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Published on: September 12, 2018
The structural basis of yeast prion strain variants
Brandon H Toyama1, Mark J S Kelly, John D Gross
1Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California San Francisco and California Institute for Quantitative Biomedical Research, San Francisco, California 94158-2542, USA.
Prion strains, like yeast Sup35 Sc4 and Sc37, exhibit distinct structures. These large-scale conformational differences in prion proteins explain their varying stability and replication, impacting disease phenotypes.
Area of Science:
- Biochemistry
- Structural Biology
- Prion Biology
Background:
- Prion biology is characterized by the strain phenomenon, where single proteins misfold into distinct infectious states causing different phenotypes.
- Understanding the structural basis of these prion strains and their physiological impact is limited.
Purpose of the Study:
- To investigate the structural differences between two yeast Sup35 prion strains, Sc4 and Sc37.
- To elucidate how these structural variations influence prion stability and replication.
Main Methods:
- Solution NMR
- Amide hydrogen/deuterium (H/D) exchange
- Mutagenesis
Main Results:
- Both Sc4 and Sc37 strains share a common amyloid core in the first 40 amino acids, protected from H/D exchange and sensitive to mutation.
- The Sc37 conformation expands this stable structure to the first 70 amino acids, correlating with increased fiber stability and reduced chaperone-mediated replication.
- Prion strains involve significant conformational differences, providing a structural basis for their varied functional and physiological impacts.
Conclusions:
- Prion strains arise from large-scale conformational variations within the protein structure.
- These structural differences directly influence prion stability, replication efficiency, and ultimately, the observed disease phenotypes.
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