PAS domain

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PAS fold
FixL 1y28.png
Crystallographic structure of the PAS domain of the bacterial oxygen sensor protein fixL. [1] The protein is depicted as a rainbow colored cartoon (N-terminus = blue, C-terminus = red) while the heme ligand is shown as sticks (carbon = white, nitrogen = blue, oxygen = red, iron = orange).
Identifiers
SymbolPAS
Pfam PF00989
InterPro IPR013767
SMART PAS
PROSITE PDOC50112
SCOP2 2phy / SCOPe / SUPFAM
CDD cd00130
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
PDB 1byw ​, 1d06 ​, 1d7e ​, 1dp6 ​, 1dp8 ​, 1dp9 ​, 1drm ​, 1ew0 ​, 1f98 ​, 1f9i ​, 1gsv ​, 1gsw ​, 1gsx ​, 1kou ​, 1ll8 ​, 1lsv ​, 1lsw ​, 1lsx ​, 1lt0 ​, 1mzu ​, 1nwz ​, 1odv ​, 1ot6 ​, 1ot9 ​, 1ota ​, 1otb ​, 1otd ​, 1ote ​, 1oti ​, 1s1y ​, 1s1z ​, 1s4r ​, 1s4s ​, 1s66 ​, 1s67 ​, 1t18 ​, 1t19 ​, 1t1a ​, 1t1b ​, 1t1c ​, 1ts0 ​, 1ts6 ​, 1ts7 ​, 1ts8 ​, 1ugu ​, 1uwn ​, 1uwp ​, 1v9y ​, 1v9z ​, 1vb6 ​, 1wa9 ​, 1xfn ​, 1xfq ​, 1xj2 ​, 1xj3 ​, 1xj4 ​, 1xj6 ​, 1y28 ​, 2d01 ​, 2d02 ​, 2phy ​, 2pyp ​, 2pyr ​, 3phy ​, 3pyp ​

A Per-Arnt-Sim (PAS) domain is a protein domain found in all kingdoms of life. [2] Generally, the PAS domain acts as a molecular sensor, whereby small molecules and other proteins associate via binding of the PAS domain. [3] [4] [5] Due to this sensing capability, the PAS domain has been shown as the key structural motif involved in protein-protein interactions of the circadian clock, and it is also a common motif found in signaling proteins, where it functions as a signaling sensor. [6] [7]

Contents

Discovery

PAS domains are found in a large number of organisms from bacteria to mammals. The PAS domain was named after the three proteins in which it was first discovered: [8]

Since the initial discovery of the PAS domain, a large quantity of PAS domain binding sites have been discovered in bacteria and eukaryotes. A subset called PAS LOV proteins are responsive to oxygen, light and voltage. [9]

Structure

Although the PAS domain exhibits a degree of sequence variability, the three-dimensional structure of the PAS domain core is broadly conserved. [10] This core consists of a five-stranded antiparallel β-sheet and several α-helices. Structural changes, as a result of signaling, predominantly originate within the β-sheet. These signals propagate via the α-helices of the core to the covalently-attached effector domain. [11] In 1998, the PAS domain core architecture was first characterized in the structure of photoactive yellow protein (PYP) from Halorhodospira halophila . [10] In many proteins, a dimer of PAS domains is required, whereby one binds a ligand and the other mediates interactions with other proteins. [5]

Examples of PAS in organisms

The PAS domains that are known share less than 20% average pairwise sequence identity, meaning they are surprisingly dissimilar. [10] PAS domains are frequently found on proteins with other environmental sensing mechanisms. Also, many PAS domains are attached to photoreceptive cells. [12]

Bacteria

Often in the bacterial kingdom, PAS domains are positioned at the amino terminus of signaling proteins such as sensor histidine kinases, cyclic-di-GMP syntheses and hydrolases, and methyl-accepting chemotaxis proteins. [10]

Neurospora

In the presence of light, White Collar-1 (WC-1) and White Collar-2 (WC-2) dimerizes via mediation by the PAS domains, which activates translation of FRQ. [13]

Drosophila

In the presence of light, CLK and CYC attach via a PAS domain, activating the translation of PER, which then associates to Tim via the PER PAS domain. The following genes contain PAS binding domains: PER, Tim, CLK, CYC.

