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bioRxiv · 10.1101/2020.10.12.332569

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

Radamaker, L.·Baur, J. D.·Huhn, S.·Haupt, C.·Hegenbart, U.·Schönland, S.·Bansal, A.·Schmidt, M.·Fändrich, M.
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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 the first ex vivo fibril structures of a {lambda}3 LC. The fibrils were extracted from the explanted heart of a patient (FOR005) and consist of 115 residues, mainly from the LC variable domain. The fibril structures imply that a 180{degrees} 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.

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Radamaker, L., Baur, J. D., Huhn, S., Haupt, C., Hegenbart, U., Schönland, S., Bansal, A., Schmidt, M., Fändrich, M.. 2020-10-12. Cryo-EM reveals structural breaks in a patient-derived amyloid fibril from systemic AL amyloidosis. https://doi.org/10.1101/2020.10.12.332569

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