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Influence of the Dynamically Disordered N-Terminal Tail Domain on the Amyloid Core Structure of Human Y145Stop Prion Protein Fibrils

The Y145Stop mutant of human prion protein (huPrP23-144) is associated with a familial prionopathy and provides a convenient in vitro model for investigating amyloid strains and cross-seeding barriers. huPrP23-144 fibrils feature a compact and relatively rigid parallel in-register β-sheet amyloid co...

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Autores principales: Qi, Zhe, Surewicz, Krystyna, Surewicz, Witold K., Jaroniec, Christopher P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8883029/
https://www.ncbi.nlm.nih.gov/pubmed/35237664
http://dx.doi.org/10.3389/fmolb.2022.841790
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author Qi, Zhe
Surewicz, Krystyna
Surewicz, Witold K.
Jaroniec, Christopher P.
author_facet Qi, Zhe
Surewicz, Krystyna
Surewicz, Witold K.
Jaroniec, Christopher P.
author_sort Qi, Zhe
collection PubMed
description The Y145Stop mutant of human prion protein (huPrP23-144) is associated with a familial prionopathy and provides a convenient in vitro model for investigating amyloid strains and cross-seeding barriers. huPrP23-144 fibrils feature a compact and relatively rigid parallel in-register β-sheet amyloid core spanning ∼30 C-terminal amino acid residues (∼112–141) and a large ∼90-residue dynamically disordered N-terminal tail domain. Here, we systematically evaluate the influence of this dynamic domain on the structure adopted by the huPrP23-144 amyloid core region, by investigating using magic-angle spinning solid-state nuclear magnetic resonance (NMR) spectroscopy a series of fibril samples formed by huPrP23-144 variants corresponding to deletions of large segments of the N-terminal tail. We find that deletion of the bulk of the N-terminal tail, up to residue 98, yields amyloid fibrils with native-like huPrP23-144 core structure. Interestingly, deletion of additional flexible residues in the stretch 99–106 located outside of the amyloid core yields shorter heterogenous fibrils with fingerprint NMR spectra that are clearly distinct from those for full-length huPrP23-144, suggestive of the onset of perturbations to the native structure and degree of molecular ordering for the core residues. For the deletion variant missing residues 99–106 we show that native huPrP23-144 core structure can be “restored” by seeding the fibril growth with preformed full-length huPrP23-144 fibrils.
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spelling pubmed-88830292022-03-01 Influence of the Dynamically Disordered N-Terminal Tail Domain on the Amyloid Core Structure of Human Y145Stop Prion Protein Fibrils Qi, Zhe Surewicz, Krystyna Surewicz, Witold K. Jaroniec, Christopher P. Front Mol Biosci Molecular Biosciences The Y145Stop mutant of human prion protein (huPrP23-144) is associated with a familial prionopathy and provides a convenient in vitro model for investigating amyloid strains and cross-seeding barriers. huPrP23-144 fibrils feature a compact and relatively rigid parallel in-register β-sheet amyloid core spanning ∼30 C-terminal amino acid residues (∼112–141) and a large ∼90-residue dynamically disordered N-terminal tail domain. Here, we systematically evaluate the influence of this dynamic domain on the structure adopted by the huPrP23-144 amyloid core region, by investigating using magic-angle spinning solid-state nuclear magnetic resonance (NMR) spectroscopy a series of fibril samples formed by huPrP23-144 variants corresponding to deletions of large segments of the N-terminal tail. We find that deletion of the bulk of the N-terminal tail, up to residue 98, yields amyloid fibrils with native-like huPrP23-144 core structure. Interestingly, deletion of additional flexible residues in the stretch 99–106 located outside of the amyloid core yields shorter heterogenous fibrils with fingerprint NMR spectra that are clearly distinct from those for full-length huPrP23-144, suggestive of the onset of perturbations to the native structure and degree of molecular ordering for the core residues. For the deletion variant missing residues 99–106 we show that native huPrP23-144 core structure can be “restored” by seeding the fibril growth with preformed full-length huPrP23-144 fibrils. Frontiers Media S.A. 2022-02-14 /pmc/articles/PMC8883029/ /pubmed/35237664 http://dx.doi.org/10.3389/fmolb.2022.841790 Text en Copyright © 2022 Qi, Surewicz, Surewicz and Jaroniec. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Qi, Zhe
Surewicz, Krystyna
Surewicz, Witold K.
Jaroniec, Christopher P.
Influence of the Dynamically Disordered N-Terminal Tail Domain on the Amyloid Core Structure of Human Y145Stop Prion Protein Fibrils
title Influence of the Dynamically Disordered N-Terminal Tail Domain on the Amyloid Core Structure of Human Y145Stop Prion Protein Fibrils
title_full Influence of the Dynamically Disordered N-Terminal Tail Domain on the Amyloid Core Structure of Human Y145Stop Prion Protein Fibrils
title_fullStr Influence of the Dynamically Disordered N-Terminal Tail Domain on the Amyloid Core Structure of Human Y145Stop Prion Protein Fibrils
title_full_unstemmed Influence of the Dynamically Disordered N-Terminal Tail Domain on the Amyloid Core Structure of Human Y145Stop Prion Protein Fibrils
title_short Influence of the Dynamically Disordered N-Terminal Tail Domain on the Amyloid Core Structure of Human Y145Stop Prion Protein Fibrils
title_sort influence of the dynamically disordered n-terminal tail domain on the amyloid core structure of human y145stop prion protein fibrils
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8883029/
https://www.ncbi.nlm.nih.gov/pubmed/35237664
http://dx.doi.org/10.3389/fmolb.2022.841790
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