Arabidopsis

A PAS domain is found in the ZTL and NPH1 genes. These domains are very similar to the PAS domain found in the Neurospora circadian-associated protein WC-1. [14]

Mammals

The circadian clock that is currently understood for mammals begins when light activates BMAL1 and CLK to bind via their PAS domains. That activator complex regulates Per1, Per2, and Per3 which all have PAS domains that are used to bind to cryptochromes 1 and 2 (CRY 1,2 family). The following mammalian genes contain PAS binding domains: Per1, Per2, Per3, Cry1, Cry2, Bmal, Clk, Pasd1.

Other mammalian PAS roles

Within Mammals, both PAS domains play important roles. PAS A is responsible for the protein-protein interactions with other PAS domain proteins, while PAS B has a more versatile role. It mediates interactions with chaperonins and other small molecules like dioxin, but PAS B domains in NPAS2, a homolog of the Drosophila clk gene, and the hypoxia inducible factor (HIF) also help to mediate ligand binding. [12] Furthermore, PAS domains containing the NPAS2 protein have been shown to be a substitute for the Clock gene in mutant mice who lack the Clock gene completely. [15]

The PAS domain also directly interacts with BHLH. It is typically located on the C-Terminus of the BHLH protein. PAS domains containing BHLH proteins form a BHLH-Pas protein, typically found and encoded in HIF, which require both the PAS domain and BHLH domain and the Clock gene. [16] [17] [18]

Related Research Articles

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<span class="mw-page-title-main">Basic helix–loop–helix</span> Protein structural motif

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<span class="mw-page-title-main">Aryl hydrocarbon receptor</span> Vertebrate transcription factor

The aryl hydrocarbon receptor is a protein that in humans is encoded by the AHR gene. The aryl hydrocarbon receptor is a transcription factor that regulates gene expression. It was originally thought to function primarily as a sensor of xenobiotic chemicals and also as the regulator of enzymes such as cytochrome P450s that metabolize these chemicals. The most notable of these xenobiotic chemicals are aromatic (aryl) hydrocarbons from which the receptor derives its name.

<span class="mw-page-title-main">Aryl hydrocarbon receptor nuclear translocator</span> Protein-coding gene in the species Homo sapiens

The ARNT gene encodes the aryl hydrocarbon receptor nuclear translocator protein that forms a complex with ligand-bound aryl hydrocarbon receptor (AhR), and is required for receptor function. The encoded protein has also been identified as the beta subunit of a heterodimeric transcription factor, hypoxia-inducible factor 1 (HIF1). A t(1;12)(q21;p13) translocation, which results in a TEL-ARNT fusion protein, is associated with acute myeloblastic leukemia. Three alternatively spliced variants encoding different isoforms have been described for this gene.

<span class="mw-page-title-main">CLOCK</span> Protein-coding gene in the species Homo sapiens

CLOCK is a gene encoding a basic helix-loop-helix-PAS transcription factor that is known to affect both the persistence and period of circadian rhythms.

An E-box is a DNA response element found in some eukaryotes that acts as a protein-binding site and has been found to regulate gene expression in neurons, muscles, and other tissues. Its specific DNA sequence, CANNTG, with a palindromic canonical sequence of CACGTG, is recognized and bound by transcription factors to initiate gene transcription. Once the transcription factors bind to the promoters through the E-box, other enzymes can bind to the promoter and facilitate transcription from DNA to mRNA.

Period (per) is a gene located on the X chromosome of Drosophila melanogaster. Oscillations in levels of both per transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of the Drosophila biological clock driving circadian rhythms in eclosion and locomotor activity. Mutations in the per gene can shorten (perS), lengthen (perL), and even abolish (per0) the period of the circadian rhythm.

<span class="mw-page-title-main">HIF1A</span> Protein-coding gene in the species Homo sapiens

Hypoxia-inducible factor 1-alpha, also known as HIF-1-alpha, is a subunit of a heterodimeric transcription factor hypoxia-inducible factor 1 (HIF-1) that is encoded by the HIF1A gene. The Nobel Prize in Physiology or Medicine 2019 was awarded for the discovery of HIF.

<span class="mw-page-title-main">NPAS2</span> Protein-coding gene in the species Homo sapiens

Neuronal PAS domain protein 2 (NPAS2) also known as member of PAS protein 4 (MOP4) is a transcription factor protein that in humans is encoded by the NPAS2 gene. NPAS2 is paralogous to CLOCK, and both are key proteins involved in the maintenance of circadian rhythms in mammals. In the brain, NPAS2 functions as a generator and maintainer of mammalian circadian rhythms. More specifically, NPAS2 is an activator of transcription and translation of core clock and clock-controlled genes through its role in a negative feedback loop in the suprachiasmatic nucleus (SCN), the brain region responsible for the control of circadian rhythms.

