Identification of a homology-independent linchpin domain controlling mouse and bank vole prion protein conversion.

Prions are unorthodox pathogens that cause fatal neurodegenerative diseases in humans and other mammals. Prion propagation occurs through the self-templating of the pathogenic conformer PrPSc, onto the cell-expressed conformer, PrPC. Here we study the conversion of PrPC to PrPSc using a recombinant...

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Main Authors: Cassandra M Burke, Kenneth M K Mark, Daniel J Walsh, Geoffrey P Noble, Alexander D Steele, Abigail B Diack, Jean C Manson, Joel C Watts, Surachai Supattapone
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2020-09-01
Series:PLoS Pathogens
Online Access:https://doi.org/10.1371/journal.ppat.1008875
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spelling doaj-56f2eed8818d434daa5cbc4eb00e32992021-04-21T17:42:40ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742020-09-01169e100887510.1371/journal.ppat.1008875Identification of a homology-independent linchpin domain controlling mouse and bank vole prion protein conversion.Cassandra M BurkeKenneth M K MarkDaniel J WalshGeoffrey P NobleAlexander D SteeleAbigail B DiackJean C MansonJoel C WattsSurachai SupattaponePrions are unorthodox pathogens that cause fatal neurodegenerative diseases in humans and other mammals. Prion propagation occurs through the self-templating of the pathogenic conformer PrPSc, onto the cell-expressed conformer, PrPC. Here we study the conversion of PrPC to PrPSc using a recombinant mouse PrPSc conformer (mouse protein-only recPrPSc) as a unique tool that can convert bank vole but not mouse PrPC substrates in vitro. Thus, its templating ability is not dependent on sequence homology with the substrate. In the present study, we used chimeric bank vole/mouse PrPC substrates to systematically determine the domain that allows for conversion by Mo protein-only recPrPSc. Our results show that that either the presence of the bank vole amino acid residues E227 and S230 or the absence of the second N-linked glycan are sufficient to allow PrPC substrates to be converted by Mo protein-only recPrPSc and several native infectious prion strains. We propose that residues 227 and 230 and the second glycan are part of a C-terminal domain that acts as a linchpin for bank vole and mouse prion conversion.https://doi.org/10.1371/journal.ppat.1008875
collection DOAJ
language English
format Article
sources DOAJ
author Cassandra M Burke
Kenneth M K Mark
Daniel J Walsh
Geoffrey P Noble
Alexander D Steele
Abigail B Diack
Jean C Manson
Joel C Watts
Surachai Supattapone
spellingShingle Cassandra M Burke
Kenneth M K Mark
Daniel J Walsh
Geoffrey P Noble
Alexander D Steele
Abigail B Diack
Jean C Manson
Joel C Watts
Surachai Supattapone
Identification of a homology-independent linchpin domain controlling mouse and bank vole prion protein conversion.
PLoS Pathogens
author_facet Cassandra M Burke
Kenneth M K Mark
Daniel J Walsh
Geoffrey P Noble
Alexander D Steele
Abigail B Diack
Jean C Manson
Joel C Watts
Surachai Supattapone
author_sort Cassandra M Burke
title Identification of a homology-independent linchpin domain controlling mouse and bank vole prion protein conversion.
title_short Identification of a homology-independent linchpin domain controlling mouse and bank vole prion protein conversion.
title_full Identification of a homology-independent linchpin domain controlling mouse and bank vole prion protein conversion.
title_fullStr Identification of a homology-independent linchpin domain controlling mouse and bank vole prion protein conversion.
title_full_unstemmed Identification of a homology-independent linchpin domain controlling mouse and bank vole prion protein conversion.
title_sort identification of a homology-independent linchpin domain controlling mouse and bank vole prion protein conversion.
publisher Public Library of Science (PLoS)
series PLoS Pathogens
issn 1553-7366
1553-7374
publishDate 2020-09-01
description Prions are unorthodox pathogens that cause fatal neurodegenerative diseases in humans and other mammals. Prion propagation occurs through the self-templating of the pathogenic conformer PrPSc, onto the cell-expressed conformer, PrPC. Here we study the conversion of PrPC to PrPSc using a recombinant mouse PrPSc conformer (mouse protein-only recPrPSc) as a unique tool that can convert bank vole but not mouse PrPC substrates in vitro. Thus, its templating ability is not dependent on sequence homology with the substrate. In the present study, we used chimeric bank vole/mouse PrPC substrates to systematically determine the domain that allows for conversion by Mo protein-only recPrPSc. Our results show that that either the presence of the bank vole amino acid residues E227 and S230 or the absence of the second N-linked glycan are sufficient to allow PrPC substrates to be converted by Mo protein-only recPrPSc and several native infectious prion strains. We propose that residues 227 and 230 and the second glycan are part of a C-terminal domain that acts as a linchpin for bank vole and mouse prion conversion.
url https://doi.org/10.1371/journal.ppat.1008875
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