Disease-relevant β2-microglobulin variants share a common amyloid fold

Abstract

β2-microglobulin (β2m) and its truncated variant ΔΝ6 are co-deposited in amyloid fibrils in the joints, causing the disorder dialysis-related amyloidosis (DRA). Point mutations of β2m result in diseases with distinct pathologies. β2m-D76N causes a rare systemic amyloidosis with protein deposited in the viscera in the absence of renal failure, whilst β2m-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.

Metadata

Item Type:	Article
Authors/Creators:	Wilkinson, M https://orcid.org/0000-0001-5490-613X Gallardo, RU Martinez, RM Guthertz, N So, M Aubrey, LD Radford, SE https://orcid.org/0000-0002-3079-8039 Ranson, N https://orcid.org/0000-0002-3640-5275
Copyright, Publisher and Additional Information:	© The Author(s) 2023. 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/.
Dates:	Published: 2 March 2023 Published (online): 2 March 2023 Accepted: 16 February 2023
Institution:	The University of Leeds
Academic Units:	The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Cryo EM, Image Processing (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Structural Molecular Biology (Leeds)
Funding Information:	Funder Grant number MRC (Medical Research Council) MR/T011149/1 Wellcome Trust 204963/Z/16/Z Royal Society RSRP\R1\211057 Wellcome Trust 101497/Z/13/Z BBSRC (Biotechnology & Biological Sciences Research Council) BB/W019485/1 Wellcome Trust Not Known
Depositing User:	Symplectic Publications
Date Deposited:	21 Feb 2023 16:10
Last Modified:	25 Jun 2023 23:15
Status:	Published
Publisher:	Nature Research
Identification Number:	10.1038/s41467-023-36791-8
Related URLs:	Dataset
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:196531

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Disease-relevant β2-microglobulin variants share a common amyloid fold

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Disease-relevant β2-microglobulin variants share a common amyloid fold

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