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Cryo-EM structure of a light chain-derived amyloid fibril from a patient with systemic AL amyloidosis

Author

Listed:
  • Lynn Radamaker

    (Ulm University)

  • Yin-Hsi Lin

    (Ulm University)

  • Karthikeyan Annamalai

    (Ulm University)

  • Stefanie Huhn

    (Heidelberg University Hospital)

  • Ute Hegenbart

    (Heidelberg University Hospital)

  • Stefan O. Schönland

    (Heidelberg University Hospital)

  • Günter Fritz

    (University of Hohenheim
    University of Freiburg)

  • Matthias Schmidt

    (Ulm University)

  • Marcus Fändrich

    (Ulm University)

Abstract

Amyloid fibrils derived from antibody light chains are key pathogenic agents in systemic AL amyloidosis. They can be deposited in multiple organs but cardiac amyloid is the major risk factor of mortality. Here we report the structure of a λ1 AL amyloid fibril from an explanted human heart at a resolution of 3.3 Å which we determined using cryo-electron microscopy. The fibril core consists of a 91-residue segment presenting an all-beta fold with ten mutagenic changes compared to the germ line. The conformation differs substantially from natively folded light chains: a rotational switch around the intramolecular disulphide bond being the crucial structural rearrangement underlying fibril formation. Our structure provides insight into the mechanism of protein misfolding and the role of patient-specific mutations in pathogenicity.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09032-0
    DOI: 10.1038/s41467-019-09032-0
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    Cited by:

    1. 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.
    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. 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.
    4. Emily G. Saccuzzo & Mubark D. Mebrat & Hailee F. Scelsi & Minjoo Kim & Minh Thu Ma & Xinya Su & Shannon E. Hill & Elisa Rheaume & Renhao Li & Matthew P. Torres & James C. Gumbart & Wade D. Van Horn & , 2024. "Competition between inside-out unfolding and pathogenic aggregation in an amyloid-forming β-propeller," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. 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.
    6. 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.
    7. 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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