Regulation of yeast Snf1 (AMPK) by a polyhistidine containing pH sensing module

• Published in: iScience Vol. 25; no. 10; p. 105083
• Main Authors: Simpson-Lavy, Kobi J., Kupiec, Martin
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 21.10.2022; Elsevier
• Subjects: biochemistry; Biological sciences; molecular biology; molecular biology; Biological sciences; biochemistry
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2022.105083

Cellular regulation of pH is crucial for internal biological processes and for the import and export of ions and nutrients. In the yeast Saccharomyces cerevisiae, the major proton pump (Pma1) is regulated by glucose. Glucose is also an inhibitor of the energy sensor Snf1/AMPK, which is conserved in all eukaryotes. Here, we demonstrate that a poly-histidine (polyHIS) tract in the pre-kinase region (PKR) of Snf1 functions as a pH-sensing module (PSM) and regulates Snf1 activity. This regulation is independent from, and unaffected by, phosphorylation at T210, the major regulatory control of Snf1, but is controlled by the Pma1 plasma-membrane proton pump. By examining the PKR from additional yeast species, and by varying the number of histidines in the PKR, we determined that the polyHIS functions progressively. This regulation mechanism links the activity of a key enzyme with the metabolic status of the cell at any given moment. [Display omitted] •Glucose inhibits Snf1 by activating Pma1 to pump protons out of the cell•Increased cytoplasmic alkalinity deprotonates the N-terminal polyhistidines of Snf1•Deprotonated polyhistidines bind the Regulatory domain to inhibit Snf1•Number of histidines in this motif correlates to Snf1 activity. Biological sciences; Biochemistry; Molecular biology