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07:17
Purification of Hsp104, a Protein Disaggregase
Published on: September 30, 2011
Dominant prion mutants induce curing through pathways that promote chaperone-mediated disaggregation
Susanne DiSalvo1, Aaron Derdowski, John A Pezza
1Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA.
Nature Structural & Molecular Biology
|March 23, 2011
Summary
Dominant-negative prion mutants disrupt prion protein aggregates, making them vulnerable to cellular clearance. This study reveals how these mutants enhance prion disease clearance by targeting aggregate biogenesis.
Area of Science:
- Biochemistry
- Molecular Biology
- Neuroscience
Background:
- Protein misfolding is implicated in neurodegenerative diseases like prion diseases.
- Prion proteins form stable aggregates that evade cellular quality control.
- Dominant-negative mutants can block prion disease progression via unknown mechanisms.
Purpose of the Study:
- To elucidate the mechanisms by which dominant-negative prion mutants cure the [PSI(+)] prion in Saccharomyces cerevisiae.
- To understand how these mutants interact with wild-type prion aggregates.
Main Methods:
- Investigated two dominant-negative mutants of the Saccharomyces cerevisiae Sup35 protein.
- Analyzed the physical properties and assembly of wild-type and mixed prion aggregates.
- Assessed the role of the molecular chaperone Hsp104 in disassembling mixed aggregates.
Main Results:
- Both mutants incorporated into wild-type aggregates, altering their assembly rate or thermodynamic stability.
- Mixed aggregates, unlike wild-type aggregates, were disassembled by Hsp104.
- Mutants did not simply block misfolding but affected aggregate biogenesis.
Conclusions:
- Dominant-negative prion mutants enhance prion clearance by making aggregates susceptible to cellular machinery.
- These mutants target multiple stages of aggregate formation and stability.
- This work provides insight into therapeutic strategies for prion diseases.
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