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Mechanistic insights into the aggregation pathway of the patient-derived immunoglobulin light chain variable domain protein FOR005

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  • Tejaswini Pradhan

    (Technical University Munich
    Helmholtz-Zentrum München (HMGU))

  • Riddhiman Sarkar

    (Technical University Munich
    Helmholtz-Zentrum München (HMGU))

  • Kevin M. Meighen-Berger

    (Technical University Munich)

  • Matthias J. Feige

    (Technical University Munich)

  • Martin Zacharias

    (Technical University Munich)

  • Bernd Reif

    (Technical University Munich
    Helmholtz-Zentrum München (HMGU))

Abstract

Systemic antibody light chain (AL) amyloidosis is characterized by deposition of amyloid fibrils. Prior to fibril formation, soluble oligomeric AL protein has a direct cytotoxic effect on cardiomyocytes. We focus on the patient derived λ-III AL variable domain FOR005 which is mutated at five positions with respect to the closest germline protein. Using solution-state NMR spectroscopy, we follow the individual steps involved in protein misfolding from the native to the amyloid fibril state. Unfavorable mutations in the complementary determining regions introduce a strain in the native protein structure which yields partial unfolding. Driven by electrostatic interactions, the protein converts into a high molecular weight, oligomeric, molten globule. The high local concentration of aggregation prone regions in the oligomer finally catalyzes the conversion into fibrils. The topology is determined by balanced electrostatic interactions in the fibril core implying a 180° rotational switch of the beta-sheets around the conserved disulfide bond.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39280-0
    DOI: 10.1038/s41467-023-39280-0
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    References listed on IDEAS

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    1. 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.
    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.
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