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

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.

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Publication Details

Journal
Nature Communications
Published
2024-11-07
DOI
https://doi.org/10.1038/s41467-024-54091-7
Citations
13
Primary Topic
Enzyme Structure and Function
Type
article
Field-Weighted Citation Impact
1.52

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article

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

Lukas C. Kühn, Sebastian Wiese, Marcus Fändrich, Stefan Schönland et al.
13 citations
Nature Communications
Enzyme Structure and Function
1.52
article

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

Lukas C. Kühn, Sebastian Wiese, Marcus Fändrich, Stefan Schönland, Kartikay Sharma, Matthias Schmidt, Peter Benedikt Pfeiffer, Nadine Schwierz, Sara Karimi-Farsijani, Ute Hegenbart, Marijana Ugrina, Christian Haupt
article en
13 citations

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.

Nature CommunicationsVol. 15(1)
University of Augsburg (DE), Universität Ulm (DE), Heidelberg University (DE), University Hospital Heidelberg (DE)
European Molecular Biology Laboratory, European Commission, Deutsche Forschungsgemeinschaft, Universität Ulm
Openalex Percentile: Top 13%
Enzyme Structure and Function
1.52
DOIOpen Access PDFOpenAlex
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