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

• DOI: 10.1016/j.molcel.2018.10.009
• Publication Date: 2018-10-25T17:45:28Z
• Authors: Mikhail A. Kostylev; Marcus D. Tuttle; Suho Lee; Lauren E. Klein; Hideyuki Takahashi; Timothy O. Cox; Erik C. Gunther; Kurt W. Zilm; Stephen M. Stritt...
• Keywords: Amyloid (mycology)

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.