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Structural basis for transthyretin amyloid formation in vitreous body of the eye

Author

Listed:
  • Irina Iakovleva

    (Umeå University)

  • Michael Hall

    (Umeå University)

  • Melanie Oelker

    (Umeå University)

  • Linda Sandblad

    (Umeå University)

  • Intissar Anan

    (Umeå University
    Wallenberg Centre for Molecular Medicine, Umeå University)

  • A. Elisabeth Sauer-Eriksson

    (Umeå University)

Abstract

Amyloid transthyretin (ATTR) amyloidosis is characterized by the abnormal accumulation of ATTR fibrils in multiple organs. However, the structure of ATTR fibrils from the eye is poorly understood. Here, we used cryo-EM to structurally characterize vitreous body ATTR fibrils. These structures were distinct from previously characterized heart fibrils, even though both have the same mutation and type A pathology. Differences were observed at several structural levels: in both the number and arrangement of protofilaments, and the conformation of the protein fibril in each layer of protofilaments. Thus, our results show that ATTR protein structure and its assembly into protofilaments in the type A fibrils can vary between patients carrying the same mutation. By analyzing and matching the interfaces between the amino acids in the ATTR fibril with those in the natively folded TTR, we are able to propose a mechanism for the structural conversion of TTR into a fibrillar form.

Suggested Citation

  • Irina Iakovleva & Michael Hall & Melanie Oelker & Linda Sandblad & Intissar Anan & A. Elisabeth Sauer-Eriksson, 2021. "Structural basis for transthyretin amyloid formation in vitreous body of the eye," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27481-4
    DOI: 10.1038/s41467-021-27481-4
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    References listed on IDEAS

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    1. Matthias Schmidt & Sebastian Wiese & Volkan Adak & Jonas Engler & Shubhangi Agarwal & Günter Fritz & Per Westermark & Martin Zacharias & Marcus Fändrich, 2019. "Cryo-EM structure of a transthyretin-derived amyloid fibril from a patient with hereditary ATTR amyloidosis," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
    2. Falk Liberta & Sarah Loerch & Matthies Rennegarbe & Angelika Schierhorn & Per Westermark & Gunilla T. Westermark & Bouke P. C. Hazenberg & Nikolaus Grigorieff & Marcus Fändrich & Matthias Schmidt, 2019. "Cryo-EM fibril structures from systemic AA amyloidosis reveal the species complementarity of pathological amyloids," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    3. Ai Woon Yee & Matteo Aldeghi & Matthew P. Blakeley & Andreas Ostermann & Philippe J. Mas & Martine Moulin & Daniele de Sanctis & Matthew W. Bowler & Christoph Mueller-Dieckmann & Edward P. Mitchell & , 2019. "A molecular mechanism for transthyretin amyloidogenesis," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    4. Lynn Radamaker & Yin-Hsi Lin & Karthikeyan Annamalai & Stefanie Huhn & Ute Hegenbart & Stefan O. Schönland & Günter Fritz & Matthias Schmidt & Marcus Fändrich, 2019. "Cryo-EM structure of a light chain-derived amyloid fibril from a patient with systemic AL amyloidosis," Nature Communications, Nature, vol. 10(1), pages 1-8, December.
    5. Benjamin Falcon & Jasenko Zivanov & Wenjuan Zhang & Alexey G. Murzin & Holly J. Garringer & Ruben Vidal & R. Anthony Crowther & Kathy L. Newell & Bernardino Ghetti & Michel Goedert & Sjors H. W. Scher, 2019. "Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules," Nature, Nature, vol. 568(7752), pages 420-423, April.
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    1. Maximilian Steinebrei & Juliane Gottwald & Julian Baur & Christoph Röcken & Ute Hegenbart & Stefan Schönland & Matthias Schmidt, 2022. "Cryo-EM structure of an ATTRwt amyloid fibril from systemic non-hereditary transthyretin amyloidosis," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    2. Robert Bücker & Carolin Seuring & Cornelia Cazey & Katharina Veith & Maria García-Alai & Kay Grünewald & Meytal Landau, 2022. "The Cryo-EM structures of two amphibian antimicrobial cross-β amyloid fibrils," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Binh An Nguyen & Virender Singh & Shumaila Afrin & Anna Yakubovska & Lanie Wang & Yasmin Ahmed & Rose Pedretti & Maria del Carmen Fernandez-Ramirez & Preeti Singh & Maja Pękała & Luis O. Cabrera Herna, 2024. "Structural polymorphism of amyloid fibrils in ATTR amyloidosis revealed by cryo-electron microscopy," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    4. Maximilian Steinebrei & Julian Baur & Anaviggha Pradhan & Niklas Kupfer & Sebastian Wiese & Ute Hegenbart & Stefan O. Schönland & Matthias Schmidt & Marcus Fändrich, 2023. "Common transthyretin-derived amyloid fibril structures in patients with hereditary ATTR amyloidosis," Nature Communications, Nature, vol. 14(1), pages 1-8, December.

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