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.