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 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 PrP C and provides a mechanistic basis for inherited prion diseases associated with anchorless PrP.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (10)
Kalpshree Gogte
Department Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum
Fatemeh Mamashli
Department Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum
Maria Georgina Herrera
Department Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum
Simon Kriegler
Physical Chemistry I - Biophysical Chemistry, Faculty of Chemistry and Chemical Biology, TU Dortmund University
Verian Bader
Department Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum
Janine Kamps
Department Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum
Prerna Grover
Department Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum
Roland Winter
Physical Chemistry I - Biophysical Chemistry, Faculty of Chemistry and Chemical Biology, TU Dortmund University
Konstanze F. Winklhofer
Department Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum
Jörg Tatzelt
Department Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum