The PAS domain-containing serine/threonine protein kinase (PASK) is an enzyme encoded by the PASK gene in humans. The PAS domain regulates the functions of various intracellular signal transduction pathways in response to external and internal stimuli. PASK is an evolutionarily conserved protein found in yeast, Drosophila and mammals. The PAS domain regulates the function of many intracellular signaling pathways in response to external and internal stimuli. Histidine kinases regulated by the PAS domain are common in prokaryotes and control a variety of basic physiological processes. Similar regulatory kinases are rare in eukaryotes and have so far been absent in mammals. PAS kinase (PASK) is an evolutionarily conserved gene product found in yeast, fruit flies, and mammals. The amino acid sequence of PASK specifies two PAS domains, followed by a typical serine/threonine kinase domain, indicating that it may represent the first mammalian PAS-regulated protein kinase.

Figure 1. Protein structure of PASK.

Introductions

The PAS domain is a small regulatory module in all kingdoms of life. Most prokaryotic PAS domains function as sensor modules for two-component systems. One of the most distinctive features of these two-component systems is the FixL/FixJ pathway of rhizobium. The system couple nitrogen fixation with oxygen concentration by measuring oxygen and directing the transcription of the product genes required for nitrogen fixation. This mechanism relies on the ability of the single PAS domain of the FixL protein to sense oxygen levels through the attached heme moiety and to couple this signal to conformational changes on the surface of the PAS domain. The conformation of the FixL PAS domain controls the activity of its transmitter histidine kinase, presumably achieved by differentially regulating the PAS domain / kinase domain interaction under oxygen-bound and anaerobic states. Histidine kinase only catalyzes a series of phosphotransfer reactions under anaerobic conditions, which ultimately leads to the phosphorylation and activation of the transcription factor FixJ. Phospho-FixJ is then able to activate the transcription of many genes whose products are essential for nitrogen fixation. Many other two-component systems containing PAS domains have been found in prokaryotes. It is speculated that most of these systems use a mechanism similar to FixL/FixJ, and under the control of specific stimuli, have the conformation of the PAS domain, thereby regulating the activity of their homologous histidine kinase, thereby controlling specific cellular responses.

Regulations

The main way in which PASK signals regulate energy utilization is almost certainly phosphorylation of protein substrates catalyzed by the classical C-terminal serine/threonine kinase domain. In contrast, the mechanism by which PASK senses the metabolic state of cells is unclear, but may be related to its N-terminal PAS domain. The PAS domain acts as a sensory module for a variety of intracellular signals, including light, oxygen, redox status, and various metabolites. In coordination with this sensing function, the PAS domain triggers an appropriate cellular response by modulating the attached functional domain. Like other PAS domains, NMR-based structural studies of PASK PAS domains have shown that it can bind to specific small molecules. The PAS domain of PASK can also directly or indirectly bind and inhibit the catalytic activity of the kinase domain. These data, along with other precedents for PAS domain research, support the hypothesis that cellular PAS domain ligands regulate PASK kinase activity by regulating PAS domain-kinase domain interactions. Most protein kinases require phosphorylation on serine, threonine, or tyrosine residues within the activation loop of the kinase domain to achieve full activation.

Figure 2. Crystal structure of the kinase domain of PASK. (Chintan K; et al. 2010)

References:

1. Chintan K; et al. Structural Bases of PAS Domain-regulated Kinase (PASK) Activation in the Absence of Activation Loop Phosphorylation.J. Biol. Chem. 2010, 285:41034-41043.
2. Rutter J; et al. PAS kinase: an evolutionarily conserved PAS domain-regulated serine/threonine kinase. Proc Natl Acad Sci U S A. 2001,98 (16): 8991–6.