Liquid and Hydrogel Phases of PrPC Linked to Conformation Shifts and Triggered by Alzheimer's Amyloid-β Oligomers

Protein phase separation by low-complexity, intrinsically disordered domains generates membrane-less organelles and links to neurodegeneration. Cellular prion protein (PrPC) contains such domains, causes spongiform degeneration, and is a receptor for Alzheimer's amyloid-beta oligomers (A beta o). Here, we show that PrPC separates as a liquid phase, in which alpha-helical Thr become unfolded. At the cell surface, PrPC Lys residues interact with A beta o to create a hydrogel containing immobile A beta o and relatively mobile PrPC. The A beta o/PrP hydrogel has a well-defined stoichiometry and dissociates with excess A beta o. NMR studies of hydrogel PrPC reveal a distinct alpha-helical conformation for natively unfolded aminoterminal Gly and Ala residues. A beta o/PrP hydrogel traps signal-transducing mGluR5 on the plasma membrane. Recombinant PrPC extracts endogenous A beta o from human Alzheimer's soluble brain lysates into hydrogel, and a PrPC antagonist releases A beta o from endogenous brain hydrogel. Thus, coupled phase and conformational transitions of PrPC are driven by A beta species from Alzheimer's disease.