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Cryo-EM structure of cardiac amyloid fibrils from an immunoglobulin light chain AL amyloidosis patient

Author

Listed:
  • Paolo Swuec

    (Università degli Studi di Milano
    Università degli Studi di Milano)

  • Francesca Lavatelli

    (University of Pavia)

  • Masayoshi Tasaki

    (University of Pavia
    Kumamoto University
    Graduate School of Medical Sciences)

  • Cristina Paissoni

    (Università degli Studi di Milano)

  • Paola Rognoni

    (University of Pavia)

  • Martina Maritan

    (Università degli Studi di Milano)

  • Francesca Brambilla

    (Institute for Biomedical Technologies-CNR)

  • Paolo Milani

    (University of Pavia)

  • Pierluigi Mauri

    (Institute for Biomedical Technologies-CNR)

  • Carlo Camilloni

    (Università degli Studi di Milano)

  • Giovanni Palladini

    (University of Pavia)

  • Giampaolo Merlini

    (University of Pavia)

  • Stefano Ricagno

    (Università degli Studi di Milano)

  • Martino Bolognesi

    (Università degli Studi di Milano
    Università degli Studi di Milano)

Abstract

Systemic light chain amyloidosis (AL) is a life-threatening disease caused by aggregation and deposition of monoclonal immunoglobulin light chains (LC) in target organs. Severity of heart involvement is the most important factor determining prognosis. Here, we report the 4.0 Å resolution cryo-electron microscopy map and molecular model of amyloid fibrils extracted from the heart of an AL amyloidosis patient with severe amyloid cardiomyopathy. The helical fibrils are composed of a single protofilament, showing typical 4.9 Å stacking and cross-β architecture. Two distinct polypeptide stretches (total of 77 residues) from the LC variable domain (Vl) fit the fibril density. Despite Vl high sequence variability, residues stabilizing the fibril core are conserved through different cardiotoxic Vl, highlighting structural motifs that may be common to misfolding-prone LCs. Our data shed light on the architecture of LC amyloids, correlate amino acid sequences with fibril assembly, providing the grounds for development of innovative medicines.

Suggested Citation

  • Paolo Swuec & Francesca Lavatelli & Masayoshi Tasaki & Cristina Paissoni & Paola Rognoni & Martina Maritan & Francesca Brambilla & Paolo Milani & Pierluigi Mauri & Carlo Camilloni & Giovanni Palladini, 2019. "Cryo-EM structure of cardiac amyloid fibrils from an immunoglobulin light chain AL amyloidosis patient," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09133-w
    DOI: 10.1038/s41467-019-09133-w
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    Cited by:

    1. Javier Garcia-Pardo & Andrea Bartolomé-Nafría & Antonio Chaves-Sanjuan & Marcos Gil-Garcia & Cristina Visentin & Martino Bolognesi & Stefano Ricagno & Salvador Ventura, 2023. "Cryo-EM structure of hnRNPDL-2 fibrils, a functional amyloid associated with limb-girdle muscular dystrophy D3," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Pamina Kazman & Ramona M. Absmeier & Harald Engelhardt & Johannes Buchner, 2021. "Dissection of the amyloid formation pathway in AL amyloidosis," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    3. 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.
    4. Tim Schulte & Antonio Chaves-Sanjuan & Giulia Mazzini & Valentina Speranzini & Francesca Lavatelli & Filippo Ferri & Carlo Palizzotto & Maria Mazza & Paolo Milani & Mario Nuvolone & Anne-Cathrine Vogt, 2022. "Cryo-EM structure of ex vivo fibrils associated with extreme AA amyloidosis prevalence in a cat shelter," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    5. 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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