An iron sensor module regulates glucose response in yeast

Iron-sulphur clusters are a key component of many enzymes and are enriched in respiration and DNA replication/repair enzymes. Upon iron scarcity respiration genes are downregulated to conserve iron with concomitant activation of the Ribonucleotide Reductase enzyme, which produces dNTPs. The Snf1/AMP-kinase is the key regulator of the switch from fermentation of glucose (off) to the respiration of poor carbon sources (on). Active, phosphorylated Snf1 forms a complex consisting of the alpha-subunit (Snf1), one of three beta subunits (Sip1, Sip2 or Gal83) which also regulate Snf1 localization and a gamma subunit (Snf4). The beta and gamma subunits bind to distinct regions of the C-terminal regulatory half of Snf1.

The far N-terminal region of Snf1 contains a unique poly-histidine tract (with 13 Histidine residues in a row) that is conserved across Saccharomyces, Kluyveromyces and Candida species. We found that the polyHIS tract is inhibitory to Snf1 function and mediates an intra-molecular interaction with the C-terminal region of Snf1 to impede binding of the beta-subunit of the AMPK complex. The polyHIS tract interacts with iron-sulphur clusters (but not free iron ions) with iron depletion inhibiting Snf1 activity through this domain. Thus, a hitherto uninvestigated region of Snf1 serves to co-ordinate the metabolic response to iron starvation. Sensing of other metals such as copper and zinc by Snf1 orthologues in other fungi will also be discussed.