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Propagation of Saccharomyces cerevisiae [PSI] Prion Is Impaired by Factors That Regulate Hsp70 Substrate Binding

Jones, Gary and Song, Youtao and Chung, Seyung and Masison, Daniel C. (2004) Propagation of Saccharomyces cerevisiae [PSI] Prion Is Impaired by Factors That Regulate Hsp70 Substrate Binding. Molecular and Cellular Biology, 24 (9). pp. 3928-3937.

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Abstract

The Saccharomyces cerevisiae [PSI] prion is believed to be a self-propagating cytoplasmic amyloid. Earlier characterization of HSP70 (SSA1) mutations suggested that [PSI] propagation is impaired by alterations that enhance Ssa1p’s substrate binding. This impairment is overcome by second-site mutations in Ssa1p’s conserved C-terminal motif (GPTVEEVD), which mediates interactions with tetratricopeptide repeat (TPR) cochaperones. Sti1p, a TPR cochaperone homolog of mammalian Hop1 (Hsp70/90 organizing protein), activates Ssa1p ATPase, which promotes substrate binding by Ssa1p. Here we find that in SSA1-21 cells depletion of Sti1p improved [PSI] propagation, while excess Sti1p weakened it. In contrast, depletion of Fes1p, a nucleotide exchange factor for Ssa1p that facilitates substrate release, weakened [PSI] propagation, while overproducing Fes1p improved it. Therefore, alterations of Hsp70 cochaperones that promote or prolong Hsp70 substrate binding impair [PSI] propagation. We also find that the GPTVEEVD motif is important for physical interaction with Hsp40 (Ydj1p), another Hsp70 cochaperone that promotes substrate binding but is dispensable for viability. We further find that depleting Cpr7p, an Hsp90 TPR cochaperone and CyP-40 cyclophilin homolog, improved [PSI] propagation in SSA1 mutants. Although Cpr7p and Sti1p are Hsp90 cochaperones, we provide evidence that Hsp90 is not involved in [PSI] propagation, suggesting that Sti1p and Cpr7p functionally interact with Hsp70 independently of Hsp90.

Item Type: Article
Keywords: saccharomyces cerevisiae
Subjects: Science & Engineering > Biology
Item ID: 324
Depositing User: Dr. Gary Jones
Date Deposited: 15 Jun 2006
Journal or Publication Title: Molecular and Cellular Biology
Publisher: American Society for Microbiology
Refereed: Yes
URI:

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