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A Per-Arnt-Sim (PAS) domain is a protein domain found in all kingdoms of life. It is found in many signaling proteins, where it functions as a signaling sensor. Generally, the PAS domain acts as a molecular velcro, whereby small molecules and other proteins via association with the PAS domain. Due to this velcro capability, the PAS domain has been shown as the key structural motif involved in protein-protein interactions of the circadian clock.

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 the PAS domain, a a large quantity of PAS binding sites have been discovered in bacteria and eukaryotes, a subset of which are responsive to oxygen, light and voltage, which gives rise to PAS LOV proteins.

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 is comprised 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. In 1998, the PAS domain core architecture was first characterized in the the structure of Halorhodospira halophila photoactive yellow protein (PYP). 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. An example of PAS B domain of Hif1a and Hif2a are oxygen-sensing domains. 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 kinases, cyclic-di-GMP synthases and hydrolases, and methyl-accepting chemotaxis proteins.

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 attach via PAS, activating the translation of PER, which then associates to Tim via the PER PAS domain.

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 currently understood for mammals begins when light activates BMAL1 and CLK to bind via their PAS domains. That activator complex regulates the Per1/Per2/Per3 which also has PAS, which it uses to bind to cryptochromes 1 and 2 (CRY 1,2 family), which do not contain PAS domains.

Other Mammalian PAS roles
Within Mammals both PAS domains play other important role. PAS A is responsible for the protein-protein interactions with other PAS 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 containing the NPAS2 protein have been shown to be a substitute for the Clock gene in mutant mice who lack the Clock gene completely.

PAS 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 and the Clock gene.