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Updated: May 5, 2026
Protein Misfolding Cyclic Amplification of Prions
Published on: November 7, 2012
Inter-allelic prion propagation reveals conformational relationships among a multitude of [PSI] strains
Jia-Yu Lin1, Tzu-Ya Liao, Han-Chung Lee
1Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
Abstract:
Immense diversity of prion strains is observed, but its underlying mechanism is less clear. Three [PSI] prion strains--named VH, VK, and VL--were previously isolated in the wild-type yeast genetic background. Here we report the generation and characterization of eight new [PSI] isolates, obtained by propagating the wild-type strains with Sup35 proteins containing single amino-acid alterations. The VH strain splits into two distinct strains when propagated in each of the three genetic backgrounds, harboring respectively single mutations of N21L, R28P, and Gi47 (i.e. insertion of a glycine residue at position 47) on the Sup35 N-terminal prion-forming segment. The six new strains exhibit complex inter-conversion patterns, and one of them continuously mutates into another. However, when they are introduced back into the wild-type background, all 6 strains revert to the VH strain. We obtain two more [PSI] isolates by propagating VK and VL with the Gi47 and N21L backgrounds, respectively. The two isolates do not transmit to other mutant backgrounds but revert to their parental strains in the wild-type background. Our data indicate that a large number of [PSI] strains can be built on three basic Sup35 amyloid structures. It is proposed that the three basic structures differ by chain folding topologies, and sub-strains with the same topology differ in distinct ways by local structural adjustments. This "large number of variations on a small number of basic themes" may also be operative in generating strain diversities in other prion elements. It thus suggests a possible general scheme to classify a multitude of prion strains.
Insights
Prion strain diversity arises from variations on basic Sup35 amyloid structures. Yeast prion [PSI] strains, modified by specific mutations, generate new strains with complex inter-conversions, suggesting a general classification scheme for prion diversity.
Area of Science:
- Molecular biology
- Biochemistry
- Yeast genetics
Background:
- Prion strains exhibit significant diversity, but the mechanisms driving this variation remain unclear.
- Three [PSI] prion strains (VH, VK, VL) were previously identified in wild-type yeast.
- Understanding prion strain generation is crucial for deciphering protein misfolding diseases.
Purpose of the Study:
- To investigate the generation and characterization of new [PSI] prion strains.
- To explore the role of specific amino acid alterations in Sup35 protein on prion strain formation.
- To propose a general model for prion strain diversity based on structural variations.
Main Methods:
- Propagation of wild-type [PSI] strains (VH, VK, VL) with Sup35 proteins containing single amino acid alterations.
- Characterization of newly generated prion isolates, including their stability and inter-conversion patterns.
- Introduction of mutant strains back into wild-type backgrounds to observe reversion.
Main Results:
- Eight new [PSI] isolates were generated by introducing mutations (N21L, R28P, Gi47) into Sup35.
- The VH strain produced two distinct strains in mutant backgrounds, exhibiting complex inter-conversion and mutation patterns.
- All generated strains reverted to the VH strain in the wild-type background, and other isolates reverted to their parental strains.
- A large number of [PSI] strains can be generated from three basic Sup35 amyloid structures, differing in folding topologies and local structural adjustments.
Conclusions:
- Specific amino acid alterations in Sup35 can generate a multitude of [PSI] prion strains.
- Prion strain diversity may arise from variations on a limited set of basic structural themes.
- The proposed model suggests a potential general scheme for classifying diverse prion strains.
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