7EEB4A71119
    GO
    Isoform BMAL1C (identifier: O00327-3) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         224-224: T → R
         225-626: Missing.

    Show »
    Length:224
    Mass (Da):25,353
    Checksum:i0A0580AEDC5A45A0
    GO
    Isoform BMAL1D (identifier: O00327-4) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         274-391: Missing.

    Show »
    Length:508
    Mass (Da):55,462
    Checksum:i5FAB2403FD8AAB32
    GO
    Isoform BMAL1E (identifier: O00327-5) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         278-301: SFCTIHSTGYLKSWPPTKMGLDED → AFCTIHSTGYFGIFTTRTSRHIVL
         302-626: Missing.

    Show »
    Length:301
    Mass (Da):33,922
    Checksum:iEC942D8A9C9219B3
    GO
    Isoform BMAL1F (identifier: O00327-6) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         443-526: ANVLEGGDPT...CGSSPLNITS → SRVDTGHLGQ...QGEPGLGQEK
         527-626: Missing.

    Show »
    Length:526
    Mass (Da):59,242
    Checksum:iED01AF63A26CE4E0
    GO
    Isoform MOP3 (identifier: O00327-7) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-59: MADQRMDISS...MDTDKDDPHG → MSKEAVSLWA...CFYLLLFPPP

    Show »
    Length:624
    Mass (Da):68,828
    Checksum:i7A3FD8FAE5E496D7
    GO
    Isoform 8 (identifier: O00327-8) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         274-274: Missing.

    Show »
    Length:625
    Mass (Da):68,691
    Checksum:i3F3F7D5688A6FFE2
    GO
    Isoform 9 (identifier: O00327-9) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-47: MADQRMDISSTISDFMSPGPTDLLSSSLGTSGVDCNRKRKGSSTDYQ → MINI
         274-274: Missing.

    Show »
    Length:582
    Mass (Da):64,136
    Checksum:iE8D6943E4DD24037
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti69 – 691R → G in AAC51213. (PubMed:9079689)Curated
    Sequence conflicti123 – 1231K → R in BAA19935. (PubMed:9144434)Curated
    Sequence conflicti173 – 1731S → P in BAA19939. (PubMed:9144434)Curated
    Sequence conflicti259 – 2591K → N in BAA19938. (PubMed:9144434)Curated
    Sequence conflicti264 – 2641D → N in BAA19938. (PubMed:9144434)Curated
    Sequence conflicti418 – 4181S → N in BAA19937. (PubMed:9144434)Curated
    Sequence conflicti513 – 5142SP → LR in AAC51213. (PubMed:9079689)Curated

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei1 – 5959MADQR…DDPHG → MSKEAVSLWALTVSLQPPVP LCVCREMTGSGRRKQQCVTL PFISRELCFYLLLFPPP in isoform MOP3. 1 PublicationVSP_002095Add
    BLAST
    Alternative sequencei1 – 4747MADQR…STDYQ → MINI in isoform BMAL1A and isoform 9. 2 PublicationsVSP_002094Add
    BLAST
    Alternative sequencei224 – 2241T → R in isoform BMAL1C. CuratedVSP_002096
    Alternative sequencei225 – 626402Missing in isoform BMAL1C. CuratedVSP_002097Add
    BLAST
    Alternative sequencei274 – 391118Missing in isoform BMAL1D. CuratedVSP_002098Add
    BLAST
    Alternative sequencei274 – 2741Missing in isoform 8 and isoform 9. 2 PublicationsVSP_035457
    Alternative sequencei278 – 30124SFCTI…GLDED → AFCTIHSTGYFGIFTTRTSR HIVL in isoform BMAL1E. CuratedVSP_002099Add
    BLAST
    Alternative sequencei302 – 626325Missing in isoform BMAL1E. CuratedVSP_002100Add
    BLAST
    Alternative sequencei443 – 52684ANVLE…LNITS → SRVDTGHLGQVERCTVLSRP NSRFLIAGMFTEPTSWKAGT QPSHSSQHPPTAWTACCPLE KVAQRGPTPLFQGFQGEPGL GQEK in isoform BMAL1F. CuratedVSP_002101Add
    BLAST
    Alternative sequencei527 – 626100Missing in isoform BMAL1F. CuratedVSP_002102Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    D89722 mRNA. Translation: BAA19968.1.
    AB000812 mRNA. Translation: BAA19935.1.
    AB000813 Genomic DNA. Translation: BAA19936.1.
    AB000814 mRNA. Translation: BAA19937.1.
    AB000815 mRNA. Translation: BAA19938.1.
    AB000816 mRNA. Translation: BAA19939.1.
    U51627 mRNA. Translation: AAC51213.1.
    U60415 mRNA. Translation: AAB37248.1.
    AF044288 mRNA. Translation: AAC24353.1.
    AK095749 mRNA. Translation: BAG53120.1.
    AK291510 mRNA. Translation: BAF84199.1.
    EF015894 Genomic DNA. Translation: ABM64205.1.
    AC016884 Genomic DNA. No translation available.
    AC022878 Genomic DNA. No translation available.
    CH471064 Genomic DNA. Translation: EAW68504.1.
    CH471064 Genomic DNA. Translation: EAW68505.1.
    CH471064 Genomic DNA. Translation: EAW68510.1.
    CH471064 Genomic DNA. Translation: EAW68511.1.
    CH471064 Genomic DNA. Translation: EAW68513.1.
    BC016674 mRNA. Translation: AAH16674.1.
    BC031214 mRNA. Translation: AAH31214.1.
    BC041129 mRNA. Translation: AAH41129.2.
    CCDSiCCDS31430.1. [O00327-8]
    CCDS44543.1. [O00327-9]
    PIRiJC5405.
    JC5407.
    PC4288.
    PC4289.
    RefSeqiNP_001025443.1. NM_001030272.1. [O00327-8]
    NP_001025444.1. NM_001030273.1. [O00327-9]
    NP_001169.3. NM_001178.4. [O00327-8]
    XP_005252986.1. XM_005252929.2. [O00327-2]
    XP_005252987.1. XM_005252930.1. [O00327-2]
    XP_006718298.1. XM_006718235.1. [O00327-1]
    UniGeneiHs.65734.

