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Disease-relevant β(2)-microglobulin variants share a common amyloid fold
β(2)-microglobulin (β(2)m) and its truncated variant ΔΝ6 are co-deposited in amyloid fibrils in the joints, causing the disorder dialysis-related amyloidosis (DRA). Point mutations of β(2)m result in diseases with distinct pathologies. β(2)m-D76N causes a rare systemic amyloidosis with protein depos...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9981686/ https://www.ncbi.nlm.nih.gov/pubmed/36864041 http://dx.doi.org/10.1038/s41467-023-36791-8 |
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author | Wilkinson, Martin Gallardo, Rodrigo U. Martinez, Roberto Maya Guthertz, Nicolas So, Masatomo Aubrey, Liam D. Radford, Sheena E. Ranson, Neil A. |
author_facet | Wilkinson, Martin Gallardo, Rodrigo U. Martinez, Roberto Maya Guthertz, Nicolas So, Masatomo Aubrey, Liam D. Radford, Sheena E. Ranson, Neil A. |
author_sort | Wilkinson, Martin |
collection | PubMed |
description | β(2)-microglobulin (β(2)m) and its truncated variant ΔΝ6 are co-deposited in amyloid fibrils in the joints, causing the disorder dialysis-related amyloidosis (DRA). Point mutations of β(2)m result in diseases with distinct pathologies. β(2)m-D76N causes a rare systemic amyloidosis with protein deposited in the viscera in the absence of renal failure, whilst β(2)m-V27M is associated with renal failure, with amyloid deposits forming predominantly in the tongue. Here we use cryoEM to determine the structures of fibrils formed from these variants under identical conditions in vitro. We show that each fibril sample is polymorphic, with diversity arising from a ‘lego-like’ assembly of a common amyloid building block. These results suggest a ‘many sequences, one amyloid fold’ paradigm in contrast with the recently reported ‘one sequence, many amyloid folds’ behaviour of intrinsically disordered proteins such as tau and Aβ. |
format | Online Article Text |
id | pubmed-9981686 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-99816862023-03-04 Disease-relevant β(2)-microglobulin variants share a common amyloid fold Wilkinson, Martin Gallardo, Rodrigo U. Martinez, Roberto Maya Guthertz, Nicolas So, Masatomo Aubrey, Liam D. Radford, Sheena E. Ranson, Neil A. Nat Commun Article β(2)-microglobulin (β(2)m) and its truncated variant ΔΝ6 are co-deposited in amyloid fibrils in the joints, causing the disorder dialysis-related amyloidosis (DRA). Point mutations of β(2)m result in diseases with distinct pathologies. β(2)m-D76N causes a rare systemic amyloidosis with protein deposited in the viscera in the absence of renal failure, whilst β(2)m-V27M is associated with renal failure, with amyloid deposits forming predominantly in the tongue. Here we use cryoEM to determine the structures of fibrils formed from these variants under identical conditions in vitro. We show that each fibril sample is polymorphic, with diversity arising from a ‘lego-like’ assembly of a common amyloid building block. These results suggest a ‘many sequences, one amyloid fold’ paradigm in contrast with the recently reported ‘one sequence, many amyloid folds’ behaviour of intrinsically disordered proteins such as tau and Aβ. Nature Publishing Group UK 2023-03-02 /pmc/articles/PMC9981686/ /pubmed/36864041 http://dx.doi.org/10.1038/s41467-023-36791-8 Text en © The Author(s) 2023 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 Wilkinson, Martin Gallardo, Rodrigo U. Martinez, Roberto Maya Guthertz, Nicolas So, Masatomo Aubrey, Liam D. Radford, Sheena E. Ranson, Neil A. Disease-relevant β(2)-microglobulin variants share a common amyloid fold |
title | Disease-relevant β(2)-microglobulin variants share a common amyloid fold |
title_full | Disease-relevant β(2)-microglobulin variants share a common amyloid fold |
title_fullStr | Disease-relevant β(2)-microglobulin variants share a common amyloid fold |
title_full_unstemmed | Disease-relevant β(2)-microglobulin variants share a common amyloid fold |
title_short | Disease-relevant β(2)-microglobulin variants share a common amyloid fold |
title_sort | disease-relevant β(2)-microglobulin variants share a common amyloid fold |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9981686/ https://www.ncbi.nlm.nih.gov/pubmed/36864041 http://dx.doi.org/10.1038/s41467-023-36791-8 |
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