The SNF1 Kinase UBA Domain Restrains its Activation, Activity, and the Yeast Lifespan [Cell Biology]

April 13th, 2015 by Jiao, R., Postnikoff, S., Harkness, T. A., Arnason, T. G.

The enzyme family of heterotrimeric AMP-dependent protein kinases (AMPKs) is activated upon low energy states, conferring a switch towards energy-conserving metabolic pathways through immediate kinase actions on enzyme targets, and delayed alterations in gene expression through its nuclear relocalization. This family is evolutionarily conserved, including the presence of an Ubiquitin-associated (UBA) motif in most catalytic subunits. The potential for the UBA domain to promote protein-associations or direct subcellular location, as seen in other UBA-containing proteins, led us to query if the UBA domain within the yeast AMPK ortholog, SNF1 kinase, was important in these aspects of its regulation. Here, we demonstrate that conserved UBA motif mutations significantly alter SNF1 kinase activation and biological activity including enhanced allosteric subunit associations, and increased oxidative stress resistance and lifespan. Significantly, the enhanced UBA-dependent longevity and oxidative stress response is at least partially dependent on the Fkh1 and Fkh2 stress response transcription factors, which are in turn shown to influence Snf1 gene expression.