Schmidt Lab

Martin C. Schmidt, PhD
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543 Bridgeside Point II
450 Technology Dr.
Pittsburgh, PA 15219

My lab studies the Snf1 kinase of yeast. The mammalian homologue of Snf1 is the AMP-activated protein kinase, an important therapeutic target for type II diabetes. Biochemical and genetic experiments have shown that Snf1 kinase is regulated by phosphorylation of the conserved threonine residue in the kinase activation loop. We have developed a phosphopeptide antibody that specifically recognizes the phosphorylated (active) form of Snf1 kinase. We have used the antibody to demonstrate that Snf1 is activated by three distinct upstream kinases called Sak1, Tos3 and Elm1. We now know that the Snf1-activating kinases are not themselves regulated by glucose. Instead, it is the DEphosphorylation of the Snf1 activation loop that responds to changes in glucose abundance. The yeast PP1 phosphatase is responsible for the dephosphorylation of Snf1 in response to changes in carbon source. We have shown that the PP1 phosphatase is active in low glucose toward most substrates. However, the Snf1 kinase becomes resistant to dephosphorylation. These data indicate that the active Snf1 kinase can adopt a phosphatase resistant structure. The phosphatase resistant structure is stabilized in vitro by binding low energy adenylate ligands such as AMP and ADP. In this way, the Snf1 kinase is a direct sensor of the cell’s energy status with low energy adenylate ligands stabilizing the active form of Snf1 which then promotes ATP synthesis and conservation. The long term goal of the lab is to identify all the components of the glucose signaling pathway in yeast and to understand how they interact in order to regulate gene expression and cellular metabolism. These studies will provide a better understanding of glucose-mediated regulation of cellular metabolism and have important implications for designing novel treatments for patients with diabetes.

Lab Members:

Dakshanyini Guddenahalli Chandrashekarappa, Senior Research Specialist

Jordan Barney, Research Specialist