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Regulatory Function of Hexokinase 2 in Glucose Signaling in Saccharomyces cerevisiae

Open AccessPublished:August 05, 2016DOI:https://doi.org/10.1074/jbc.L116.735514
      Vega et al. (
      • Vega M.
      • Riera A.
      • Fernández-Cid A.
      • Herrero P.
      • Moreno F.
      • et al.
      Hexokinase 2 is an intracellular glucose sensor of yeast cells that maintains the structure and activity of Mig1 protein repressor complex.
      ) analyze the mechanism by which hexokinase 2 (Hxk2) contributes to glucose-dependent signal transduction in Saccharomyces cerevisiae. Considering the absence of experimental data on Hxk2 conformation, phosphorylation state, and structural integrity, the authors' interpretation of underlying molecular events deserves comment.
      First, the possibility is highlighted that Hxk2 constitutes an intracellular glucose sensor, which operates in response to glucose levels via the conformational change that is associated with the open/close induced fit domain movement of the enzyme to control its recruitment to the SUC2 repressor complex. The authors do not, however, provide direct evidence proving such a mode of action. In particular, the hypothesis that xylose could induce an open conformation mimicking low glucose conditions is presented without support by structural data. By contrast, it seems rather likely that due to similar binding modes xylose and glucose may stabilize a closed hexokinase conformation (
      • Nishimasu H.
      • Fushinobu S.
      • Shoun H.
      • Wakagi T.
      • et al.
      Crystal structures of an ATP-dependent hexokinase with broad substrate specificity from the hyperthermophilic archaeon Sulfolobus tokodaii.
      ).
      Second, the authors conclude from the analysis of the Hxk2-SUC2 promoter interaction in a Δsnf1 background that Hxk2-S15 phosphorylation is not essential for regulation of complex formation. This conclusion ignores the finding that protein kinase Ymr291w/Tda1 rather than Snf1 is indispensable for the above modification (
      • Kaps S.
      • Kettner K.
      • Migotti R.
      • Kanashova T.
      • Krause U.
      • Rödel G.
      • Dittmar G.
      • Kriegel T.M.
      • et al.
      Protein kinase Ymr291w/Tda1 is essential for glucose signaling in Saccharomyces cerevisiae on the level of hexokinase isoenzyme ScHxk2 phosphorylation.
      ). Therefore, the involvement of Hxk2-S15 phosphorylation in SUC2 promoter binding cannot be excluded.
      Finally, the authors do not consider the existence of multiple molecular forms of hexokinases in yeast that differ in their oligomeric state, conformation, and state of phosphorylation (
      • Kuettner E.B.
      • Kettner K.
      • Keim A.
      • Svergun D.I.
      • Volke D.
      • Singer D.
      • Hoffmann R.
      • Müller E.C.
      • Otto A.
      • Kriegel T.M.
      • Sträter N.
      • et al.
      Crystal structure of hexokinase KlHxk1 of Kluyveromyces lactis: a molecular basis for understanding the control of yeast hexokinase functions via covalent modification and oligomerization.
      ). In consequence, the molecular form of Hxk2 that is a constituent of the SUC2 repressor complex remains to be identified.

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