Astbury Centre for Structural Molecular Biology, School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.
Aelin Therapeutics, Bio-Incubator Leuven, Gaston Geenslaan 1, 3001, Leuven, Belgium.
Nat Commun. 2023 Mar 2;14(1):1190. doi: 10.1038/s41467-023-36791-8.
β-microglobulin (βm) and its truncated variant ΔΝ6 are co-deposited in amyloid fibrils in the joints, causing the disorder dialysis-related amyloidosis (DRA). Point mutations of βm result in diseases with distinct pathologies. βm-D76N causes a rare systemic amyloidosis with protein deposited in the viscera in the absence of renal failure, whilst βm-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.
β-微球蛋白（βm）及其截断变体 ΔΝ6 共同沉积在关节的淀粉样纤维中，导致透析相关淀粉样变性（DRA）。βm 的点突变导致具有不同病理的疾病。βm-D76N 引起罕见的系统性淀粉样变性，其蛋白质沉积在没有肾衰竭的内脏中，而 βm-V27M 与肾衰竭相关，淀粉样沉积物主要在舌头上形成。在这里，我们使用 cryoEM 在体外相同条件下确定由这些变体形成的纤维的结构。我们表明，每个纤维样品都是多态的，多样性源于常见淀粉样结构单元的“乐高式”组装。这些结果表明存在“许多序列，一种淀粉样折叠”的范例，与最近报道的tau 和 Aβ 等无规卷曲蛋白质的“一个序列，多种淀粉样折叠”行为形成对比。
