Biology:Basic helix-loop-helix ARNT-like protein 1

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Short description: Human protein and coding gene


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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 transcription factor with a basic helix-loop-helix (bHLH) and two PAS domains. The human BMAL1 gene has a predicted 24 exons, located on the p15 band of the 11th chromosome.[1] The BMAL1 protein is 626 amino acids long and plays a key role as one of the positive elements in the mammalian auto-regulatory transcription-translation negative feedback loop (TTFL), which is responsible for generating molecular circadian rhythms. Research has revealed that BMAL1 is the only clock gene without which the circadian clock fails to function in humans.[2] BMAL1 has also been identified as a candidate gene for susceptibility to hypertension, diabetes, and obesity,[3][4] and mutations in BMAL1 have been linked to infertility, gluconeogenesis and lipogenesis problems, and altered sleep patterns.[5] 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.[6]

History

The BMAL1 gene was originally discovered in 1997 by two groups of researchers, John B. Hogenesch et al. in March under the name MOP3 [7] and Ikeda and Nomura in April[8] as part of a superfamily of PAS domain transcription factors.[7] In 1998, Hogenesch's additional characterization of MOP3 revealed that its role as the partner of bHLH-PAS transcription factor CLOCK was essential to mammalian circadian clock function.[9] The MOP3 protein, as it was originally known by the Hogenesch group, was found to dimerize with MOP4, CLOCK, and hypoxia-inducible factors.[7] The names BMAL1 and ARNTL were adopted in later papers. One of BMAL1 protein's earliest discovered functions in circadian regulation was related to the CLOCK-BMAL1 (CLOCK-ARNTL) heterodimer, which would bind through an E-box enhancer to activate the transcription of the AVP gene which encodes for vasopressin.[10] However, the gene's importance in 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.[11]

Genetics

Regulation of Bmal1 activity

SIRT1 regulates PER protein degradation by inhibiting transcriptional activity of the BMAL1:CLOCK heterodimer in a circadian manner through deacetylation.[12] 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.[13]

In addition to the circadian regulatory TTFL loop, Bmal1 transcription is regulated by competitive binding to the retinoic acid-related orphan receptor response element-binding site (RORE) within the promoter of Bmal1. The CLOCK/BMAL1 heterodimer also binds to E-box elements in promoter regions of Rev-Erbα and RORα/ß genes, upregulating transcription and translation of REV-ERB and ROR proteins. REV-ERBα and ROR proteins regulate BMAL1 expression through a secondary feedback loop and compete to bind to Rev-Erb/ROR response elements in the Bmal1 promoter, resulting in BMAL1 expression repressed by REV-ERBα and activated by ROR proteins. Other nuclear receptors of the same families (NR1D2 (Rev-erb-β); NR1F2 (ROR-β); and NR1F3 (ROR-γ)) have also been shown to act on Bmal1 transcriptional activity in a similar manner.[14][15][16][17]

Several posttranslational modifications of BMAL1 dictate the timing of the CLOCK/BMAL1 feedback loops. Phosphorylation of BMAL1 targets it for ubiquitination and degradation, as well as deubiquitination and stabilization. Acetylation of BMAL1 recruits CRY1 to suppress the transactivation of CLOCK/BMAL1.[18] The sumoylation of BMAL1 by small ubiquitin-related modifier 3 signals its ubiquitination in the nucleus, leading to transactivation of the CLOCK/BMAL1 heterodimer.[19] CLOCK/BMAL1 transactivation,[20] is activated by phosphorylation by casein kinase 1ε and inhibited by phosphorylation by MAPK.[21] Phosphorylation by CK2α regulates BMAL1 intracellular localization [22] and phosphorylation by GSK3B controls BMAL1 stability and primes it for ubiquitination.[23]

In 2004, Rora was discovered to be an activator of Bmal1 transcription within the suprachiasmatic nucleus (SCN), regulated by its core clock.[24] Rora was found to be required for normal Bmal1 expression as well as consolidation of daily locomotor activity.[24] This suggests that the opposing activities of the orphan nuclear receptors RORA and REV-ERBα, the latter of which represses Bmal1 expression, are important in the maintenance of circadian clock function.[24] Currently, Rora is under investigation for its link to autism, which may be a consequence of its function as a circadian regulator.[25]

