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Cryo-EM reveals structural breaks in a patient-derived amyloid fibril from systemic AL amyloidosis

Systemic AL amyloidosis is a debilitating and potentially fatal disease that arises from the misfolding and fibrillation of immunoglobulin light chains (LCs). The disease is patient-specific with essentially each patient possessing a unique LC sequence. In this study, we present two ex vivo fibril s...

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Main Authors: Radamaker, Lynn (Author) , Baur, Julian (Author) , Huhn, Stefanie (Author) , Haupt, Christian (Author) , Hegenbart, Ute (Author) , Schönland, Stefan (Author) , Bansal, Akanksha (Author) , Schmidt, Matthias (Author) , Fändrich, Marcus (Author)
Format: Article (Journal)
Language:English
Published: 08 February 2021
In: Nature Communications
Year: 2021, Volume: 12, Pages: 1-10
ISSN:2041-1723
DOI:10.1038/s41467-021-21126-2
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41467-021-21126-2
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41467-021-21126-2
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Author Notes:Lynn Radamaker, Julian Baur, Stefanie Huhn, Christian Haupt, Ute Hegenbart, Stefan Schönland, Akanksha Bansal, Matthias Schmidt & Marcus Fändrich
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Summary:Systemic AL amyloidosis is a debilitating and potentially fatal disease that arises from the misfolding and fibrillation of immunoglobulin light chains (LCs). The disease is patient-specific with essentially each patient possessing a unique LC sequence. In this study, we present two ex vivo fibril structures of a λ3 LC. The fibrils were extracted from the explanted heart of a patient (FOR005) and consist of 115-residue fibril proteins, mainly from the LC variable domain. The fibril structures imply that a 180° rotation around the disulfide bond and a major unfolding step are necessary for fibrils to form. The two fibril structures show highly similar fibril protein folds, differing in only a 12-residue segment. Remarkably, the two structures do not represent separate fibril morphologies, as they can co-exist at different z-axial positions within the same fibril. Our data imply the presence of structural breaks at the interface of the two structural forms.
Item Description:Gesehen am 06.08.2021
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-021-21126-2

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