The role of PAS kinase in PASsing the glucose signal

Abstract

PAS kinase is an evolutionarily conserved nutrient responsive protein kinase that regulates glucose homeostasis. Mammalian PAS kinase is activated by glucose in pancreatic beta cells, and knockout mice are protected from obesity, liver triglyceride accumulation, and insulin resistance when fed a high-fat diet. Yeast PAS kinase is regulated by both carbon source and cell integrity stress and stimulates the partitioning of glucose toward structural carbohydrate biosynthesis. In our current model for PAS kinase regulation, a small molecule metabolite binds the sensory PAS domain and activates the enzyme. Although bona fide PAS kinase substrates are scarce, in vitro substrate searches provide putative targets for exploration.

Keywords: PAS domain; PAS kinase; PASKIN; glucose sensor; metabolic syndrome; protein phosphorylation.

Figure 1.

A model for PAS kinase regulation and function. The PAS domain binds to and inhibits the kinase domain. A metabolite (green star) or protein activates PAS kinase by binding to the PAS domain and relieving PAS domain inhibition. This transient activation may be subsequently stabilized through auto- or transphosphorylation. PAS kinase is then competent to phosphorylate substrates involved in glucose partitioning and translation (in S. cerevisiae) to elicit the appropriate physiological response.

Figure 2.

Alignment of the PAS and kinase domains from selected PAS kinase orthologs. (A) Schematic of PAS kinase homologs. Regions of similarity are boxed in grey, with non-homologous regions indicated by gaps between the grey boxes. Alignment of the PAS (B) and kinase (C) domains from selected PAS kinase orthologs. Secondary structure elements (α-helical and β-sheet) were derived from the published NMR structure of the PAS domain [27] as well as amino acid alignment of the kinase domain with the published structure of microtubule-associate protein/microtubule affinity regulating kinase 2 (MARK2) [33], and are shown above the amino acids in green and purple respectively. Amino acid sequences were aligned using the Clustal W program [34]. The degree of amino acid conservation is indicated both by color and “*” (identical residues in all sequences), “:” (highly conserved amino acids), and “.” (weakly conserved amino acids). Red indicates a small hydrophobic or aromatic amino acid (-Y), blue indicates acidic, magenta is basic, and green is hydroxyl plus amine plus basic (-Q), all other amino acids are grey.