<span class="mw-page-title-main">ARNTL2</span> Protein-coding gene in humans

Aryl hydrocarbon receptor nuclear translocator-like 2, also known as Arntl2, Mop9, Bmal2, or Clif, is a gene.

<span class="mw-page-title-main">EPAS1</span> Protein-coding gene in the species Homo sapiens

Endothelial PAS domain-containing protein 1 is a protein that is encoded by the EPAS1 gene in mammals. It is a type of hypoxia-inducible factor, a group of transcription factors involved in the physiological response to oxygen concentration. The gene is active under hypoxic conditions. It is also important in the development of the heart, and for maintaining the catecholamine balance required for protection of the heart. Mutation often leads to neuroendocrine tumors.

<span class="mw-page-title-main">BHLHE41</span> Protein-coding gene in humans

"Basic helix-loop-helix family, member e41", or BHLHE41, is a gene that encodes a basic helix-loop-helix transcription factor repressor protein in various tissues of both humans and mice. It is also known as DEC2, hDEC2, and SHARP1, and was previously known as "basic helix-loop-helix domain containing, class B, 3", or BHLHB3. BHLHE41 is known for its role in the circadian molecular mechanisms that influence sleep quantity as well as its role in immune function and the maturation of T helper type 2 cell lineages associated with humoral immunity.

<span class="mw-page-title-main">Basic helix-loop-helix ARNT-like protein 1</span> Protein-coding gene in the species Homo sapiens

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.

<i>Cycle</i> (gene)

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White Collar-1 (wc-1) is a gene in Neurospora crassa encoding the protein WC-1. WC-1 has two separate roles in the cell. First, it is the primary photoreceptor for Neurospora and the founding member of the class of principle blue light photoreceptors in all of the fungi. Second, it is necessary for regulating circadian rhythms in FRQ. It is a key component of a circadian molecular pathway that regulates many behavioral activities, including conidiation. WC-1 and WC-2, an interacting partner of WC-1, comprise the White Collar Complex (WCC) that is involved in the Neurospora circadian clock. WCC is a complex of nuclear transcription factor proteins, and contains transcriptional activation domains, PAS domains, and zinc finger DNA-binding domains (GATA). WC-1 and WC-2 heterodimerize through their PAS domains to form the White Collar Complex (WCC).

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<i>Drosophila</i> circadian rhythm

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Carrie L. Partch is an American protein biochemist and circadian biologist. Partch is currently a Professor in the Department of Chemistry and Biochemistry at the University of California, Santa Cruz. She is noted for her work using biochemical and biophysical techniques to study the mechanisms of circadian rhythmicity across multiple organisms. Partch applies principles of chemistry and physics to further her research in the field of biological clocks.

