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Purification of Hsp104, a Protein Disaggregase
07:17

Purification of Hsp104, a Protein Disaggregase

Published on: September 30, 2011

Hsp104, Hsp70 and Hsp40 interplay regulates formation, growth and elimination of Sup35 prions

James Shorter1, Susan Lindquist

  • 1Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Stellar-Chance Laboratories, Philadelphia, PA 19104, USA. jshorter@mail.med.upenn.edu

The EMBO Journal
|October 4, 2008
PubMed

Insights

The Hsp70 chaperone system, including Ssb1, directly inhibits yeast prion [PSI(+)] formation by interacting with Sup35. Hsp104 cooperates with Hsp70 chaperones to regulate prion inheritance.

Area of Science:

  • Molecular Biology
  • Protein Folding
  • Yeast Genetics

Background:

  • The yeast prion [PSI(+)], formed by self-templating amyloid aggregates of the Sup35 protein, is regulated by protein remodellers like Hsp104.
  • The precise roles of other chaperones, particularly the Hsp70 system, in Sup35 prionogenesis and inheritance are not fully understood.

Purpose of the Study:

  • To investigate how the Hsp70 chaperone system components (Ssa and Ssb) interact with Sup35 and influence prion formation.
  • To elucidate the cooperative mechanisms between Hsp70, Hsp40 chaperones, and Hsp104 in regulating yeast prion [PSI(+)] inheritance.

Main Methods:

  • Investigated interactions between Sup35, Hsp70 (Ssa1, Ssb1), Hsp40 (Sis1, Ydj1), and Hsp104.
  • Assessed the effects of chaperone complexes on Sup35 prion nucleation, assembly, and seeded polymerization.
  • Analyzed the impact of the Ssb1:Zuo1:Ssz1 complex and nucleotide exchange factor Fes1 on prionogenesis.

Main Results:

  • The Ssb1:Zuo1:Ssz1 complex acts as a potent inhibitor of Sup35 prion formation.
  • Hsp40 chaperones Sis1 and Ydj1 bind Sup35 oligomers and fibers, facilitating Hsp70 binding and inhibiting prion nucleation and seeded assembly.
  • Hsp70:Hsp40 pairs block prion formation by disassembling oligomers and binding fibers, with activity modulated by Fes1.
  • Hsp104 at low concentrations stimulates prionogenesis, while high concentrations eliminate prions, with its activity influenced by Ssa1 and Ssb1 incorporation.

Conclusions:

  • The Hsp70 chaperone system, in conjunction with Hsp40s, directly antagonizes Sup35 prion formation through multiple mechanisms.
  • Hsp104 collaborates with Hsp70 chaperones, with distinct roles at different concentrations, to control yeast prion inheritance.
  • These findings reveal intricate chaperone interplay critical for maintaining or eliminating the [PSI(+)] prion state.

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