Cryo-EM structure of a lysozyme-derived amyloid fibril from hereditary amyloidosis

Sara Karimi-Farsijani (), Kartikay Sharma, Marijana Ugrina, Lukas Kuhn, Peter Benedikt Pfeiffer, Christian Haupt, Sebastian Wiese, Ute Hegenbart, Stefan O. Schönland, Nadine Schwierz, Matthias Schmidt and Marcus Fändrich
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Sara Karimi-Farsijani: Ulm University
Kartikay Sharma: Ulm University
Marijana Ugrina: University of Augsburg
Lukas Kuhn: Ulm University
Peter Benedikt Pfeiffer: Ulm University
Christian Haupt: Ulm University
Sebastian Wiese: Ulm University
Ute Hegenbart: Heidelberg University Hospital
Stefan O. Schönland: Heidelberg University Hospital
Nadine Schwierz: University of Augsburg
Matthias Schmidt: Ulm University
Marcus Fändrich: Ulm University

Nature Communications, 2024, vol. 15, issue 1, 1-9

Abstract: Abstract Systemic ALys amyloidosis is a debilitating protein misfolding disease that arises from the formation of amyloid fibrils from C-type lysozyme. We here present a 2.8 Å cryo-electron microscopy structure of an amyloid fibril, which was isolated from the abdominal fat tissue of a patient who expressed the D87G variant of human lysozyme. We find that the fibril possesses a stable core that is formed by all 130 residues of the fibril precursor protein. There are four disulfide bonds in each fibril protein that connect the same residues as in the globularly folded protein. As the conformation of lysozyme in the fibril is otherwise fundamentally different from native lysozyme, our data provide a structural rationale for the need of protein unfolding in the development of systemic ALys amyloidosis.

Date: 2024
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DOI: 10.1038/s41467-024-54091-7

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