Cryo-EM fibril structures from systemic AA amyloidosis reveal the species complementarity of pathological amyloids

Falk Liberta, Sarah Loerch, Matthies Rennegarbe, Angelika Schierhorn, Per Westermark, Gunilla T. Westermark, Bouke P. C. Hazenberg, Nikolaus Grigorieff, Marcus Fändrich () and Matthias Schmidt ()
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Falk Liberta: Ulm University
Sarah Loerch: Howard Hughes Medical Institute
Matthies Rennegarbe: Ulm University
Angelika Schierhorn: Martin-Luther-University
Per Westermark: Uppsala University
Gunilla T. Westermark: Uppsala University
Bouke P. C. Hazenberg: University of Groningen, University Medical Center Groningen
Nikolaus Grigorieff: Howard Hughes Medical Institute
Marcus Fändrich: Ulm University
Matthias Schmidt: Ulm University

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

Abstract: Abstract Systemic AA amyloidosis is a worldwide occurring protein misfolding disease of humans and animals. It arises from the formation of amyloid fibrils from the acute phase protein serum amyloid A. Here, we report the purification and electron cryo-microscopy analysis of amyloid fibrils from a mouse and a human patient with systemic AA amyloidosis. The obtained resolutions are 3.0 Å and 2.7 Å for the murine and human fibril, respectively. The two fibrils differ in fundamental properties, such as presence of right-hand or left-hand twisted cross-β sheets and overall fold of the fibril proteins. Yet, both proteins adopt highly similar β-arch conformations within the N-terminal ~21 residues. Our data demonstrate the importance of the fibril protein N-terminus for the stability of the analyzed amyloid fibril morphologies and suggest strategies of combating this disease by interfering with specific fibril polymorphs.

Date: 2019
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DOI: 10.1038/s41467-019-09033-z

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