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 [12]
FBLX3 Positive Indirect Poly-ubiquitination of PER promotes PER degradation [13]
REV-ERBα/β Negative Direct Repression by binding Bmal1 promoter [15][16][17]
ROR-α/β/γ Positive Direct Activation by binding Bmal1 promoter [14][15][16][24]
Acetylation Negative Direct Recruits CRY1 to inhibit the BMAL1:CLOCK heterodimer [18]
Small ubiquitin-related modifier 3 Positive Direct Sumoylation of BMAL1 [19]
Casein kinase 1ε Positive Direct Phosphorylation of the CLOCK/BMAL1 heterodimer [20]
MAPK Negative Direct Phosphorylation of the CLOCK/BMAL1 heterodimer [21]
CK2α Unclear Direct Phosphorylation of BMAL1 [22]
GSK3B Positive Direct Phosphorylation of BMAL1 [23]

Species distribution

Along with mammals such as humans and mice, orthologs of the Arntl gene are also found in fish (AF144690.1),[26] birds (Arntl),[27] reptiles, amphibians (XI.2098), and Drosophila (Cycle, which encodes a protein lacking the homologous C-terminal domain, but still dimerizes with the CLOCK protein).[28] Unlike mammalian Arntl, circadian regulated, the Drosophila Cycle (gene) is constitutively expressed.[29] In humans, three transcript variants encoding two different isoforms have been found for this gene.[8] 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 single nucleotide polymorphisms (SNPs) within this loci found two polymorphisms that occurred in the sequence encoding for Arntl and were associated with type II diabetes and hypertension. When translated from a rat model to a human model, this research suggests a causative role of Arntl gene variation in the pathology of type II diabetes.[30] Recent phenotype data also suggest this gene[31] and its partner Clock[32] play a role in the regulation of glucose homeostasis and metabolism, which can lead to hypoinsulinaemia or diabetes when disrupted.[33]

In regards to other functions, another study shows that the CLOCK/BMAL1 complex upregulates human LDLR promoter activity, suggesting the Arntl gene also plays a role in cholesterol homeostasis.[34] Furthermore, BMAL1 has been shown to influence excitability and seizure threshold.[35] In addition, BMAL1 gene expression, along with that of other core clock genes, were discovered to be lower in patients with bipolar disorder, suggesting a problem with circadian function in these patients.[36] An SNP in Bmal1 was identified as having a link with bipolar disorder.[37] Arntl, Npas2, and Per2 have also been associated with seasonal affective disorder in humans.[38] Alzheimer's patients have different rhythms in BMAL1 methylation suggesting that its misregulation contributes to cognitive deficits.[39] Research has also shown that BMAL1 and other clock genes drive the expression of clock-controlled genes that are associated with Autism Spectrum Disorder (ASD).[40] Lastly, BMAL1 has been identified through functional genetic screening as a putative regulator of the p53 tumor suppressor pathway suggesting potential involvement in the circadian rhythms exhibited by cancer cells.[41][42]

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.[43] 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.[44] 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.[44]

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.[45] 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.[45] Key interactions with specific amino acid residues, specially CLOCK His 84 and BMAL1 Leu125, are important in the dimerization of these molecules.[46]

Function

Circadian clock

The protein encoded by the BMAL1 gene in mammals binds with a second bHLH-PAS protein via the PAS domain, CLOCK (or its paralog, NPAS2) to form a heterodimer in the nucleus.[13] Via its BHLH domain, this heterodimer binds to E-box response elements[13] in the promoter regions of Per (Per1 and Per2) and Cry genes (Cry1 and Cry2).[13] 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 [47] 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.[13][48] 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.[49]

