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Updated: Jun 12, 2025
12:57
Investigating the Spreading and Toxicity of Prion-like Proteins Using the Metazoan Model Organism C. elegans
Published on: January 8, 2015
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Cellular Prion Protein Conformational Shift after Liquid-Liquid Phase Separation Regulated by a Polymeric Antagonist
Yangyi Liu1,2, Marcus D Tuttle1, Mikhail A Kostylev2
1Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06511, United States.
Journal of the American Chemical Society
|September 26, 2024
Summary
Liquid-liquid phase separation (LLPS) of prion protein (PrPC) involves a maturation process. This conformational change, accelerated by mutations and PSCMA, may drive neurodegeneration.
Area of Science:
- Biochemistry
- Neuroscience
- Molecular Biology
Background:
- Liquid-liquid phase separation (LLPS) of intrinsically disordered proteins is linked to neurodegenerative diseases.
- The precise mechanisms by which LLPS contributes to neurodegeneration remain unclear.
- Cellular prion protein (PrPC) is implicated in neurodegenerative disorders.
Purpose of the Study:
- To investigate the maturation process of PrPC following LLPS.
- To explore the regulatory roles of mutations and poly(4-styrenesulfonic acid-co-maleic acid) (PSCMA) in PrPC LLPS and maturation.
- To elucidate the potential role of PrPC conformational changes post-LLPS in neurodegeneration.
Main Methods:
- Induction of PrPC liquid-liquid phase separation using PSCMA.
- Nuclear Magnetic Resonance (NMR) spectroscopy to detect conformational states.
- Analysis of PrPC maturation kinetics and molecular dynamics.
Main Results:
- PSCMA induces reentrant LLPS of PrPC, reducing its saturation concentration (Csat) by 100-fold.
- PrPC undergoes a maturation process, transitioning to a more solid-like state with restricted molecular motion, irrespective of induction method.
- The E200K mutation associated with prion diseases accelerates PrPC maturation.
- PSCMA-induced LLPS stabilizes an intermediate conformational state, while the final β-sheet-rich state is consistent across conditions.
Conclusions:
- PrPC undergoes a conformational maturation post-LLPS, transitioning to a more rigid state.
- This post-LLPS conformational shift and altered dynamics represent a potential mechanism for LLPS-induced neurodegeneration.
- PSCMA modulates PrPC LLPS and maturation, offering insights into therapeutic strategies for prion and related diseases.
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