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

• Published in: Molecular cell Vol. 72; no. 3; p. 426
• Main Authors: Kostylev, Mikhail A, Tuttle, Marcus D, Lee, Suho, Klein, Lauren E, Takahashi, Hideyuki, Cox, Timothy O, Gunther, Erik C, Zilm, Kurt W, Strittmatter, Stephen M
• Format: Journal Article
• Language: English
• Published: United States 01.11.2018
• ISSN: 1097-4164

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.