Major prion protein
molecular condensate scaffold activity
Liquid and Hydrogel Phases of PrP<sup>C</sup> 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<sup>C</sup>) contains such domains, causes spongiform degeneration, and is a receptor for Alzheimer's amyloid-β oligomers (Aβo). Here, we show that PrP<sup>C</sup> separates as a liquid phase, in which α-helical Thr become unfolded. At the cell surface, PrP<sup>C</sup> Lys residues interact with Aβo to create a hydrogel containing immobile Aβo and relatively mobile PrP<sup>C</sup>. The Aβo/PrP hydrogel has a well-defined stoichiometry and dissociates with excess Aβo. NMR studies of hydrogel PrP<sup>C</sup> 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<sup>C</sup> extracts endogenous Aβo from human Alzheimer's soluble brain lysates into hydrogel, and a PrP<sup>C</sup> antagonist releases Aβo from endogenous brain hydrogel. Thus, coupled phase and conformational transitions of PrP<sup>C</sup> are driven by Aβ species from Alzheimer's disease.