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54  structures 5888  species 0  interactions 58162  sequences 9431  architectures

Family: PAS_4 (PF08448)

Summary: PAS fold

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PAS domain Edit Wikipedia article

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).

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]


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]


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]


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.[10]


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]


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.[14]


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]


  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.
  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. 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. ^ a b 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. ^ a b c d 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. ^ a b 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. doi:10.1073/pnas.92.12.5510. PMC 41725. PMID 7539918.

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PAS fold Provide feedback

The PAS fold corresponds to the structural domain that has previously been defined as PAS and PAC motifs [4]. The PAS fold appears in archaea, eubacteria and eukarya. This domain is associated to signalling systems and works as a signal sensor domain. It recognises differently substituted aromatic hydrocarbons, oxygen, different dodecanoic acids, autoinducers, 3,5-dimethyl-pyrazin-2-ol and N-alanyl-aminoacetone (Matilla et. al., FEMS Microbiology Reviews, fuab043, 45, 2021, 1.

Literature references

  1. Zhulin IB, Taylor BL, Dixon R; , Trends Biochem Sci 1997;22:331-333.: PAS domain S-boxes in archaea, bacteria and sensors for oxygen and redox. PUBMED:9301332 EPMC:9301332

  2. Borgstahl GE, Williams DR, Getzoff ED; , Biochemistry 1995;34:6278-6287.: 1.4 A structure of photoactive yellow protein, a cytosolic photoreceptor: unusual fold, active site, and chromophore. PUBMED:7756254 EPMC:7756254

  3. Ponting CP, Aravind L; , Curr Biol 1997;7:674-677.: PAS: a multifunctional domain family comes to light. PUBMED:9382818 EPMC:9382818

  4. Hefti MH, Francoijs KJ, de Vries SC, Dixon R, Vervoort J; , Eur J Biochem 2004;271:1198-1208.: The PAS fold: a redefination of the PAS domain based upon structural prediction. PUBMED:15009198 EPMC:15009198

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR013656

The PAS fold corresponds to the structural domain that has previously been defined as PAS and PAC motifs [ PUBMED:15009198 ]. The PAS fold appears in archaea, eubacteria and eukarya.

Domain organisation

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Pfam Clan

This family is a member of clan PAS_Fold (CL0183), which has the following description:

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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Curation and family details

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Seed source: Pfam-B_493 (Release 18.0)
Previous IDs: none
Type: Domain
Sequence Ontology: SO:0000417
Author: Bateman A
Number in seed: 49
Number in full: 58162
Average length of the domain: 109.70 aa
Average identity of full alignment: 16 %
Average coverage of the sequence by the domain: 17.65 %

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HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 23.1 23.1
Trusted cut-off 23.1 23.1
Noise cut-off 23.0 23.0
Model length: 110
Family (HMM) version: 13
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Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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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_4 domain has been found. There are 54 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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