Summary: PAS domain
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PAS domain Edit Wikipedia article
|SCOP2||2phy / SCOPe / SUPFAM|
A Per-Arnt-Sim (PAS) domain is a protein domain found in all kingdoms of life. Generally, the PAS domain acts as a molecular sensor, whereby small molecules and other proteins associate via binding of the PAS domain. 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.
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:
- Per â€“ period circadian protein
- Arnt â€“ aryl hydrocarbon receptor nuclear translocator protein
- Sim â€“ single-minded protein
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.
Although the PAS domain exhibits a degree of sequence variability, the three-dimensional structure of the PAS domain core is broadly conserved. This core consists of a five-stranded antiparallel Î²-sheet and several Î±-helices. Structural changes, as a result of signaling, predominantly originate within the Î²-sheet. These signals propagate via the Î±-helices of the core to the covalently-attached effector domain. In 1998, the PAS domain core architecture was first characterized in the structure of photoactive yellow protein (PYP) from Halorhodospira halophila. In many proteins, a dimer of PAS domains is required, whereby one binds a ligand and the other mediates interactions with other proteins.
Examples of PAS in organisms
The PAS domains that are known share less than 20% average pairwise sequence identity, meaning they are surprisingly dissimilar. PAS domains are frequently found on proteins with other environmental sensing mechanisms. Also, many PAS domains are attached to photoreceptive cells.
Often in the bacterial kingdom, PAS domains are positioned at the amino terminus of signaling proteins such as sensor histidine kinases, cyclic-di-GMP synthases and hydrolases, and methyl-accepting chemotaxis proteins.
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.
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.
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. 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.
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.
- "A distal arginine in oxygen-sensing heme-PAS domains is essential to ligand binding, signal transduction, and structure". Biochemistry. 42 (25): 7701â€“8. doi:10.1021/bi0343370. PMIDÂ 12820879. â€‹; Dunham CM, Dioum EM, Tuckerman JR, Gonzalez G, Scott WG, Gilles-Gonzalez MA (July 2003).
- Henry, Jonathan T.; Crosson, Sean (1 January 2011). "Ligand-binding PAS domains in a genomic, cellular, and structural context". Annual Review of Microbiology. 65: 261â€“286. doi:10.1146/annurev-micro-121809-151631. PMCÂ 3298442. PMIDÂ 21663441.
- 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): 2127â€“2136. doi:10.1107/S139900471501384X. PMIDÂ 26457436.
- MÃ¶glich, Andreas; Ayers, Rebecca A.; Moffat, Keith (14 October 2009). "Structure and signaling mechanism of Per-ARNT-Sim domains". Structure. 17 (10): 1282â€“1294. doi:10.1016/j.str.2009.08.011. PMCÂ 3092527. PMIDÂ 19836329.
- Hennig, Sven; Strauss, Holger M.; Vanselow, Katja; Yildiz, Ã–zkan; 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. PMCÂ 2671562. PMIDÂ 19402751.
- Ponting CP, Aravind L (November 1997). "PAS: a multi-functional domain family comes to light". Curr. Biol. 7 (11): R674â€“7. doi:10.1016/S0960-9822(06)00352-6. PMIDÂ 9382818. S2CIDÂ 14105830.
- Hefti MH, FranÃ§oijs 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): 1198â€“208. doi:10.1111/j.1432-1033.2004.04023.x. PMIDÂ 15009198.
- MÃ¶glich, Andreas; Ayers, Rebecca A.; Moffat, Keith (14 October 2009). "Structure and Signaling Mechanism of Per-ARNT-Sim Domains". Structure. 17 (10): 1282â€“1294. doi:10.1016/j.str.2009.08.011. PMCÂ 3092527. PMIDÂ 19836329.
- 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): 729â€“738. doi:10.1038/sj.ejhg.5201547. PMIDÂ 16721409.
- Henry, Jonathan T.; Crosson, Sean (1 January 2011). "Ligand-Binding PAS Domains in a Genomic, Cellular, and Structural Context". Annual Review of Microbiology. 65: 261â€“286. doi:10.1146/annurev-micro-121809-151631. PMCÂ 3298442. PMIDÂ 21663441.
- MÃ¶glich, A; Ayers, RA; Moffat, K (2009). "Structure and Signaling Mechanism of Per-ARNT-Sim Domains". Structure. 17 (10): 1282â€“94. doi:10.1016/j.str.2009.08.011. PMCÂ 3092527. PMIDÂ 19836329.
