Basic helix-loop-helix ARNT-like protein 1

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ARNTL
)
ARNTL
Available structures
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000133794

ENSMUSG00000055116

UniProt

O00327

Q9WTL8

RefSeq (mRNA)

NM_001243048
NM_007489
NM_001357070
NM_001368412
NM_001374642

RefSeq (protein)

NP_001229977
NP_031515
NP_001343999
NP_001355341
NP_001361571

Location (UCSC)n/aChr 7: 112.81 – 112.91 Mb
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse

Basic helix-loop-helix ARNT-like protein 1 or aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL), or brain and muscle ARNT-like 1 is a protein that in humans is encoded by the BMAL1 gene on chromosome 11, region p15.3. It's also known as MOP3, and, less commonly, bHLHe5, BMAL, BMAL1C, JAP3, PASD3, and TIC.

BMAL1 encodes a

circadian rhythms. Research has revealed that BMAL1 is the only clock gene without which the circadian clock fails to function in humans.[5] BMAL1 has also been identified as a candidate gene for susceptibility to hypertension, diabetes, and obesity,[6][7] and mutations in BMAL1 have been linked to infertility, gluconeogenesis and lipogenesis problems, and altered sleep patterns.[8] BMAL1, according to genome-wide profiling, is estimated to target more than 150 sites in the human genome, including all of the clock genes and genes encoding for proteins that regulate metabolism.[9]

History

The BMAL1 gene was originally discovered in 1997 by two groups of researchers,

circadian rhythms was not fully realized until the knockout of the gene in mice showed complete loss of circadian rhythms in locomotion and other behaviors.[14]

Genetics

Regulation of Bmal1 activity

deacetylation.[15] The degradation of PER proteins prevents the formation of the large protein complex, and thus disinhibits the transcriptional activity of the BMAL1:CLOCK heterodimer. The CRY protein is also signaled for degradation by poly-ubiquitination from the FBXL3 protein resulting in the disinhibition of BMAL1:CLOCK heterodimer activity.[16]

In addition to the circadian regulatory TTFL loop, Bmal1 transcription is regulated by competitive binding to the

NR1F2 (ROR-β); and NR1F3 (ROR-γ)) have also been shown to act on Bmal1 transcriptional activity in a similar manner.[17][18][19][20]

Several

ubiquitination.[26]

In 2004, Rora was discovered to be an activator of Bmal1 transcription within the suprachiasmatic nucleus (SCN), regulated by its core clock.

autism, which may be a consequence of its function as a circadian regulator.[28]

Summary of regulation of Bmal1 activity
Bmal1 Regulator/Modifier Positive Or Negative Regulator Direct or Indirect Mechanism Source(s)
SIRT1 Negative Direct BMAL1:CLOCK heterodimer deacetylation [15]
FBLX3 Positive Indirect Poly-ubiquitination of PER promotes PER degradation [16]
REV-ERBα/β Negative Direct Repression by binding Bmal1 promoter [18][19][20]
ROR-α/β/γ Positive Direct Activation by binding Bmal1 promoter [17][18][19][27]
Acetylation Negative Direct Recruits CRY1 to inhibit the BMAL1:CLOCK heterodimer [21]
Small ubiquitin-related modifier 3 Positive Direct Sumoylation of BMAL1 [22]
Casein kinase 1ε Positive Direct Phosphorylation of the CLOCK/BMAL1 heterodimer [23]
MAPK Negative Direct Phosphorylation of the CLOCK/BMAL1 heterodimer [24]
CK2α Unclear Direct Phosphorylation of BMAL1 [25]
GSK3B
 Positive Direct Phosphorylation of BMAL1 [26]

Species distribution

Along with mammals such as humans and mice,

orthologs of the Arntl gene are also found in fish (AF144690.1),[29] birds (Arntl),[30] reptiles, amphibians (XI.2098), and Drosophila (Cycle, which encodes a protein lacking the homologous C-terminal domain, but still dimerizes with the CLOCK protein).[31] Unlike mammalian Arntl, circadian regulated, the Drosophila Cycle (gene) is constitutively expressed.[32] In humans, three transcript variants encoding two different isoforms have been found for this gene.[11]
The importance of these transcript variants is unknown.

