Glucokinase Polymerization Regulates Enzyme Activity in Response to Environmental Shifts
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CitationStoddard, Patrick. 2019. Glucokinase Polymerization Regulates Enzyme Activity in Response to Environmental Shifts. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractUnlike cells in a multicellular organism, free living microbes are subject to abrupt changes in environment that can come with no warning. Cells must be prepared to react to these changes on timescales too short for them to change their composition and thus must have mechanisms in place to maintain homeostasis until they can reach a new steady-state. One particularly dangerous transition is the reintroduction to rich carbon sources. In the case of the budding yeast, Saccharomyces cerevisiae, the reintroduction to a glucose-rich environment after a period of starvation can result in death; cells can over invest energy in the first steps of glycolysis before they begin to receive returns on this investment. In our investigation of this phenomenon, we have found that one mechanism in place to prevent overinvestment is the polymerization of the glucokinase, Glk1, which catalyzes the first step in glycolysis. Glk1 is a structural homolog of actin, one of the best studied polymer forming proteins, however, that the polymerization of these two proteins has arisen independently. Glk1 polymerization appears to have arisen in the last common ancestor of a group of yeast that existed approximately 150 million years ago. I have found that Glk1 polymerization inhibits Glk1 enzyme activity. Structural studies of the Glk1 protein and Glk1 filaments have allowed us to design a mutant that cannot polymerize and thus lacks the concentration- dependent inhibition of Glk1 enzyme activity. I have leveraged this mutant to demonstrate that without Glk1 polymerization, cells die more frequently when they are refed glucose and that these cells show additional defects growing on sugars. Thus, the polymerization of Glk1 is important for yeast cells ability to respond to unexpected increases in the concentration of glucose.
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