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-Structure paper
Title | Disease-relevant β-microglobulin variants share a common amyloid fold. |
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Journal, issue, pages | Nat Commun, Vol. 14, Issue 1, Page 1190, Year 2023 |
Publish date | Mar 2, 2023 |
Authors | Martin Wilkinson / Rodrigo U Gallardo / Roberto Maya Martinez / Nicolas Guthertz / Masatomo So / Liam D Aubrey / Sheena E Radford / Neil A Ranson / |
PubMed Abstract | 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 ...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. |
External links | Nat Commun / PubMed:36864041 / PubMed Central |
Methods | EM (helical sym.) |
Resolution | 2.8 - 4.1 Å |
Structure data | EMDB-15222, PDB-8a7o: EMDB-15223, PDB-8a7p: EMDB-15224, PDB-8a7q: EMDB-15225, PDB-8a7t: EMDB-15226: beta-2-microglobulin D76N amyloid fibril form 1PFa EMDB-15227: beta-2-microglobulin D76N amyloid fibril form 1PFb |
Source |
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Keywords | PROTEIN FIBRIL / Amyloid / fibril / helical / cross-beta / dialysis-related amyloidosis / b2m / polymorph |