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.[11] In addition to defects in the clock, these Arntl-null mice also have reproductive problems,[50] are small in stature, age quickly,[51] and have progressive arthropathy[52] that results in having less overall locomotor activity than wild type mice. However, recent research suggests that there might be some redundancy in the circadian function of Arntl with its paralog Bmal2.[53] BMAL1 KO is not embryonically lethal and mice with BMAL1 ablated in adulthood do not express the symptoms of BMAL1 KO mice.[54] 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.[55]

BMAL1 binding is regulated in a tissue-specific manner by numerous factors including non-circadian ones.[56] Following, tissue-specific KOs cause unique effects. BMAL1 has been shown to be important in bone metabolism as osteoblast BMAL1 KO mice have lower bone mass than their wild type counterparts.[57] It is also important for energy metabolism as BMAL1 modulates the regulation of hepatic metabolites, the secretion of insulin and proliferation of pancreatic islets, and adipocyte differentiation and lipogenesis.[39] Curiously, global KO of BMAL1 has no effect on food anticipatory activity (FAA) in mice but in BMAL1 deletions in certain regions in the hypothalamus outside the SCN eliminate FAA.[58] Knockout studies have demonstrated that BMAL1 is a key mediator between the circadian clock and the immune system response. By loss of Ccl2 regulation, BMAL1 KO in myeloid cells results in hindered monocyte recruitment, pathogen clearance, and anti-inflammatory response (consistent with the arthropathy phenotype).[59] Immune cells such as TNF-α and IL-1β  reciprocally repress BMAL1 activity.[59] 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.[60]

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.[61]

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.[67]
  • Cycle - Cycle is the Drosophila melanogaster ortholog of Arntl.

