In Vivo Monitoring of the Prion Replication Cycle Reveals a Critical Role for Sis1 in Delivering Substrates to Hsp104

Prions in Saccharomyces cerevisiae are inherited ordered aggregates reliant upon the disaggregase Hsp104 for stable maintenance. The function of other factors in the natural prion cycle is unclear. We constructed yeast-bacterial chimeric chaperones to resolve the roles of Hsp104 domains, and by exte...

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Bibliographic Details
Published in:Molecular cell 2008-11, Vol.32 (4), p.584-591
Main Authors: Tipton, Kimberly A., Verges, Katherine J., Weissman, Jonathan S.
Format: Article
Language:English
Subjects:
DNA Replication
Fungal Proteins - chemistry
Fungal Proteins - genetics
Fungal Proteins - metabolism
Genes, Fungal
Heat-Shock Proteins - chemistry
Heat-Shock Proteins - genetics
Heat-Shock Proteins - metabolism
HSP40 Heat-Shock Proteins
Models, Biological
Molecular Chaperones - chemistry
Molecular Chaperones - genetics
Molecular Chaperones - metabolism
Prions - chemistry
Prions - genetics
Prions - metabolism
Protein Binding - genetics
Protein Conformation
Protein Structure, Tertiary - genetics
PROTEINS
Saccharomyces cerevisiae - genetics
Saccharomyces cerevisiae - metabolism
Saccharomyces cerevisiae Proteins - metabolism
Substrate Specificity
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Summary:Prions in Saccharomyces cerevisiae are inherited ordered aggregates reliant upon the disaggregase Hsp104 for stable maintenance. The function of other factors in the natural prion cycle is unclear. We constructed yeast-bacterial chimeric chaperones to resolve the roles of Hsp104 domains, and by extension chaperones that interact with these domains, in prion propagation. Our results show that, as with amorphous aggregate dissolution, the Hsp70/40 system recruits prion substrates to Hsp104 via its top ring. By adapting our chimera to couple to an inactive protease “trap,” we monitored the reaction products of prion propagation in vivo. We find that prion maintenance is accompanied by translocation of prion proteins through Hsp104 hexamers and that both processes critically rely upon the Hsp40 Sis1. Our data suggest that yeast prion replication is a natural extension of chaperone activity in dissolving amorphous aggregates, distinguished from its ancestral reaction by the ordered, self-propagating structure of the substrate.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2008.11.003