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Role of mutations and post-translational modifications in systemic AL amyloidosis studied by cryo-EM

Author

Listed:
  • Lynn Radamaker

    (Institute of Protein Biochemistry, Ulm University)

  • Sara Karimi-Farsijani

    (Institute of Protein Biochemistry, Ulm University)

  • Giada Andreotti

    (Institute of Protein Biochemistry, Ulm University)

  • Julian Baur

    (Institute of Protein Biochemistry, Ulm University)

  • Matthias Neumann

    (Institute of Stochastics, Ulm University)

  • Sarah Schreiner

    (Medical Department V, Section of Multiple Myeloma, Heidelberg University Hospital)

  • Natalie Berghaus

    (Medical Department V, Section of Multiple Myeloma, Heidelberg University Hospital)

  • Raoul Motika

    (Middle Eastern History and Culture, University of Hamburg)

  • Christian Haupt

    (Institute of Protein Biochemistry, Ulm University)

  • Paul Walther

    (Central Facility for Electron Microscopy, Ulm University)

  • Volker Schmidt

    (Institute of Stochastics, Ulm University)

  • Stefanie Huhn

    (Medical Department V, Section of Multiple Myeloma, Heidelberg University Hospital)

  • Ute Hegenbart

    (Medical Department V, Amyloidosis Center, Heidelberg University Hospital)

  • Stefan O. Schönland

    (Medical Department V, Amyloidosis Center, Heidelberg University Hospital)

  • Sebastian Wiese

    (Core Unit Mass Spectrometry and Proteomics, Medical Faculty, Ulm University)

  • Clarissa Read

    (Central Facility for Electron Microscopy, Ulm University
    Institute of Virology, Ulm University Medical Center)

  • Matthias Schmidt

    (Institute of Protein Biochemistry, Ulm University)

  • Marcus Fändrich

    (Institute of Protein Biochemistry, Ulm University)

Abstract

Systemic AL amyloidosis is a rare disease that is caused by the misfolding of immunoglobulin light chains (LCs). Potential drivers of amyloid formation in this disease are post-translational modifications (PTMs) and the mutational changes that are inserted into the LCs by somatic hypermutation. Here we present the cryo electron microscopy (cryo-EM) structure of an ex vivo λ1-AL amyloid fibril whose deposits disrupt the ordered cardiomyocyte structure in the heart. The fibril protein contains six mutational changes compared to the germ line and three PTMs (disulfide bond, N-glycosylation and pyroglutamylation). Our data imply that the disulfide bond, glycosylation and mutational changes contribute to determining the fibril protein fold and help to generate a fibril morphology that is able to withstand proteolytic degradation inside the body.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26553-9
    DOI: 10.1038/s41467-021-26553-9
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    References listed on IDEAS

    as
    1. 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.
    2. 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.
    3. Akanksha Bansal & Matthias Schmidt & Matthies Rennegarbe & Christian Haupt & Falk Liberta & Sabrina Stecher & Ioana Puscalau-Girtu & Alexander Biedermann & Marcus Fändrich, 2021. "AA amyloid fibrils from diseased tissue are structurally different from in vitro formed SAA fibrils," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
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