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Cryo-EM reveals structural breaks in a patient-derived amyloid fibril from systemic AL amyloidosis

Author

Listed:
  • Lynn Radamaker

    (Ulm University)

  • Julian Baur

    (Ulm University)

  • Stefanie Huhn

    (Heidelberg University Hospital)

  • Christian Haupt

    (Ulm University)

  • Ute Hegenbart

    (Heidelberg University Hospital)

  • Stefan Schönland

    (Heidelberg University Hospital)

  • Akanksha Bansal

    (Ulm University)

  • Matthias Schmidt

    (Ulm University)

  • Marcus Fändrich

    (Ulm University)

Abstract

Systemic AL amyloidosis is a debilitating and potentially fatal disease that arises from the misfolding and fibrillation of immunoglobulin light chains (LCs). The disease is patient-specific with essentially each patient possessing a unique LC sequence. In this study, we present two ex vivo fibril structures of a λ3 LC. The fibrils were extracted from the explanted heart of a patient (FOR005) and consist of 115-residue fibril proteins, mainly from the LC variable domain. The fibril structures imply that a 180° rotation around the disulfide bond and a major unfolding step are necessary for fibrils to form. The two fibril structures show highly similar fibril protein folds, differing in only a 12-residue segment. Remarkably, the two structures do not represent separate fibril morphologies, as they can co-exist at different z-axial positions within the same fibril. Our data imply the presence of structural breaks at the interface of the two structural forms.

Suggested Citation

  • Lynn Radamaker & Julian Baur & Stefanie Huhn & Christian Haupt & Ute Hegenbart & Stefan Schönland & Akanksha Bansal & Matthias Schmidt & Marcus Fändrich, 2021. "Cryo-EM reveals structural breaks in a patient-derived amyloid fibril from systemic AL amyloidosis," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21126-2
    DOI: 10.1038/s41467-021-21126-2
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    Cited by:

    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. Kartikay Sharma & Fabian Stockert & Jayakrishna Shenoy & Mélanie Berbon & Muhammed Bilal Abdul-Shukkoor & Birgit Habenstein & Antoine Loquet & Matthias Schmidt & Marcus Fändrich, 2024. "Cryo-EM observation of the amyloid key structure of polymorphic TDP-43 amyloid fibrils," Nature Communications, Nature, vol. 15(1), pages 1-8, December.
    3. Sara Karimi-Farsijani & Kartikay Sharma & Marijana Ugrina & Lukas Kuhn & Peter Benedikt Pfeiffer & Christian Haupt & Sebastian Wiese & Ute Hegenbart & Stefan O. Schönland & Nadine Schwierz & Matthias , 2024. "Cryo-EM structure of a lysozyme-derived amyloid fibril from hereditary amyloidosis," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    4. Tejaswini Pradhan & Riddhiman Sarkar & Kevin M. Meighen-Berger & Matthias J. Feige & Martin Zacharias & Bernd Reif, 2023. "Mechanistic insights into the aggregation pathway of the patient-derived immunoglobulin light chain variable domain protein FOR005," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    5. 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.
    6. 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.
    7. Sara Karimi-Farsijani & Peter Benedikt Pfeiffer & Sambhasan Banerjee & Julian Baur & Lukas Kuhn & Niklas Kupfer & Ute Hegenbart & Stefan O. Schönland & Sebastian Wiese & Christian Haupt & Matthias Sch, 2024. "Light chain mutations contribute to defining the fibril morphology in systemic AL amyloidosis," Nature Communications, Nature, vol. 15(1), pages 1-8, December.
    8. Tim Schulte & Antonio Chaves-Sanjuan & Valentina Speranzini & Kevin Sicking & Melissa Milazzo & Giulia Mazzini & Paola Rognoni & Serena Caminito & Paolo Milani & Chiara Marabelli & Alessandro Corbelli, 2024. "Helical superstructures between amyloid and collagen in cardiac fibrils from a patient with AL amyloidosis," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    9. Li-Qiang Wang & Yeyang Ma & Han-Ye Yuan & Kun Zhao & Mu-Ya Zhang & Qiang Wang & Xi Huang & Wen-Chang Xu & Bin Dai & Jie Chen & Dan Li & Delin Zhang & Zhengzhi Wang & Liangyu Zou & Ping Yin & Cong Liu , 2022. "Cryo-EM structure of an amyloid fibril formed by full-length human SOD1 reveals its conformational conversion," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    10. 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.
    11. Lynn Radamaker & Sara Karimi-Farsijani & Giada Andreotti & Julian Baur & Matthias Neumann & Sarah Schreiner & Natalie Berghaus & Raoul Motika & Christian Haupt & Paul Walther & Volker Schmidt & Stefan, 2021. "Role of mutations and post-translational modifications in systemic AL amyloidosis studied by cryo-EM," Nature Communications, Nature, vol. 12(1), pages 1-11, December.

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