- McIntosh, Brian; Hogenesch, John; Bradfield, Christopher (2010). "Mammalian Per-Arnt-Sim Proteins in Environmental Adaptation". Annual Review of Physiology. 72: 625â€“645. doi:10.1146/annurev-physiol-021909-135922. PMIDÂ 20148691.
- Harmer, Stacey L.; Panda, Satchidananda; Kay, Steve A. (28 November 2003). "Molecular Bases of Circadian Rhythms". Annual Review of Cell and Developmental Biology. 17: 215â€“253. doi:10.1146/annurev.cellbio.17.1.215. PMIDÂ 11687489.
- Somers, David; Schultz, Thomas; Kay, Steve; Milnamow, Maureen (2000). "ZEITLUPE Encodes a Novel Clock-Associated PAS Protein from Arabidopsis". Cell. 101 (3): 319â€“329. doi:10.1016/S0092-8674(00)80841-7. PMIDÂ 10847686. S2CIDÂ 3013788.
- 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): 465â€“77. doi:10.1016/j.neuron.2006.03.041. PMIDÂ 16675400. S2CIDÂ 19028601.
- 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. PMCÂ 463060. PMIDÂ 15186484.
- Ke, Qingdong; Costa, Max (1 November 2006). "Hypoxia-Inducible Factor-1 (HIF-1)". Molecular Pharmacology. 70 (5): 1469â€“1480. doi:10.1124/mol.106.027029. PMIDÂ 16887934. S2CIDÂ 2522614.
- 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): 5510â€“5514. doi:10.1073/pnas.92.12.5510. PMCÂ 41725. PMIDÂ 7539918.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
PAS domain Provide feedback
This domain is found in many signalling proteins in which it functions as a sensor domain. It recognises FMN, Zn(II), FAD and riboflavin (MAtilla et. al., FEMS Microbiology Reviews, fuab043, 45, 2021, 1. https://doi.org/10.1093/femsre/fuab043).
Internal database links
|SCOOP:||MEKHLA PAS PAS_10 PAS_11 PAS_12 PAS_3 PAS_4 PAS_7 PAS_8 STAS|
|Similarity to PfamA using HHSearch:||PAS PAS_2 PAS_3 PAS_4 MEKHLA PAS_7 PAS_8 PAS_10 PAS_11|
This tab holds annotation information from the InterPro database.
InterPro entry IPR000014
PAS domains are involved in many signalling proteins where they are used as a signal sensor domain [ PUBMED:10357859 ]. PAS domains appear in archaea, bacteria and eukaryotes. Several PAS-domain proteins are known to detect their signal by way of an associated cofactor. Heme, flavin, and a 4-hydroxycinnamyl chromophore are used in different proteins. The PAS domain was named after three proteins that it occurs in:
- Per- period circadian protein
- Arnt- Ah receptor nuclear translocator protein
- Sim- single-minded protein.
PAS domains are often associated with PAC domains INTERPRO . It appears that these domains are directly linked, and that together they form the conserved 3D PAS fold. The division between the PAS and PAC domains is caused by major differences in sequences in the region connecting these two motifs [ PUBMED:15009198 ]. In human PAS kinase, this region has been shown to be very flexible, and adopts different conformations depending on the bound ligand [ PUBMED:12377121 ]. Probably the most surprising identification of a PAS domain was that in EAG-like K -channels [ PUBMED:9301332 ].
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
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a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
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EGFdomains, and finally a single
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This clan contains PAS domains that are found in a wide variety of bacterial signaling proteins.
The clan contains the following 17 members:AbfS_sensor CpxA_peri DUF5593 MEKHLA MLTR_LBD PAS PAS_10 PAS_11 PAS_12 PAS_2 PAS_3 PAS_4 PAS_5 PAS_6 PAS_7 PAS_8 PAS_9
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
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|Number in seed:||118|
|Number in full:||38837|
|Average length of the domain:||104.70 aa|
|Average identity of full alignment:||20 %|
|Average coverage of the sequence by the domain:||15.02 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||10|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
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How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
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Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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The tree shows the occurrence of this domain across different species. More...
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the PAS_9 domain has been found. There are 345 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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AlphaFold Structure Predictions
The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.