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

• 成果类型: Article
• 署名作者: Gogte, Kalpshree; Mamashli, Fatemeh; Herrera, Maria Georgina; Kriegler, Simon; Bader, Verian; Kamps, Janine; Grover, Prerna; Winter, Roland; Winklhofer, Konstanze F.; Tatzelt, Joerg
• 署名单位: Ruhr University Bochum; Ruhr University Bochum; Dortmund University of Technology; Ruhr University Bochum
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11529
• DOI: 10.1073/pnas.2415250121
• 发表日期: 2025-01-07
• 关键词: liquid-liquid; release; conformation; impairment; activation; mutations; prpc

摘要

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 prevents LLPS and spontaneous aggregation of PrP. Upon release from the membrane, PrP undergoes a conformational transition to detergent- insoluble aggregates. Our study demonstrates an essential role of the GPI anchor in preventing spontaneous misfolding of PrPC and provides a mechanistic basis for inherited prion diseases associated with anchorless PrP.