References

  1. ↑ "ARNTL aryl hydrocarbon receptor nuclear translocator-like [ Homo sapiens (human) "]. https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=406. 
  2. ↑ "Coordination of circadian timing in mammals". Nature 418 (6901): 935–41. August 2002. doi:10.1038/nature00965. PMID 12198538. Bibcode: 2002Natur.418..935R. 
  3. ↑ "The major circadian pacemaker ARNT-like protein-1 (BMAL1) is associated with susceptibility to gestational diabetes mellitus". Diabetes Research and Clinical Practice 99 (2): 151–7. February 2013. doi:10.1016/j.diabres.2012.10.015. PMID 23206673. 
  4. ↑ "Clock genes in hypertension: novel insights from rodent models". Blood Pressure Monitoring 19 (5): 249–54. October 2014. doi:10.1097/MBP.0000000000000060. PMID 25025868. 
  5. ↑ "ARNTL Gene". Gene Cards: The Human Genome Compendium. Lifemap Sciences, Inc.. https://www.genecards.org/cgi-bin/carddisp.pl?gene=ARNTL. 
  6. ↑ "Genome-wide profiling of the core clock protein BMAL1 targets reveals a strict relationship with metabolism". Molecular and Cellular Biology 30 (24): 5636–48. December 2010. doi:10.1128/MCB.00781-10. PMID 20937769. 
  7. ↑ 7.0 7.1 7.2 7.3 "Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway". The Journal of Biological Chemistry 272 (13): 8581–93. March 1997. doi:10.1074/jbc.272.13.8581. PMID 9079689. 
  8. ↑ 8.0 8.1 "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". Biochemical and Biophysical Research Communications 233 (1): 258–64. April 1997. doi:10.1006/bbrc.1997.6371. PMID 9144434. 
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  19. ↑ 19.0 19.1 19.2 "Dual modification of BMAL1 by SUMO2/3 and ubiquitin promotes circadian activation of the CLOCK/BMAL1 complex". Molecular and Cellular Biology 28 (19): 6056–65. October 2008. doi:10.1128/MCB.00583-08. PMID 18644859. 
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  23. ↑ 23.0 23.1 "Regulation of BMAL1 protein stability and circadian function by GSK3beta-mediated phosphorylation". PLOS ONE 5 (1): e8561. January 2010. doi:10.1371/journal.pone.0008561. PMID 20049328. Bibcode: 2010PLoSO...5.8561S. 
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  42. ↑ "A large scale shRNA barcode screen identifies the circadian clock component ARNTL as putative regulator of the p53 tumor suppressor pathway". PLOS ONE 4 (3): e4798. 2009. doi:10.1371/journal.pone.0004798. PMID 19277210. Bibcode: 2009PLoSO...4.4798M. 
  43. ↑ "Lymphocyte Circadian Clocks Control Lymph Node Trafficking and Adaptive Immune Responses". Immunity 46 (1): 120–132. January 2017. doi:10.1016/j.immuni.2016.12.011. PMID 28087238. 
  44. ↑ 44.0 44.1 "Chronobiological regulation of psychosocial and physiological outcomes in multiple sclerosis". Neuroscience and Biobehavioral Reviews 88: 73–83. May 2018. doi:10.1016/j.neubiorev.2018.03.011. PMID 29548931. 
  45. ↑ 45.0 45.1 "Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional activator complex". Science 337 (6091): 189–94. July 2012. doi:10.1126/science.1222804. PMID 22653727. Bibcode: 2012Sci...337..189H. 
  46. ↑ "Intermolecular recognition revealed by the complex structure of human CLOCK-BMAL1 basic helix-loop-helix domains with E-box DNA". Cell Research 23 (2): 213–24. February 2013. doi:10.1038/cr.2012.170. PMID 23229515. 
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  52. ↑ "Progressive arthropathy in mice with a targeted disruption of the Mop3/Bmal-1 locus". Genesis 41 (3): 122–32. March 2005. doi:10.1002/gene.20102. PMID 15739187. 
  53. ↑ "Circadian clock gene Bmal1 is not essential; functional replacement with its paralog, Bmal2". Current Biology 20 (4): 316–21. February 2010. doi:10.1016/j.cub.2009.12.034. PMID 20153195. 
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  56. ↑ "Help from my friends-cooperation of BMAL1 with noncircadian transcription factors". Genes & Development 33 (5–6): 255–257. March 2019. doi:10.1101/gad.324046.119. PMID 30824531. 
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  61. ↑ 61.0 61.1 "BMAL1 regulates mitochondrial fission and mitophagy through mitochondrial protein BNIP3 and is critical in the development of dilated cardiomyopathy". Protein & Cell 11 (9): 661–679. September 2020. doi:10.1007/s13238-020-00713-x. PMID 32277346. 
  62. ↑ 62.0 62.1 62.2 62.3 "The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors". Proceedings of the National Academy of Sciences of the United States of America 95 (10): 5474–9. May 1998. doi:10.1073/pnas.95.10.5474. PMID 9576906. Bibcode: 1998PNAS...95.5474H. 
  63. ↑ "Identification of a novel basic helix-loop-helix-PAS factor, NXF, reveals a Sim2 competitive, positive regulatory role in dendritic-cytoskeleton modulator drebrin gene expression". Molecular and Cellular Biology 24 (2): 608–16. January 2004. doi:10.1128/MCB.24.2.608-616.2004. PMID 14701734. 
  64. ↑ 64.0 64.1 "Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: a humoral mechanism to reset a peripheral clock". Cell 105 (7): 877–89. June 2001. doi:10.1016/S0092-8674(01)00401-9. PMID 11439184. 
  65. ↑ "Transactivation mechanisms of mouse clock transcription factors, mClock and mArnt3". Genes to Cells 5 (9): 739–47. September 2000. doi:10.1046/j.1365-2443.2000.00363.x. PMID 10971655. 
  66. ↑ 66.0 66.1 66.2 "Cryptochrome 1 regulates the circadian clock through dynamic interactions with the BMAL1 C terminus". Nature Structural & Molecular Biology 22 (6): 476–484. June 2015. doi:10.1038/nsmb.3018. PMID 25961797. 
  67. ↑ "The basic helix-loop-helix-PAS protein MOP9 is a brain-specific heterodimeric partner of circadian and hypoxia factors". The Journal of Neuroscience 20 (13): RC83. July 2000. doi:10.1523/JNEUROSCI.20-13-j0002.2000. 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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