Mutations and disease

The Arntl gene is located within the hypertension susceptibility loci of chromosome 1 in rats. A study of

hypoinsulinaemia or diabetes when disrupted.[36]

In regards to other functions, another study shows that the CLOCK/BMAL1 complex upregulates human

p53 tumor suppressor pathway suggesting potential involvement in the circadian rhythms exhibited by cancer cells.[44][45]

In animal models of multiple sclerosis (MS), namely the experimental autoimmune encephalomyelitis (EAE) model, it has been shown that daily circadian rhythms can play an important role in disease pathology.[46] Inducing EAE through the active immunization of mice with myelin oligodendrocyte glycoprotein (MOG) peptide during the rest phase is more efficient in comparison to that during the active phase.[47] Disparity in EAE induction is critically dependent on BMAL1 expression in T cells and myeloid cells. T cell or myeloid-specific deletion of Bmal1 has been shown to cause more severe pathology and is sufficient to abolish the rest vs. active induction effect.[47]

Structure

The BMAL1 protein contains fours domains according to its crystallographic structure: a

basic helix-loop-helix (bHLH) domain, two PAS domains called PAS-A and PAS-B, and a trans-activating domain. The dimerization of CLOCK:BMAL1 proteins involves strong interactions between the bHLH, PAS A, and PAS B domains of both CLOCK and BMAL1 and forms an asymmetrical heterodimer with three distinct protein interfaces. The PAS-A interactions between CLOCK and BMAL1 involves an interaction, in which an α-helix of CLOCK PAS-A and the β-sheet of BMAL1 PAS-A, and an α-helix motif of the BMAL1 PAS-A domain and the β-sheet of CLOCK PAS-A.[48] CLOCK and BMAL1 PAS-B domains stack in a parallel fashion, resulting in the concealment of different hydrophobic residues on the β-sheet of BMAL1 PAS-B and the helical surface of CLOCK PAS-B, such as Tyr 310 and Phe 423.[48] Key interactions with specific amino acid residues, specially CLOCK His 84 and BMAL1 Leu125, are important in the dimerization of these molecules.[49]

Function

Circadian clock

The protein encoded by the BMAL1 gene in mammals binds with a second bHLH-PAS protein via the PAS domain,

Cry2).[16]
This binding upregulates the transcription of Per1, Per2, Cry1 and Cry2 mRNAs.

TTFL loops of Bmal1 activity

After the PER and CRY proteins have accumulated to sufficient levels, they interact by their PAS motifs to form a large repressor complex that travels into the nucleus to inhibit the transcriptional activity of the CLOCK:BMAL1 heterodimer [50] This inhibits the heterodimer activation of the transcription of Per and Cry genes, and causes protein levels of PER and CRY drop. This transcription-translation negative feedback loop (TTFL) is modulated in the cytoplasm by phosphorylation of PER proteins by casein kinase 1ε or δ (CK1 ε or CK1 δ), targeting these proteins for degradation by the 26S proteasome.[16][51] The TTFL loop of nocturnal mice transcription levels of the Bmal1 gene peak at CT18, during the mid-subjective night, anti-phase to the transcription levels of Per, Cry, and other clock control genes, which peak at CT6, during the mid-subjective day. This process occurs with a period length of approximately 24 hours and supports the notion that this molecular mechanism is rhythmic.[52]

Pregnancy

Basic helix-loop-helix ARNT-like protein 1, or more commonly known as Bmal1, encodes for a transcriptional factor that when it heterodimerizes with Clock and Npas2 proteins, regulates gene expression for circadian rhythms via E-box elements.[53] It dictates the timing of different physiological process by synchronizing them to environmental cues.[54] The center of this orchestration is most notably, in mammals, the suprachiasmatic nucleus (SCN).[55] Defects in Bmal1 result in disrupted circadian rhythms across different organ systems that are associated with sleep disorders,[56] metabolic disorders,[57] immune dysfunction,[58] and tumorigenesis.[59] Bmal1’s regulation in circadian rhythms influences reproductive physiology such as ovulation, fertilization, and embryonic and fetal development via maternal circadian communication.[60] Studies have suggested mice that lack Bmal1 display reproductive ineffectiveness such as irregular cycles and reduced fertility.[61] Shift work and chronic jet lag have been suggested to correlate with outcomes such as preterm labor, low birth weight, and gestational diabetes.[62] Gene knockout models in mice have helped to understand the role Bmal1 has in transcriptional translational feedback loops and the effects of its absence on circadian rhythms and other physiological processes.[63] These knockout models have helped in revealing new insights into individualistic healthcare and disease prevention.[64]

