Martin C. Schmidt, PhD
521 Bridgeside Point II
450 Technology Drive
PhD in Biochemistry, University of California, Berkeley
Our recent studies have focused on 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 would like to determine the mechanism by which glucose abundance determines the phosphorylation status of the Snf1 activation loop. Our most recent work has shown 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. Future studies will focus on understanding the molecular mechanisms regulating the dephosphorylation reaction.
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.
Research Lab Affiliation
Chandrashekarappa, D. G; McCartney, R. R; and Schmidt, M. C. (2013) Ligand binding to the AMP-activated protein kinase active site mediates protection of the activation loop from dephosphorylation. J Biol Chem. 288: 89-98. | View Abstract
Chandrashekarappa, D. G; McCartney, R. R; and Schmidt, M. C. (2011) Subunit and domain requirements for adenylate-mediated protection of Snf1 activation loop from dephosphorylation. J Biol Chem. 286: 44532-44541. | View Abstract
Mayer, F. V; Heath, R; Underwood, E; Sanders, M. J; Carmena, D; McCartney, R. R; Leiper, F. C; Xiao, B; Jing, C; Walker, P. A; Haire, L. F; Ogrodowicz, R; Martin, S. R; Schmidt, M. C; Gamblin, S. J; and Carling, D. (2011) ADP regulates SNF1, the Saccharomyces cerevisiae homologue of AMP-activated protein kinase. Cell Metab. 14: 707-714. | View Abstract
Zhang, Y; McCartney, R. R; Chandrashekarappa, D. G; Mangat, S; and Schmidt, M. C. (2011) Reg1 protein regulates phosphorylation all three Snf1 isoforms but preferentially associates with the Gal83 isoform. Eukaryotic Cell. 10: 1628-1636. | View Abstract
Tabba, S; Mangat, S; McCartney, R; and Schmidt, M. C. (2010) PP1 phosphatase-binding motif in Reg1 protein of Saccharomyces cerevisiae is required for interaction with both the PP1 phosphatase Glc7 and the Snf1 protein kinase. Cell Signal. 22: 1013-1021. | View Abstract
Mangat, S; Chandrashekarappa, D; McCartney, R. R; Elbing, K; and Schmidt, M. C. (2010) Differential roles of the glycogen-binding domains of beta subunits in regulation of the Snf1 kinase complex. Eukaryotic Cell. 9: 173-183. | View Abstract
Rubenstein, E. M; McCartney, R. R; Zhang, C; Shokat, K. M; Shirra, M. K; Arndt, K. M; and Schmidt, M. C. (2008 ) Access Denied: Snf1 Activation Loop Phosphorylation is Controlled by Availability of the Phosphorylated Threonine 210 to the PP1 Phosphatase. J Biol Chem. 283: 222-230. | View Abstract