The SNF1 Kinase Ubiquitin-associated Domain Restrains Its Activation, Activity, and the Yeast Life Span

The enzyme family of heterotrimeric AMP-dependent protein kinases is activated upon low energy states, conferring a switch toward 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 a 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 whether the UBA domain within the yeast AMP-dependent protein kinase 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 life span. Significantly, the enhanced UBA-dependent longevity and oxidative stress response are at least partially dependent on the Fkh1 and Fkh2 stress response transcription factors, which in turn are shown to influence Snf1 gene expression. The UBA domain in the AMP kinase family is poorly defined. This motif restrains kinase activity, resulting in decreased life span and oxidative stress resistance. This inhibitory domain has defined influences with FOXOs on stress and aging. The overactive kinase created by UBA mutations has positive stress resistance and aging influences that may translate to human metabolic benefits.