title: The SNF1 Kinase Ubiquitin-associated Domain Restrains Its Activation, Activity, and the Yeast Life Span.
abstract: 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.
authors: Departments of Anatomy and Cell Biology and University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.
authors: Rubin
authors: R
authors: Jiao
authors: Departments of Anatomy and Cell Biology and University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.
authors: Spike
authors: S
authors: Postnikoff
authors: Departments of Anatomy and Cell Biology and University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.
authors: Troy A
authors: TA
authors: Harkness
authors: Departments of Anatomy and Cell Biology and University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada; Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada. Electronic address: terra.arnason@usask.ca.
authors: Terra G
authors: TG
authors: Arnason
mesh_terms: D020816:Amino Acid Motifs; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D015966:Gene Expression Regulation, Fungal / Q000502:physiology*; D009154:Mutation; D018384:Oxidative Stress / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C464906:Fkh1 protein, S cerevisiae; C464958:Fkh2 protein, S cerevisiae; D051858:Forkhead Transcription Factors; D029701:Saccharomyces cerevisiae Proteins; C071570:SNF1-related protein kinases; D017346:Protein Serine-Threonine Kinases
keywords: AMP-activated kinase (AMPK); FOXO; SNF1 kinase; Saccharomyces cerevisiae; UBA domain; aging; allosteric regulation; oxidative stress