Knockout studies

The Arntl gene is an essential component within the mammalian clock gene regulatory network. It is a point of sensitivity within the network, as it is the only gene whose single knockout in a mouse model generates arrhythmicity at both the molecular and behavioral levels.

Bmal2.[68] BMAL1 KO is not embryonically lethal and mice with BMAL1 ablated in adulthood do not express the symptoms of BMAL1 KO mice.[69] A recent study finds that BMAL1 KO mice exhibit autistic-like behavioral changes, including impaired sociability, excessive stereotyped and repetitive behaviors, and motor learning disabilities. These changes are associated with hyperactivation of the mTOR signaling pathway in the brain and can be ameliorated by an antidiabetic drug metformin.[70]

BMAL1 binding is regulated in a tissue-specific manner by numerous factors including non-circadian ones.

TNF-α and IL-1β  reciprocally repress BMAL1 activity.[74] Finally, BMAL1 interactions with HSF1 triggers clock synchronization and the release of pro-survival factors, highlighting the contribution of BMAL1 to cell stress and survival responses.[75]

BMAL1 deficient hESC-derived cardiomyocytes exhibited typical phenotypes of dilated cardiomyopathy including attenuated contractility, calcium dysregulation, and disorganized myofilaments. In addition, mitochondrial fission and mitophagy were suppressed in BMAL1 deficient hESC-cardiomyocytes, which resulted in significantly attenuated mitochondrial oxidative phosphorylation and compromised cardiomyocyte function.[76]

Interactions

Arntl has been shown to

interact
with:

See also

  • Arntl2 - Arntl2 (Bmal2) is a paralog of Arntl (Bmal1) that encodes for a basic helix-loop-helix PAS domain transcription factor. It, too, has been shown to play a circadian role, with its protein BMAL2 forming a transcriptionally active heterodimer with the CLOCK protein. It may also play a role in hypoxia.[82]
  • Cycle - Cycle is the Drosophila melanogaster ortholog of Arntl.

