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The structure of a β2-microglobulin fibril suggests a molecular basis for its amyloid polymorphism

Author

Listed:
  • Matthew G. Iadanza

    (University of Leeds)

  • Robert Silvers

    (Massachusetts Institute of Technology
    Florida State University)

  • Joshua Boardman

    (University of Leeds)

  • Hugh I. Smith

    (University of Leeds)

  • Theodoros K. Karamanos

    (University of Leeds
    NIH)

  • Galia T. Debelouchina

    (Massachusetts Institute of Technology
    University of California San Diego)

  • Yongchao Su

    (Massachusetts Institute of Technology
    Merck & Co., Inc.)

  • Robert G. Griffin

    (Massachusetts Institute of Technology)

  • Neil A. Ranson

    (University of Leeds)

  • Sheena E. Radford

    (University of Leeds)

Abstract

All amyloid fibrils contain a cross-β fold. How this structure differs in fibrils formed from proteins associated with different diseases remains unclear. Here, we combine cryo-EM and MAS-NMR to determine the structure of an amyloid fibril formed in vitro from β2-microglobulin (β2m), the culprit protein of dialysis-related amyloidosis. The fibril is composed of two identical protofilaments assembled from subunits that do not share β2m’s native tertiary fold, but are formed from similar β-strands. The fibrils share motifs with other amyloid fibrils, but also contain unique features including π-stacking interactions perpendicular to the fibril axis and an intramolecular disulfide that stabilises the subunit fold. We also describe a structural model for a second fibril morphology and show that it is built from the same subunit fold. The results provide insights into the mechanisms of fibril formation and the commonalities and differences within the amyloid fold in different protein sequences.

Suggested Citation

  • Matthew G. Iadanza & Robert Silvers & Joshua Boardman & Hugh I. Smith & Theodoros K. Karamanos & Galia T. Debelouchina & Yongchao Su & Robert G. Griffin & Neil A. Ranson & Sheena E. Radford, 2018. "The structure of a β2-microglobulin fibril suggests a molecular basis for its amyloid polymorphism," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06761-6
    DOI: 10.1038/s41467-018-06761-6
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    Cited by:

    1. Kichitaro Nakajima & Keiichi Yamaguchi & Masahiro Noji & César Aguirre & Kensuke Ikenaka & Hideki Mochizuki & Lianjie Zhou & Hirotsugu Ogi & Toru Ito & Ichiei Narita & Fumitake Gejyo & Hironobu Naiki , 2022. "Macromolecular crowding and supersaturation protect hemodialysis patients from the onset of dialysis-related amyloidosis," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. 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.

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