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

journal_name

Mol Cell

journal_title

Molecular cell

authors

Kostylev MA,Tuttle MD,Lee S,Klein LE,Takahashi H,Cox TO,Gunther EC,Zilm KW,Strittmatter SM

doi

10.1016/j.molcel.2018.10.009

subject

Has Abstract

pub_date

2018-11-01 00:00:00

pages

426-443.e12

issue

3

eissn

1097-2765

issn

1097-4164

pii

S1097-2765(18)30841-4

journal_volume

72

pub_type

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