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

Author

Listed:
  • Martin Wilkinson

    (Faculty of Biological Sciences, University of Leeds)

  • Rodrigo U. Gallardo

    (Faculty of Biological Sciences, University of Leeds
    Aelin Therapeutics, Bio-Incubator Leuven)

  • Roberto Maya Martinez

    (Faculty of Biological Sciences, University of Leeds
    Peak Proteins, Birchwood House, Larkwood Way, Macclesfield)

  • Nicolas Guthertz

    (Faculty of Biological Sciences, University of Leeds
    Bicycle Therapeutics, Blocks A & B, Portway Building, Grant Park, Abingdon)

  • Masatomo So

    (Faculty of Biological Sciences, University of Leeds
    Nara Medical University)

  • Liam D. Aubrey

    (Faculty of Biological Sciences, University of Leeds)

  • Sheena E. Radford

    (Faculty of Biological Sciences, University of Leeds)

  • Neil A. Ranson

    (Faculty of Biological Sciences, University of Leeds)

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.

Suggested Citation

  • Martin Wilkinson & Rodrigo U. Gallardo & Roberto Maya Martinez & Nicolas Guthertz & Masatomo So & Liam D. Aubrey & Sheena E. Radford & Neil A. Ranson, 2023. "Disease-relevant β2-microglobulin variants share a common amyloid fold," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36791-8
    DOI: 10.1038/s41467-023-36791-8
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