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

ABSTRACT: 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-? oligomers (A?o). Here, we show that PrPC separates as a liquid phase, in which ?-helical Thr become unfolded. At the cell surface, PrPC Lys residues interact with A?o to create a hydrogel containing immobile A?o and relatively mobile PrPC. The A?o/PrP hydrogel has a well-defined stoichiometry and dissociates with excess A?o. NMR studies of hydrogel PrPC reveal a distinct ?-helical conformation for natively unfolded amino-terminal Gly and Ala residues. A?o/PrP hydrogel traps signal-transducing mGluR5 on the plasma membrane. Recombinant PrPC extracts endogenous A?o from human Alzheimer's soluble brain lysates into hydrogel, and a PrPC antagonist releases A?o from endogenous brain hydrogel. Thus, coupled phase and conformational transitions of PrPC are driven by A? species from Alzheimer's disease.

SUBMITTER: Kostylev MA 

PROVIDER: S-EPMC6226277 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature