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 membraneless organelles and links to neurodegeneration. Cellular prion protein (PrPC) contains such domains, causes spongiform degeneration, and is a receptor for Alzheimer’s amyloid-β oligomers (Aβo). Here, we show that PrPC separates as a liquid phase, in which α-helical Thr become unfolded. At the cell surface, PrPC Lys residues interact with Aβo to create a hydrogel containing immobile Aβo and relatively mobile PrPC. The Aβo/PrP hydrogel has a well-defined stoichiometry and dissociates with excess Aβo. NMR studies of hydrogel PrPC 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 PrPC extracts endogenous Aβo from human Alzheimer’s soluble brain lysates into hydrogel, and a PrPC antagonist releases Aβo from endogenous brain hydrogel. Thus, coupled phase and conformational transitions of PrPC are driven by Aβ species from Alzheimer’s disease. [Display omitted] •PrPC undergoes liquid phase separation with unfolding of α-helical Thr residues•Aβ oligomers require PrPC Lys residues to induce a hydrogel, reversible by excess Aβo•Hydrogel PrPC has α-helical Gly and Ala residues that are unstructured in PrPC monomer•Aβo/PrP hydrogel traps mGluR5 at the cell surface and is present in human AD brain Kostylev et al. investigate phase states of cellular prion protein, identifying liquid-liquid phase separation with C-terminal conformation changes. In a complex with amyloid-β oligomers from Alzheimer’s disease, prion protein forms a stoichiometric reversible hydrogel. In this cell surface hydrogel, there is extensive α-helical folding of the natively unstructured prion N terminus.