Liquid and Hydrogel Phases of PrP
| Autor: | Mikhail A, Kostylev, Marcus D, Tuttle, Suho, Lee, Lauren E, Klein, Hideyuki, Takahashi, Timothy O, Cox, Erik C, Gunther, Kurt W, Zilm, Stephen M, Strittmatter |
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| Rok vydání: | 2017 |
| Předmět: |
Neurons
Amyloid beta-Peptides Prions animal diseases Receptor Metabotropic Glutamate 5 Cell Membrane Molecular Conformation Brain Hydrogels Magnetic Resonance Imaging Article nervous system diseases Cell Line HEK293 Cells Alzheimer Disease COS Cells Chlorocebus aethiops Animals Humans PrPC Proteins Protein Binding Signal Transduction |
| Zdroj: | Molecular cell. 72(3) |
| ISSN: | 1097-4164 |
| Popis: | Protein phase separation by low complexity, intrinsically disordered domains generates membraneless organelles and links to neurodegeneration. Cellular prion protein (PrP(C)) contains such domains, causes spongiform degeneration and is a receptor for Alzheimer’s amyloid-β oligomers (Aβo). Here, we show that PrP(C) separates as a liquid phase, in which α-helical Thr become unfolded. At the cell surface, PrP(C) Lys residues interact with Aβo to create a hydrogel containing immobile Aβo and relatively mobile PrP(C). The Aβo/PrP hydrogel has a well-defined stoichiometry, and dissociates with excess Aβo. NMR studies of hydrogel PrP(C) 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(C) extracts endogenous Aβo from human Alzheimer’s soluble brain lysates into hydrogel, and a PrP(C) antagonist releases Aßo from endogenous brain hydr ogel. Thus, coupled phase and conformational transitions of PrP(C) are driven by Aβ species from Alzheimer’s disease. |
| Databáze: | OpenAIRE |
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