This elegant study by Eichner et al. considerably advances atomic-level understanding of the molecular features that underlie human β2
m) amyloidogenecity, and should facilitate the development of novel therapeutics for dialysis-related amyloidosis (DRA). Using NMR, they solved a solution structure of an amyloidogenic intermediate of N-terminal truncated β2
m (ΔN6), a protein variant that is present in renal amyloid deposits of DRA patients. Furthermore, using NMR, Eichner et al. established specific conformational changes in full-length β2
m that arose from bimolecular interactions with ΔN6 that presumably reflected the truncated protein’s prion-like seeding of β2
m fibrils. Their findings reinforce that invaluable insight on the molecular basis of amyloidogenic polypeptides can be obtained by probing, at the atomic level, the native and non-native structures and aggregation propensities of pathogenically relevant variants (unmodified and post-translationally modified forms).
In contrast with the central...