Bhamra, Savroop;
Arora, Parineeta;
Manka, Szymon W;
Schmidt, Christian;
Brown, Craig;
Rayner, Melissa LD;
Klöhn, Peter-Christian;
... Jat, Parmjit S; + view all
(2023)
Prion propagation is dependent on key amino acids in Charge cluster 2 within the prion protein.
Journal of Molecular Biology
, 435
(4)
, Article 167925. 10.1016/j.jmb.2022.167925.
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Abstract
To dissect the N-terminal residues within the cellular prion protein (PrPC) that are critical for efficient prion propagation, we generated a library of point, double, or triple alanine replacements within residues 23-111 of PrP, stably expressed them in cells silenced for endogenous mouse PrPC and challenged the reconstituted cells with four common but biologically diverse mouse prion strains. Amino acids (aa) 105-111 of Charge Cluster 2 (CC2), which is disordered in PrPC, were found to be required for propagation of all four prion strains; other residues had no effect or exhibited strain-specific effects. Replacements in CC2, including aa105-111, dominantly inhibited prion propagation in the presence of endogenous wild type PrPC whilst other changes were not inhibitory. Single alanine replacements within aa105-111 identified leucine 108 and valine 111 or the cluster of lysine 105, threonine 106 and asparagine 107 as critical for prion propagation. These residues mediate specific ordering of unstructured CC2 into β-sheets in the infectious prion fibrils from Rocky Mountain Laboratory (RML) and ME7 mouse prion strains.
| Type: | Article |
|---|---|
| Title: | Prion propagation is dependent on key amino acids in Charge cluster 2 within the prion protein |
| Location: | Netherlands |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.jmb.2022.167925 |
| Publisher version: | https://doi.org/10.1016/j.jmb.2022.167925 |
| Language: | English |
| Additional information: | Copyright © 2022 The Authors. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/). |
| Keywords: | alanine site-directed mutagenesis, prion propagation, prion protein, prion strains, scrapie cell assay |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > MRC Prion Unit at UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10162182 |
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