Cryo-EM structure of a light chain-derived amyloid fibril from a patient with systemic AL amyloidosis

Lynn Radamaker, Yin-Hsi Lin, Karthikeyan Annamalai, Stefanie Huhn, Ute Hegenbart, Stefan O. Schönland, Günter Fritz, Matthias Schmidt and Marcus Fändrich ()
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Lynn Radamaker: Ulm University
Yin-Hsi Lin: Ulm University
Karthikeyan Annamalai: Ulm University
Stefanie Huhn: Heidelberg University Hospital
Ute Hegenbart: Heidelberg University Hospital
Stefan O. Schönland: Heidelberg University Hospital
Günter Fritz: University of Hohenheim
Matthias Schmidt: Ulm University
Marcus Fändrich: Ulm University

Nature Communications, 2019, vol. 10, issue 1, 1-8

Abstract: Abstract Amyloid fibrils derived from antibody light chains are key pathogenic agents in systemic AL amyloidosis. They can be deposited in multiple organs but cardiac amyloid is the major risk factor of mortality. Here we report the structure of a λ1 AL amyloid fibril from an explanted human heart at a resolution of 3.3 Å which we determined using cryo-electron microscopy. The fibril core consists of a 91-residue segment presenting an all-beta fold with ten mutagenic changes compared to the germ line. The conformation differs substantially from natively folded light chains: a rotational switch around the intramolecular disulphide bond being the crucial structural rearrangement underlying fibril formation. Our structure provides insight into the mechanism of protein misfolding and the role of patient-specific mutations in pathogenicity.

Date: 2019
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09032-0

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DOI: 10.1038/s41467-019-09032-0

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