1. Cellular Prion Protein Conformational Shift after Liquid-Liquid Phase Separation Regulated by a Polymeric Antagonist and Mutations.
- Author
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Liu Y, Tuttle MD, Kostylev MA, Roseman GP, Zilm KW, and Strittmatter SM
- Subjects
- Humans, Maleates chemistry, Maleates pharmacology, Protein Conformation, PrPC Proteins chemistry, PrPC Proteins metabolism, PrPC Proteins genetics, PrPC Proteins antagonists & inhibitors, Prion Proteins chemistry, Prion Proteins genetics, Prion Proteins metabolism, Sulfonic Acids chemistry, Phase Separation, Mutation
- Abstract
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 (PrP
C ) 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.- Published
- 2024
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