L P Hosszu, Laszlo;
Sangar, Daljit;
Batchelor, Mark;
Risse, Emmanuel;
Hounslow, Andrea M;
Collinge, John;
Waltho, Jonathan P;
(2023)
Loss of residues 119 – 136, including the first β-strand of human prion protein, generates an aggregation-competent partially “open” form.
Journal of Molecular Biology
, Article 168158. 10.1016/j.jmb.2023.168158.
(In press).
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Abstract
In prion replication, the cellular form of prion protein (PrPC) must undergo a full conformational transition to its disease-associated fibrillar form. Transmembrane forms of PrP have been implicated in this structural conversion. The cooperative unfolding of a structural core in PrPC presents a substantial energy barrier to prion formation, with membrane insertion and detachment of parts of PrP presenting a plausible route to its reduction. Here, we examined the removal of residues 119 - 136 of PrP, a region which includes the first β-strand and a substantial portion of the conserved hydrophobic region of PrP, a region which associates with the ER membrane, on the structure, stability and self-association of the folded domain of PrPC. We see an "open" native-like conformer with increased solvent exposure which fibrilises more readily than the native state. These data suggest a stepwise folding transition, which is initiated by the conformational switch to this "open" form of PrPC.
| Type: | Article |
|---|---|
| Title: | Loss of residues 119 – 136, including the first β-strand of human prion protein, generates an aggregation-competent partially “open” form |
| Location: | Netherlands |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.jmb.2023.168158 |
| Publisher version: | https://doi.org/10.1016/j.jmb.2023.168158 |
| Language: | English |
| Additional information: | © 2021 Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | Biophysics, Hydrogen-deuterium exchange, Neurodegeneration, Prion protein |
| 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/10171038 |
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