How Sup35 monomer conformation and amyloid fibril polymorphism determine yeast strain phenotypes
Year: 2025
Type: preprint
Abstract: In the [ PSI + ] prion system, the yeast prion protein Sup35 can form structurally distinct amyloid fibrils that lead to distinct transmissible prion states, or strains. However, our understanding of how different Sup35 fibril structures arise and translate to phenotypic variations is limited. Here, using cryo-EM and single-monomer force spectroscopy with optical tweezers, we reveal the structural basis of yeast prion propagation in four wild-type and S17R mutant variants of Sup35 that underlie different [ PSI + ] strains. Cryo-EM structures show that the four variants form strikingly distinct fibril structures, which exhibit varying stability and chaperone-accessibility. Force spectroscopy suggests the different distinct fibril structures are derived from distinct monomer conformational ensembles. Further, cryo-EM structures indicate that prion strain strength is correlated with enhanced fibril propagation caused by a combination of low fibril stability and a large separation between the Sup35 fibril core and the Ssa1/Sis1 chaperone-binding region. These results provide a structure-based mechanism for the yeast prion strain phenomenon with implications for understanding amyloid propagation in human neurodegenerative diseases.
Source: Research Square
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: National Science Foundation, BrightFocus Foundation, Japan Agency for Medical Research and Development, Ministry of Education, Culture, Sports, Science and Technology, Yazaki Memorial Foundation for Science and Technology, National Institutes of Health, Japan Society for the Promotion of Science, RIKEN, National Institute on Aging, National Institute of General Medical Sciences, California NanoSystems Institute, Core Research for Evolutional Science and Technology, SLAC National Accelerator Laboratory
Awards: G1602689630, G2576085165, Analysis of prion prpagation using optical tweezers, 細胞内を模倣した再構成系の開発とアミロイドの伝播機序解明, G5613623313, G5806950731, Development of inhibitors and diagnostics for amyloid diseases, 時間分解構造解析によるアミロイド脱凝集メカニズムの研究, G6335154345, G7879866177, The Stanford-SLAC CryoEM Center, Atomic Structure Determination of A-beta oligomers associated with Alzheimer’s disease, Physical Chemistry of Nucleic Acids, Towards Treatment of Alzheimer’s Disease by Targeting Pathogenic Tau and Beta-Amyloid Structures
OpenAlex ID: W4415781480