Pas-kinase regulates multiple steps in the glycogen synthesis
pathway.
Jared Rutter, Brandon Probst, Steve McKnight
Dept. of Biochemistry, U of Texas-Southwestern Med Ct, 5323 Harry Hines,
Dallas, TX 75390-9152, USA
The PAS domain is a sequence motif shown
in a number of systems to bind small molecules and regulate the activity
of other domains within the protein. PAS-Kinase (PASK) contains two PAS
domains followed by a serine/threonine kinase domain, and is
evolutionarily conserved, with structural homologs in yeast, fly, mouse
and human genomes. We have found that the N-terminal portion of the
protein, including the two PAS domains, is a cis-repressor of catalytic
activity. Furthermore, the N-terminal PAS domain when added to the
isolated kinase domain in trans specifically binds to and
inhibits the kinase domain. Biochemical and biophysical data suggest a
model wherein the PASK enzyme is repressed in cis by its PAS
domain, with this negative regulation subject to derepression by a
diffusible ligands. We have also employed genetics and biochemistry to
understand the biological function of PASK. Using S. cerevisiae,
we obtained independent genetic and biochemical evidence that PASK
regulates both translation and glucose utilization. In vitro,
PASK phosphorylates three translation factors and two enzymes in the
glycogen synthesis pathway. Accordingly, glycogen accumulation is
dysregulated in a yeast strain deleted for the two PASK genes. We
hypothesize that PASK senses specific metabolite levels via the PAS
domains, and regulates two important adaptive pathways, translation and
sugar utilization.
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