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Dissection of the amyloid formation pathway in AL amyloidosis

Author

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  • Pamina Kazman

    (Technische Universität München)

  • Ramona M. Absmeier

    (Technische Universität München)

  • Harald Engelhardt

    (Max-Planck-Institute of Biochemistry)

  • Johannes Buchner

    (Technische Universität München)

Abstract

In antibody light chain (AL) amyloidosis, overproduced light chain (LC) fragments accumulate as fibrils in organs and tissues of patients. In vitro, AL fibril formation is a slow process, characterized by a pronounced lag phase. The events occurring during this lag phase are largely unknown. We have dissected the lag phase of a patient-derived LC truncation and identified structural transitions that precede fibril formation. The process starts with partial unfolding of the VL domain and the formation of small amounts of dimers. This is a prerequisite for the formation of an ensemble of oligomers, which are the precursors of fibrils. During oligomerization, the hydrophobic core of the LC domain rearranges which leads to changes in solvent accessibility and rigidity. Structural transitions from an anti-parallel to a parallel β-sheet secondary structure occur in the oligomers prior to amyloid formation. Together, our results reveal a rate-limiting multi-step mechanism of structural transitions prior to fibril formation in AL amyloidosis, which offers, in the long run, opportunities for therapeutic intervention.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26845-0
    DOI: 10.1038/s41467-021-26845-0
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    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 & 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.
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    1. 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.

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