    Genome annotation databases

    EnsembliENST00000389707; ENSP00000374357; ENSG00000133794. [O00327-8]
    ENST00000401424; ENSP00000385915; ENSG00000133794. [O00327-1]
    ENST00000403290; ENSP00000384517; ENSG00000133794. [O00327-2]
    ENST00000403482; ENSP00000385897; ENSG00000133794. [O00327-7]
    ENST00000403510; ENSP00000385581; ENSG00000133794. [O00327-9]
    GeneIDi406.
    KEGGihsa:406.
    UCSCiuc001mko.3. human. [O00327-9]
    uc001mkp.3. human. [O00327-8]
    uc001mkr.3. human. [O00327-2]
    uc001mks.3. human. [O00327-1]
    uc001mkx.3. human. [O00327-7]
    uc009ygm.1. human. [O00327-4]

    Keywords - Coding sequence diversityi

    Alternative splicing

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    D89722 mRNA. Translation: BAA19968.1 .
    AB000812 mRNA. Translation: BAA19935.1 .
    AB000813 Genomic DNA. Translation: BAA19936.1 .
    AB000814 mRNA. Translation: BAA19937.1 .
    AB000815 mRNA. Translation: BAA19938.1 .
    AB000816 mRNA. Translation: BAA19939.1 .
    U51627 mRNA. Translation: AAC51213.1 .
    U60415 mRNA. Translation: AAB37248.1 .
    AF044288 mRNA. Translation: AAC24353.1 .
    AK095749 mRNA. Translation: BAG53120.1 .
    AK291510 mRNA. Translation: BAF84199.1 .
    EF015894 Genomic DNA. Translation: ABM64205.1 .
    AC016884 Genomic DNA. No translation available.
    AC022878 Genomic DNA. No translation available.
    CH471064 Genomic DNA. Translation: EAW68504.1 .
    CH471064 Genomic DNA. Translation: EAW68505.1 .
    CH471064 Genomic DNA. Translation: EAW68510.1 .
    CH471064 Genomic DNA. Translation: EAW68511.1 .
    CH471064 Genomic DNA. Translation: EAW68513.1 .
    BC016674 mRNA. Translation: AAH16674.1 .
    BC031214 mRNA. Translation: AAH31214.1 .
    BC041129 mRNA. Translation: AAH41129.2 .
    CCDSi CCDS31430.1. [O00327-8 ]
    CCDS44543.1. [O00327-9 ]
    PIRi JC5405.
    JC5407.
    PC4288.
    PC4289.
    RefSeqi NP_001025443.1. NM_001030272.1. [O00327-8 ]
    NP_001025444.1. NM_001030273.1. [O00327-9 ]
    NP_001169.3. NM_001178.4. [O00327-8 ]
    XP_005252986.1. XM_005252929.2. [O00327-2 ]
    XP_005252987.1. XM_005252930.1. [O00327-2 ]
    XP_006718298.1. XM_006718235.1. [O00327-1 ]
    UniGenei Hs.65734.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    4H10 X-ray 2.40 A 66-128 [» ]
    ProteinModelPortali O00327.
    SMRi O00327. Positions 69-442.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 106899. 25 interactions.
    DIPi DIP-46008N.
    IntActi O00327. 3 interactions.

