Loss of Residues 119-136, Including the First β-strand of Human Prion Protein, Generates an Aggregation-competent Partially "Open" Form.

Autor: Hosszu LLP; MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London W1W 7FF, UK(†)., Sangar D; MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London W1W 7FF, UK(†)., Batchelor M; MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London W1W 7FF, UK(†)., Risse E; MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London W1W 7FF, UK(†)., Hounslow AM; Department of Molecular Biology and Biotechnology, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, UK., Collinge J; MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London W1W 7FF, UK(†)., Waltho JP; Department of Molecular Biology and Biotechnology, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, UK; Manchester Institute of Biotechnology, University of Manchester, 131 Princess Street, Manchester M1 7DN, UK., Bieschke J; MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London W1W 7FF, UK(†). Electronic address: j.bieschke@prion.ucl.ac.uk.
Jazyk: angličtina
Zdroj: Journal of molecular biology [J Mol Biol] 2023 Aug 01; Vol. 435 (15), pp. 168158. Date of Electronic Publication: 2023 May 25.
DOI: 10.1016/j.jmb.2023.168158
Abstrakt: In prion replication, the cellular form of prion protein (PrP C ) 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 PrP C 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 PrP C . 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 PrP C .
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: J.C. is a Director and shareholder of D-Gen Limited, an academic spin-out company working in the field of prion disease diagnosis, decontamination, and therapeutics. The other authors declare no competing interests.
(Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: