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

Lynn Radamaker, Julian Baur, Stefanie Huhn, Christian Haupt, Ute Hegenbart, Stefan Schönland, Akanksha Bansal, Matthias Schmidt and Marcus Fändrich ()
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Lynn Radamaker: Ulm University
Julian Baur: Ulm University
Stefanie Huhn: Heidelberg University Hospital
Christian Haupt: Ulm University
Ute Hegenbart: Heidelberg University Hospital
Stefan Schönland: Heidelberg University Hospital
Akanksha Bansal: Ulm University
Matthias Schmidt: Ulm University
Marcus Fändrich: Ulm University

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-21126-2

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