    PTM databases

    PhosphoSitei O00327.

    Proteomic databases

    MaxQBi O00327.
    PaxDbi O00327.
    PRIDEi O00327.

    Protocols and materials databases

    DNASUi 406.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000389707 ; ENSP00000374357 ; ENSG00000133794 . [O00327-8 ]
    ENST00000401424 ; ENSP00000385915 ; ENSG00000133794 . [O00327-1 ]
    ENST00000403290 ; ENSP00000384517 ; ENSG00000133794 . [O00327-2 ]
    ENST00000403482 ; ENSP00000385897 ; ENSG00000133794 . [O00327-7 ]
    ENST00000403510 ; ENSP00000385581 ; ENSG00000133794 . [O00327-9 ]
    GeneIDi 406.
    KEGGi hsa:406.
    UCSCi uc001mko.3. human. [O00327-9 ]
    uc001mkp.3. human. [O00327-8 ]
    uc001mkr.3. human. [O00327-2 ]
    uc001mks.3. human. [O00327-1 ]
    uc001mkx.3. human. [O00327-7 ]
    uc009ygm.1. human. [O00327-4 ]

    Organism-specific databases

    CTDi 406.
    GeneCardsi GC11P013299.
    HGNCi HGNC:701. ARNTL.
    HPAi CAB045962.
    HPA050938.
    HPA054172.
    MIMi 602550. gene.
    neXtProti NX_O00327.
    PharmGKBi PA24996.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi NOG293303.
    HOGENOMi HOG000234379.
    HOVERGENi HBG107503.
    InParanoidi O00327.
    KOi K02296.
    OMAi EKINTNC.
    OrthoDBi EOG7V1FQ8.
    PhylomeDBi O00327.
    TreeFami TF319983.

    Enzyme and pathway databases

    Reactomei REACT_111118. BMAL1:CLOCK,NPAS2 activates circadian gene expression.
    REACT_116145. PPARA activates gene expression.
    REACT_118659. RORA activates circadian gene expression.
    REACT_118789. REV-ERBA represses gene expression.
    REACT_24941. Circadian Clock.

    Miscellaneous databases

    GeneWikii ARNTL.
    GenomeRNAii 406.
    NextBioi 1701.
    PROi O00327.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi O00327.
    Bgeei O00327.
    Genevestigatori O00327.

