It is shown that the different frequency of prion fragmentation is determined by their stability, rather than the efficiency of chaperone binding, which is a key for the prion phenotype and maintenance.
Abstract
Human prions and amyloids exhibit structural diversity that correlates with different pathological manifestations. Yeast prions represent a convenient model for studying fundamental properties of prions and their strain diversity. The Sup35 yeast prion has multiple structural variants, divided into “strong” and “weak” groups differing in frequency of fibril fragmentation and resulting nonsense-suppression. The molecular origin of these distinctions remains unclear. Here, we show that the different frequency of prion fragmentation is determined by their stability, rather than the efficiency of chaperone binding. The fully protease-resistant part (residues 2-32) of the Sup35 prion core is a key for the prion phenotype and maintenance, whereas partially resistant part (33-72) is less important. We established the cryo-EM structure of a strong Sup35 prion variant purified from yeast, comprising residues 2–64, with 2.7 Å resolution. Comparison of this structure with that of Sup35 amyloid formed in vitro at 4˚C revealed their significant difference.
Deletion analysis demonstrates that the N-proximal prion domain (Sup35N) of Sup35 is sufficient for chaperone-dependent prion propagation and that various regions of this domain show differential impacts on LLPS, amyloid aggregation, and prion inheritance.
A. Grizel, Natalia A. Gorsheneva, Ismat Jahan Anee et al.· International Journal of Mol...· 0 citations
Findings establish 7-HCAA as a site-specific and sensitive probe of local PrP conformation as a site-specific and sensitive probe of local PrP conformation and suggest a new strategy for studying conformational dynamics in amyloid-forming proteins.
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This study enhances the understanding of the E. coli-genome nature and suggests the existence of specific and experimentally testable novel prions in this organism, and moves a step forward towards the identification of new prion proteins in bacteria.
Katherine Shreeve, Jinoh Jang, Mr. S Srivathsan et al.· Proteins: Structure, Functio...· 0 citations
Amyloid fibrils are implicated in a myriad of human diseases. A striking observation is that fibrils extracted from diseased tissues are characterized by a restricted set of folds unique to the specific pathology. In contrast, fibrils grown in vitro exhibit extensive structural diversity, suggesting that specific envir...
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Prion strains in infected animals may exist as heterogeneous populations composed of a major prion conformer responsible for the dominant disease phenotype and minor conformers that are phenotypically silent or difficult to detect. However, the presence and biological significance of such minor conformers in natural pr...
M. Imamura, Kohtaro Miyazawa, H. Okada et al.· PLoS Pathogens· 0 citations
Transmembrane protein 106B (TMEM106B) is a type II transmembrane glycoprotein localized in late endosomes and lysosomes. This protein has been attributed to relevant roles in disease risk and progression of multiple neurodegenerative disorders. In experimental models, TMEM106B has been linked with the prion-like spread...
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