title: NMR structure of Hsp12, a protein induced by and required for dietary restriction-induced lifespan extension in yeast.
abstract: Dietary restriction (DR) extends lifespan in yeast, worms, flies and mammals, suggesting that it may act via conserved processes. However, the downstream mechanisms by which DR increases lifespan remain unclear. We used a gel based proteomic strategy to identify proteins whose expression was induced by DR in yeast and thus may correlate with longevity. One protein up-regulated by DR was Hsp12, a small heat shock protein induced by various manipulations known to retard ageing. Lifespan extension by growth on 0.5% glucose (DR) was abolished in an hsp12Δ strain, indicating that Hsp12 is essential for the longevity effect of DR. In contrast, deletion of HSP12 had no effect on growth under DR conditions or a variety of environmental stresses, indicating that the effect of Hsp12 on lifespan is not due to increased general stress resistance. Unlike other small heat shock proteins, recombinant Hsp12 displayed negligible in vitro molecular chaperone activity, suggesting that its cellular function does not involve preventing protein aggregation. NMR analysis indicated that Hsp12 is monomeric and intrinsically unfolded in solution, but switches to a 4-helical conformation upon binding to membrane-mimetic SDS micelles. The structure of micelle-bound Hsp12 reported here is consistent with its recently proposed function as a membrane-stabilising 'lipid chaperone'. Taken together, our data suggest that DR-induced Hsp12 expression contributes to lifespan extension, possibly via membrane alterations.
authors: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors: Andrew P
authors: AP
authors: Herbert
authors: Michèle
authors: M
authors: Riesen
authors: Leanne
authors: L
authors: Bloxam
authors: Effie
authors: E
authors: Kosmidou
authors: Brian M
authors: BM
authors: Wareing
authors: James R
authors: JR
authors: Johnson
authors: Marie M
authors: MM
authors: Phelan
authors: Stephen R
authors: SR
authors: Pennington
authors: Lu-Yun
authors: LY
authors: Lian
authors: Alan
authors: A
authors: Morgan
mesh_terms: D015966:Gene Expression Regulation, Fungal; D005947:Glucose / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010641:Phenotype; D017433:Protein Structure, Secondary; D040901:Proteomics; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000378:metabolism*; D013997:Time Factors
chemical_list: C112591:HSP12 protein, S cerevisiae; D006360:Heat-Shock Proteins; D029701:Saccharomyces cerevisiae Proteins; D005947:Glucose