A Per-Arnt-Sim (PAS) domain is a

protein domain In molecular biology, a protein domain is a region of a protein's polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact folded three-dimensional structure. Many proteins consist of s ...

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 In a polymer, chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a common Biomolecular structure#Tertiary structure, three-dimensional structure that appears in a variety of different, evolutionarily unrel ...

involved in protein-protein interactions of the

circadian clock A circadian clock, or circadian oscillator, is a biochemical oscillator that cycles with a stable phase (waves), phase and is synchronized with solar time. Such a clock's ''in vivo'' period is necessarily almost exactly 24 hours (the earth's curre ...

, and it is also a common motif found in signaling proteins, where it functions as a signaling sensor.

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: * Per – period circadian protein * Arnt – aryl hydrocarbon receptor nuclear translocator protein * Sim – 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.

Structure

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 β-sheet and several α-helices. Structural changes, as a result of signaling, predominantly originate within the

β-sheet The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gen ...

. These signals propagate via the

α-helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...

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 ''Halorhodospira halophila'' is a species of Halorhodospira distinguished by its ability to grow optimally in an environment of 15–20% salinity. It was formerly called ''Ectothiorhodospira halophila''. It is an anaerobic, rod-shaped Gram-negati ...

''. 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.

Bacteria

Often in the bacterial kingdom, PAS domains are positioned at the amino terminus of signaling proteins such as sensor

histidine kinase Histidine kinases (HK) are multifunctional, and in non-animal kingdoms, typically transmembrane, proteins of the transferase class of enzymes that play a role in signal transduction across the cellular membrane. The vast majority of HKs are homod ...

s, cyclic-di-GMP synthases and hydrolases, and

methyl-accepting chemotaxis protein The Methyl-accepting chemotaxis proteins (MCP, also aspartate receptor) are a family of transmembrane receptors that mediate chemotactic response in certain enteric bacteria, such as Salmonella typhimurium and Escherichia coli. These methyl-a ...

''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.

''Drosophila''

In the presence of light, CLK and

CYC Cyc (pronounced ) is a long-term artificial intelligence project that aims to assemble a comprehensive ontology and knowledge base that spans the basic concepts and rules about how the world works. Hoping to capture common sense knowledge, Cyc f ...

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.

Mammals

The circadian clock that is currently understood for mammals begins when light activates

BMAL1 Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL) or brain and muscle ARNT-Like 1 (BMAL1) is a protein that in humans is encoded by the gene on chromosome 11, region p15.3. It's also known as ''BMAL1'', ''MOP3'', and, less com ...

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

chaperonin HSP60, also known as chaperonins (Cpn), is a family of heat shock proteins originally sorted by their 60kDa molecular mass. They prevent misfolding of proteins during stressful situations such as high heat, by assisting protein folding. HSP60 bel ...

s and other small molecules like

dioxin Dioxin may refer to: * 1,2-Dioxin or 1,4-Dioxin, two unsaturated heterocyclic 6-membered rings where two carbon atoms have been replaced by oxygen atoms, giving the molecular formula C4H4O2 *Dibenzo-1,4-dioxin, the parent compound also known as ...

, but PAS B domains in

NPAS2 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 maintenan ...

, a homolog of the Drosophila clk gene, and the

hypoxia inducible factor Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or hypoxia. They are only present in parahoxozoan animals. Discovery The HIF transcriptional complex w ...

(HIF) also help to mediate

ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...

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 The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

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.

References

{{Protein domains