References

  1. ↑ PDB: 1y28 ​; Dunham CM, Dioum EM, Tuckerman JR, Gonzalez G, Scott WG, Gilles-Gonzalez MA (July 2003). "A distal arginine in oxygen-sensing heme-PAS domains is essential to ligand binding, signal transduction, and structure". Biochemistry. 42 (25): 7701–8. doi:10.1021/bi0343370. PMID   12820879. S2CID   14090693.
  2. ↑ Henry, Jonathan T.; Crosson, Sean (1 January 2011). "Ligand-binding PAS domains in a genomic, cellular, and structural context". Annual Review of Microbiology . 65: 261–286. doi:10.1146/annurev-micro-121809-151631. PMC   3298442 . PMID   21663441.
  3. ↑ Liu, Yu C.; Machuca, Mayra A.; Beckham, Simone A.; Gunzburg, Menachem J.; Roujeinikova, Anna (1 October 2015). "Structural basis for amino-acid recognition and transmembrane signalling by tandem Per-Arnt-Sim (tandem PAS) chemoreceptor sensory domains". Acta Crystallographica Section D. 71 (10): 2127–2136. Bibcode:2015AcCrD..71.2127L. doi:10.1107/S139900471501384X. PMID   26457436.
  4. ↑ Möglich, Andreas; Ayers, Rebecca A.; Moffat, Keith (14 October 2009). "Structure and signaling mechanism of Per-ARNT-Sim domains". Structure. 17 (10): 1282–1294. doi:10.1016/j.str.2009.08.011. PMC   3092527 . PMID   19836329.
  5. 1 2 Hennig, Sven; Strauss, Holger M.; Vanselow, Katja; Yildiz, Özkan; Schulze, Sabrina; Arens, Julia; Kramer, Achim; Wolf, Eva (28 April 2009). "Structural and Functional Analyses of PAS Domain Interactions of the Clock Proteins Drosophila PERIOD and Mouse PERIOD2". PLOS Biology. 7 (4): e1000094. doi: 10.1371/journal.pbio.1000094 . PMC   2671562 . PMID   19402751.
  6. ↑ Ponting CP, Aravind L (November 1997). "PAS: a multi-functional domain family comes to light". Curr. Biol. 7 (11): R674–7. doi: 10.1016/S0960-9822(06)00352-6 . PMID   9382818. S2CID   14105830.
  7. ↑ Hefti MH, Françoijs KJ, de Vries SC, Dixon R, Vervoort J (March 2004). "The PAS fold. A redefinition of the PAS domain based upon structural prediction". Eur. J. Biochem. 271 (6): 1198–208. doi: 10.1111/j.1432-1033.2004.04023.x . PMID   15009198.
  8. ↑ Möglich, Andreas; Ayers, Rebecca A.; Moffat, Keith (14 October 2009). "Structure and Signaling Mechanism of Per-ARNT-Sim Domains". Structure. 17 (10): 1282–1294. doi:10.1016/j.str.2009.08.011. PMC   3092527 . PMID   19836329.
  9. ↑ Rosato, Ezio; Tauber, Eran; Kyriacou, Charalambos P. (1 January 2006). "Molecular genetics of the fruit-fly circadian clock". European Journal of Human Genetics. 14 (6): 729–738. doi: 10.1038/sj.ejhg.5201547 . PMID   16721409.
  10. 1 2 3 4 Henry, Jonathan T.; Crosson, Sean (1 January 2011). "Ligand-Binding PAS Domains in a Genomic, Cellular, and Structural Context". Annual Review of Microbiology . 65: 261–286. doi:10.1146/annurev-micro-121809-151631. PMC   3298442 . PMID   21663441.
  11. ↑ Möglich, A; Ayers, RA; Moffat, K (2009). "Structure and Signaling Mechanism of Per-ARNT-Sim Domains". Structure. 17 (10): 1282–94. doi:10.1016/j.str.2009.08.011. PMC   3092527 . PMID   19836329.
  12. 1 2 McIntosh, Brian; Hogenesch, John; Bradfield, Christopher (2010). "Mammalian Per-Arnt-Sim Proteins in Environmental Adaptation". Annual Review of Physiology . 72: 625–645. doi:10.1146/annurev-physiol-021909-135922. PMID   20148691.
  13. ↑ Harmer, Stacey L.; Panda, Satchidananda; Kay, Steve A. (28 November 2003). "Molecular Bases of Circadian Rhythms". Annual Review of Cell and Developmental Biology . 17: 215–253. doi:10.1146/annurev.cellbio.17.1.215. PMID   11687489.
  14. ↑ Somers, David; Schultz, Thomas; Kay, Steve; Milnamow, Maureen (2000). "ZEITLUPE Encodes a Novel Clock-Associated PAS Protein from Arabidopsis". Cell. 101 (3): 319–329. doi: 10.1016/S0092-8674(00)80841-7 . PMID   10847686. S2CID   3013788.
  15. ↑ Debruyne JP, Noton E, Lambert CM, Maywood ES, Weaver DR, Reppert SM (May 2006). "A clock shock: mouse CLOCK is not required for circadian oscillator function". Neuron. 50 (3): 465–77. doi: 10.1016/j.neuron.2006.03.041 . PMID   16675400. S2CID   19028601.
  16. ↑ Jones, Susan (1 January 2004). "An overview of the basic helix-loop-helix proteins". Genome Biology. 5 (6): 226. doi: 10.1186/gb-2004-5-6-226 . PMC   463060 . PMID   15186484.
  17. ↑ Ke, Qingdong; Costa, Max (1 November 2006). "Hypoxia-Inducible Factor-1 (HIF-1)". Molecular Pharmacology. 70 (5): 1469–1480. doi:10.1124/mol.106.027029. PMID   16887934. S2CID   2522614.
  18. ↑ Wang, G. L.; Jiang, B. H.; Rue, E. A.; Semenza, G. L. (6 June 1995). "Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension". Proceedings of the National Academy of Sciences of the United States of America. 92 (12): 5510–5514. Bibcode:1995PNAS...92.5510W. doi: 10.1073/pnas.92.12.5510 . PMC   41725 . PMID   7539918.
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