title: Structural variants of yeast prions show conformer-specific requirements for chaperone activity.
abstract: Molecular chaperones monitor protein homeostasis and defend against the misfolding and aggregation of proteins that is associated with protein conformational disorders. In these diseases, a variety of different aggregate structures can form. These are called prion strains, or variants, in prion diseases, and cause variation in disease pathogenesis. Here, we use variants of the yeast prions [RNQ+] and [PSI+] to explore the interactions of chaperones with distinct aggregate structures. We found that prion variants show striking variation in their relationship with Hsp40s. Specifically, the yeast Hsp40 Sis1 and its human orthologue Hdj1 had differential capacities to process prion variants, suggesting that Hsp40 selectivity has likely changed through evolution. We further show that such selectivity involves different domains of Sis1, with some prion conformers having a greater dependence on particular Hsp40 domains. Moreover, [PSI+] variants were more sensitive to certain alterations in Hsp70 activity as compared to [RNQ+] variants. Collectively, our data indicate that distinct chaperone machinery is required, or has differential capacity, to process different aggregate structures. Elucidating the intricacies of chaperone-client interactions, and how these are altered by particular client structures, will be crucial to understanding how this system can go awry in disease and contribute to pathological variation.
authors: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors: Kevin C
authors: KC
authors: Stein
authors: Heather L
authors: HL
authors: True
mesh_terms: D019143:Evolution, Molecular; D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D011328:Prions / Q000235:genetics*; D015003:Yeasts / Q000235:genetics* / Q000378:metabolism
chemical_list: C494647:DNAJB1 protein, human; D005656:Fungal Proteins; D050956:HSP40 Heat-Shock Proteins; D018832:Molecular Chaperones; D011328:Prions