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Updated: Jun 12, 2025

Investigating the Spreading and Toxicity of Prion-like Proteins Using the Metazoan Model Organism C. elegans
Published on: January 8, 2015
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.
None:
Liquid-liquid phase separation (LLPS) of intrinsically disordered proteins has been associated with neurodegenerative diseases, although direct mechanisms are poorly defined. Here, we report on a maturation process for the cellular prion protein (PrPC) that involves a conformational change after LLPS and is regulated by mutations and poly(4-styrenesulfonic acid-co-maleic acid) (PSCMA), a molecule that has been reported to rescue Alzheimer's disease-related cognitive deficits by antagonizing the interaction between PrPC and amyloid-β oligomers (Aβo). We show that PSCMA can induce reentrant LLPS of PrPC and lower the saturation concentration (Csat) of PrPC by 100-fold. Regardless of the induction method, PrPC molecules subsequently undergo a maturation process to restrict molecular motion in a more solid-like state. The PSCMA-induced LLPS of PrPC stabilizes the intermediate LLPS conformational state detected by NMR, though the final matured β-sheet-rich state of PrPC is indistinguishable between induction conditions. The disease-associated E200 K mutation of PrPC also accelerates maturation. This post-LLPS shift in protein conformation and dynamics is a possible mechanism of LLPS-induced neurodegeneration.
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