    Family and domain databases

    Gene3Di 4.10.280.10. 1 hit.
    InterProi IPR011598. bHLH_dom.
    IPR001067. Nuc_translocat.
    IPR001610. PAC.
    IPR000014. PAS.
    IPR013767. PAS_fold.
    [Graphical view ]
    Pfami PF00010. HLH. 1 hit.
    PF00989. PAS. 1 hit.
    [Graphical view ]
    PRINTSi PR00785. NCTRNSLOCATR.
    SMARTi SM00353. HLH. 1 hit.
    SM00086. PAC. 1 hit.
    SM00091. PAS. 2 hits.
    [Graphical view ]
    SUPFAMi SSF47459. SSF47459. 1 hit.
    SSF55785. SSF55785. 3 hits.
    TIGRFAMsi TIGR00229. sensory_box. 1 hit.
    PROSITEi PS50888. BHLH. 1 hit.
    PS50112. PAS. 2 hits.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "cDNA cloning and tissue-specific expression of a novel basic helix-loop-helix/PAS protein (BMAL1) and identification of alternatively spliced variants with alternative translation initiation site usage."
      Ikeda M., Nomura M.
      Biochem. Biophys. Res. Commun. 233:258-264(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], ALTERNATIVE SPLICING (ISOFORMS BMAL1A; BMAL1B; BMAL1C; BMAL1D; BMAL1E AND BMAL1F).
      Tissue: Brain.
    2. "Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway."
      Hogenesch J.B., Chan W.K., Jackiw V.H., Brown R.C., Gu Y.-Z., Pray-Grant M., Perdew G.H., Bradfield C.A.
      J. Biol. Chem. 272:8581-8593(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM MOP3), INTERACTION WITH HSP90 AND AHR.
      Tissue: Fetal brain.
    3. "JAP3: a novel ARNT-like bHLH-PAS protein."
      Tian H., Russell D.W., McKnight S.L.
      Submitted (DEC-1996) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM BMAL1B).
    4. "The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors."
      Hogenesch J.B., Gu Y.Z., Jain S., Bradfield C.A.
      Proc. Natl. Acad. Sci. U.S.A. 95:5474-5479(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM BMAL1B).
    5. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
      Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
      , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
      Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS BMAL1B AND 9).
      Tissue: Brain.
    6. "ARNTL resequence."
      Kripke D.F., Klimecki W.
      Submitted (SEP-2006) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    7. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    8. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    9. "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] (ISOFORMS 8 AND BMAL1A).
      Tissue: Brain and Skin.
    10. Cited for: INTERACTION WITH CLOCK.
    11. "Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors."
      Rutter J., Reick M., Wu L.C., McKnight S.L.
      Science 293:510-514(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, DNA-BINDING.
    12. "Regulation of the PAI-1 promoter by circadian clock components: differential activation by BMAL1 and BMAL2."
      Schoenhard J.A., Smith L.H., Painter C.A., Eren M., Johnson C.H., Vaughan D.E.
      J. Mol. Cell. Cardiol. 35:473-481(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION.
    13. "Histone acetyltransferase-dependent chromatin remodeling and the vascular clock."
      Curtis A.M., Seo S.B., Westgate E.J., Rudic R.D., Smyth E.M., Chakravarti D., FitzGerald G.A., McNamara P.
      J. Biol. Chem. 279:7091-7097(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH KAT2B AND EP300.
    14. Cited for: MUTAGENESIS OF SER-9; SER-10; ALA-611 AND GLY-612.
    15. "CLOCK/BMAL1 regulates human nocturnin transcription through binding to the E-box of nocturnin promoter."
      Li R., Yue J., Zhang Y., Zhou L., Hao W., Yuan J., Qiang B., Ding J.M., Peng X., Cao J.M.
      Mol. Cell. Biochem. 317:169-177(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION.
    16. "Mechanism of the circadian clock in physiology."
      Richards J., Gumz M.L.
      Am. J. Physiol. 304:R1053-R1064(2013) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW.
    17. "The clock gene brain and muscle Arnt-like protein-1 (BMAL1) is involved in hair growth."
      Watabe Y., Tomioka M., Watabe A., Aihara M., Shimba S., Inoue H.
      Arch. Dermatol. Res. 305:755-761(2013) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION.
    18. "p75 neurotrophin receptor is a clock gene that regulates oscillatory components of circadian and metabolic networks."
      Baeza-Raja B., Eckel-Mahan K., Zhang L., Vagena E., Tsigelny I.F., Sassone-Corsi P., Ptacek L.J., Akassoglou K.
      J. Neurosci. 33:10221-10234(2013) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION.
    19. "Metabolism and the circadian clock converge."
      Eckel-Mahan K., Sassone-Corsi P.
      Physiol. Rev. 93:107-135(2013) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW.
    20. "Gene model 129 (Gm129) encodes a novel transcriptional repressor that modulates circadian gene expression."
      Annayev Y., Adar S., Chiou Y.Y., Lieb J., Sancar A., Ye R.
      J. Biol. Chem. 289:5013-5024(2014) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH CIART.
    21. "A meeting of two chronobiological systems: circadian proteins Period1 and BMAL1 modulate the human hair cycle clock."
      Al-Nuaimi Y., Hardman J.A., Biro T., Haslam I.S., Philpott M.P., Toth B.I., Farjo N., Farjo B., Baier G., Watson R.E., Grimaldi B., Kloepper J.E., Paus R.
      J. Invest. Dermatol. 134:610-619(2014) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN HAIR GROWTH, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
    22. "Molecular architecture of the mammalian circadian clock."
      Partch C.L., Green C.B., Takahashi J.S.
      Trends Cell Biol. 24:90-99(2014) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW.

    Entry informationi

    Entry nameiBMAL1_HUMAN
    AccessioniPrimary (citable) accession number: O00327
    Secondary accession number(s): A2I2N6
    , A8K645, B5ME11, B7WPG7, D3DQW6, O00313, O00314, O00315, O00316, O00317, Q4G136, Q8IUT4, Q99631, Q99649
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: December 15, 1998
    Last sequence update: August 15, 2003
    Last modified: October 1, 2014
    This is version 153 of the entry and version 2 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Miscellaneous

    CLOCK-ARNTL/BMAL1 double mutations within the PAS domains result in syngernistic desensitization to high levels of CRY on repression of CLOCK-ARNTL/BMAL1 transcriptional activity of PER1 and, disrupt circadian rhythmicity.

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Human chromosome 11
      Human chromosome 11: entries, gene names and cross-references to MIM
    2. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    3. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    4. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3