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Huntingtin fibrils with different toxicity, structure, and seeding potential can be interconverted
The first exon of the huntingtin protein (HTTex1) important in Huntington’s disease (HD) can form cross-β fibrils of varying toxicity. We find that the difference between these fibrils is the degree of entanglement and dynamics of the C-terminal proline-rich domain (PRD) in a mechanism analogous to...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277859/ https://www.ncbi.nlm.nih.gov/pubmed/34257293 http://dx.doi.org/10.1038/s41467-021-24411-2 |
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author | Mario Isas, J. Pandey, Nitin K. Xu, Hui Teranishi, Kazuki Okada, Alan K. Fultz, Ellisa K. Rawat, Anoop Applebaum, Anise Meier, Franziska Chen, Jeannie Langen, Ralf Siemer, Ansgar B. |
author_facet | Mario Isas, J. Pandey, Nitin K. Xu, Hui Teranishi, Kazuki Okada, Alan K. Fultz, Ellisa K. Rawat, Anoop Applebaum, Anise Meier, Franziska Chen, Jeannie Langen, Ralf Siemer, Ansgar B. |
author_sort | Mario Isas, J. |
collection | PubMed |
description | The first exon of the huntingtin protein (HTTex1) important in Huntington’s disease (HD) can form cross-β fibrils of varying toxicity. We find that the difference between these fibrils is the degree of entanglement and dynamics of the C-terminal proline-rich domain (PRD) in a mechanism analogous to polyproline film formation. In contrast to fibril strains found for other cross-β fibrils, these HTTex1 fibril types can be interconverted. This is because the structure of their polyQ fibril core remains unchanged. Further, we find that more toxic fibrils of low entanglement have higher affinities for protein interactors and are more effective seeds for recombinant HTTex1 and HTTex1 in cells. Together these data show how the structure of a framing sequence at the surface of a fibril can modulate seeding, protein-protein interactions, and thereby toxicity in neurodegenerative disease. |
format | Online Article Text |
id | pubmed-8277859 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-82778592021-07-20 Huntingtin fibrils with different toxicity, structure, and seeding potential can be interconverted Mario Isas, J. Pandey, Nitin K. Xu, Hui Teranishi, Kazuki Okada, Alan K. Fultz, Ellisa K. Rawat, Anoop Applebaum, Anise Meier, Franziska Chen, Jeannie Langen, Ralf Siemer, Ansgar B. Nat Commun Article The first exon of the huntingtin protein (HTTex1) important in Huntington’s disease (HD) can form cross-β fibrils of varying toxicity. We find that the difference between these fibrils is the degree of entanglement and dynamics of the C-terminal proline-rich domain (PRD) in a mechanism analogous to polyproline film formation. In contrast to fibril strains found for other cross-β fibrils, these HTTex1 fibril types can be interconverted. This is because the structure of their polyQ fibril core remains unchanged. Further, we find that more toxic fibrils of low entanglement have higher affinities for protein interactors and are more effective seeds for recombinant HTTex1 and HTTex1 in cells. Together these data show how the structure of a framing sequence at the surface of a fibril can modulate seeding, protein-protein interactions, and thereby toxicity in neurodegenerative disease. Nature Publishing Group UK 2021-07-13 /pmc/articles/PMC8277859/ /pubmed/34257293 http://dx.doi.org/10.1038/s41467-021-24411-2 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Mario Isas, J. Pandey, Nitin K. Xu, Hui Teranishi, Kazuki Okada, Alan K. Fultz, Ellisa K. Rawat, Anoop Applebaum, Anise Meier, Franziska Chen, Jeannie Langen, Ralf Siemer, Ansgar B. Huntingtin fibrils with different toxicity, structure, and seeding potential can be interconverted |
title | Huntingtin fibrils with different toxicity, structure, and seeding potential can be interconverted |
title_full | Huntingtin fibrils with different toxicity, structure, and seeding potential can be interconverted |
title_fullStr | Huntingtin fibrils with different toxicity, structure, and seeding potential can be interconverted |
title_full_unstemmed | Huntingtin fibrils with different toxicity, structure, and seeding potential can be interconverted |
title_short | Huntingtin fibrils with different toxicity, structure, and seeding potential can be interconverted |
title_sort | huntingtin fibrils with different toxicity, structure, and seeding potential can be interconverted |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277859/ https://www.ncbi.nlm.nih.gov/pubmed/34257293 http://dx.doi.org/10.1038/s41467-021-24411-2 |
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