References

  1. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000055116 – Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "ARNTL aryl hydrocarbon receptor nuclear translocator-like [ Homo sapiens (human) ]". National Center for Biotechnology Information.
  5. S2CID 4430366
    .
  6. PMID 23206673
    .
  7. PMID 25025868
    .
  8. ^ "ARNTL Gene". Gene Cards: The Human Genome Compendium. Lifemap Sciences, Inc.
  9. PMID 20937769
    .
  10. ^
    PMID 9079689
    .
  11. ^
    PMID 9144434
    .
  12. PMID 16987893
    .
  13. S2CID 6916996
    .
  14. ^
    PMID 11163178
    .
  15. ^
    S2CID 17267748
    .
  16. ^
    PMID 23604473
    .
  17. ^
    S2CID 20040952
    .
  18. ^
    S2CID 33279857
    .
  19. ^
    S2CID 18112337
    .
  20. ^
    PMID 18454201
    .
  21. ^
    S2CID 4340848
    .
  22. ^
    PMID 18644859
    .
  23. ^
    PMID 11875063
    .
  24. ^
    PMID 11687575
    .
  25. ^
    PMID 19330005
    .
  26. ^
    PMID 20049328
    .
  27. ^
    S2CID 8938983
    .
  28. PMID 20375269
    .
  29. PMID 10760301
    .
  30. S2CID 45261835
    .
  31. S2CID 18175560
    .
  32. PMID 17069657
    .
  33. PMID 17728404
    .
  34. PMID 15523558
    .
  35. PMID 15845877
    .
  36. PMID 20562852
    .
  37. PMID 22913986
    .
  38. S2CID 53101791
    .
  39. PMID 18301395
    .
  40. PMID 28468274
    .
  41. S2CID 36387074
    .
  42. ^
    PMID 28721811
    .
  43. S2CID 28295989
    .
  44. S2CID 91120424
    .
  45. PMID 19277210
    .
  46. PMID 28087238
    .
  47. ^
    S2CID 3910164
    .
  48. ^
    PMID 22653727
    .
  49. PMID 23229515
    .
  50. PMID 25058693
    .
  51. PMID 24682205
    .
  52. S2CID 4406987
    .
  53. ^ Zheng, Y., et al., Neural function of Bmal1: an overview. Cell Biosci, 2023. 13(1): p. 1.
  54. ^ Tamaru, T. and K. Takamatsu, Circadian modification network of a core clock driver BMAL1 to harmonize physiology from brain to peripheral tissues. Neurochem Int, 2018. 119: p. 11-16.
  55. ^ Tamaru, T. and K. Takamatsu, Circadian modification network of a core clock driver BMAL1 to harmonize physiology from brain to peripheral tissues. Neurochem Int, 2018. 119: p. 11-16.
  56. ^ Hu, Y., J. Yin, and G. Yang, Melatonin upregulates BMAL1 to attenuate chronic sleep deprivation-related cognitive impairment by alleviating oxidative stress. Brain Behav, 2023. 13(1): p. e2836.
  57. ^ Sahar, S. and P. Sassone-Corsi, Regulation of metabolism: the circadian clock dictates the time. Trends Endocrinol Metab, 2012. 23(1): p. 1-8
  58. ^ Hergenhan, S., S. Holtkamp, and C. Scheiermann, Molecular Interactions Between Components of the Circadian Clock and the Immune System. J Mol Biol, 2020. 432(12): p. 3700-3713.
  59. ^ Li, W., et al., Decreased circadian component Bmal1 predicts tumor progression and poor prognosis in human pancreatic ductal adenocarcinoma. Biochem Biophys Res Commun, 2016. 472(1): p. 156-62.
  60. ^ Jiang, Y., et al., Critical Roles of the Circadian Transcription Factor BMAL1 in Reproductive Endocrinology and Fertility. Front Endocrinol (Lausanne), 2022. 13: p. 818272.
  61. ^ Tonsfeldt, K.J., et al., The Contribution of the Circadian Gene Bmal1 to Female Fertility and the Generation of the Preovulatory Luteinizing Hormone Surge. J Endocr Soc, 2019. 3(4): p. 716-733.
  62. ^ Gamble, K.L., D. Resuehr, and C.H. Johnson, Shift work and circadian dysregulation of reproduction. Front Endocrinol (Lausanne), 2013. 4: p. 92.
  63. ^ Ray, S., et al., Circadian rhythms in the absence of the clock gene Bmal1. Science, 2020. 367(6479): p. 800-806.
  64. ^ Abe, Y.O., et al., Rhythmic transcription of Bmal1 stabilizes the circadian timekeeping system in mammals. Nat Commun, 2022. 13(1): p. 4652.
  65. PMID 16940279
    .
  66. S2CID 5910503
    .
  67. S2CID 7290891
    .
  68. PMID 20153195
    .
  69. PMID 29258993
    .
  70. PMID 35301425
    .
  71. PMID 30824531
    .
  72. PMID 30363685
    .
  73. PMID 29881373
    .
  74. ^
    PMID 24560196
    .
  75. S2CID 5171959
    .
  76. ^
    PMID 32277346
    .
  77. ^
    PMID 9576906
    .
  78. PMID 14701734
    .
  79. ^
    S2CID 6251321
    .
  80. S2CID 41625860
    .
  81. ^
    PMID 25961797
    .
  82. PMID 10864977
    .

External links

  • Human ARNTL genome location and ARNTL gene details page in the UCSC Genome Browser.
  • Overview of all the structural information available in the PDB for UniProt: O00327 (Human Aryl hydrocarbon receptor nuclear translocator-like protein 1) at the PDBe-KB.
  • Overview of all the structural information available in the PDB for UniProt: Q9WTL8 (Mouse Aryl hydrocarbon receptor nuclear translocator-like protein 1) at the PDBe-KB.
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