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

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