Polymerization in the actin ATPase clan regulates hexokinase activity in yeast

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Science  28 Feb 2020:
Vol. 367, Issue 6481, pp. 1039-1042
DOI: 10.1126/science.aay5359

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Polymerization regulates hexokinase activity

The yeast hexokinase Glk1 is an actin-fold protein that forms polymers in response to binding its substrates and products. Stoddard et al. now show that Glk1 polymers are structurally distinct from actin filaments and suggest that polymerization of Glk1 evolved independently of the polymerization of other actin-like polymers. Glk1 polymerization inhibits its hexokinase activity, and the monomerpolymer equilibrium appears to set a maximum rate for the entire enzyme pool rather than a maximum rate per enzyme. This inhibition was found to be important for cell viability in the context of nutrient shifts, allowing yeast cells to modulate their metabolism rapidly in response to stochastic changes in the environment.

Science, this issue p. 1039


The actin fold is found in cytoskeletal polymers, chaperones, and various metabolic enzymes. Many actin-fold proteins, such as the carbohydrate kinases, do not polymerize. We found that Glk1, a Saccharomyces cerevisiae glucokinase, forms two-stranded filaments with ultrastructure that is distinct from that of cytoskeletal polymers. In cells, Glk1 polymerized upon sugar addition and depolymerized upon sugar withdrawal. Polymerization inhibits enzymatic activity; the Glk1 monomer-polymer equilibrium sets a maximum rate of glucose phosphorylation regardless of Glk1 concentration. A mutation that eliminated Glk1 polymerization alleviated concentration-dependent enzyme inhibition. Yeast containing nonpolymerizing Glk1 were less fit when growing on sugars and more likely to die when refed glucose. Glk1 polymerization arose independently from other actin-related filaments and may allow yeast to rapidly modulate glucokinase activity as nutrient availability changes.

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