Topological confinement by a membrane anchor suppresses phase separation into protein aggregates: Implications for prion diseases.

ABSTRACT: Protein misfolding and aggregation are a hallmark of various neurodegenerative disorders. However, the underlying mechanisms driving protein misfolding in the cellular context are incompletely understood. Here, we show that the two-dimensional confinement imposed by a membrane anchor stabilizes the native protein conformation and suppresses liquid-liquid phase separation (LLPS) and protein aggregation. Inherited prion diseases in humans and neurodegeneration in transgenic mice are linked to the expression of anchorless prion protein (PrP), suggesting that the C-terminal glycosylphosphatidylinositol (GPI) anchor of native PrP impedes spontaneous formation of neurotoxic and infectious PrP species. Combining unique in vitro and in vivo approaches, we demonstrate that anchoring to membranes pr

SUBMITTER: Gogte K 

PROVIDER: S-EPMC11725851 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature