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Role of mutations and post-translational modifications in systemic AL amyloidosis studied by cryo-EM

Systemic AL amyloidosis is a rare disease that is caused by the misfolding of immunoglobulin light chains (LCs). Potential drivers of amyloid formation in this disease are post-translational modifications (PTMs) and the mutational changes that are inserted into the LCs by somatic hypermutation. Here...

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Hauptverfasser: Radamaker, Lynn (VerfasserIn) , Karimi-Farsijani, Sara (VerfasserIn) , Andreotti, Giada (VerfasserIn) , Baur, Julian (VerfasserIn) , Neumann, Matthias (VerfasserIn) , Schreiner, Sarah (VerfasserIn) , Berghaus, Natalie (VerfasserIn) , Motika, Raoul (VerfasserIn) , Haupt, Christian (VerfasserIn) , Walther, Paul (VerfasserIn) , Schmidt, Volker (VerfasserIn) , Huhn, Stefanie (VerfasserIn) , Hegenbart, Ute (VerfasserIn) , Schönland, Stefan (VerfasserIn) , Wiese, Sebastian (VerfasserIn) , Read, Clarissa (VerfasserIn) , Schmidt, Matthias (VerfasserIn) , Fändrich, Marcus (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 05 November 2021
In: Nature Communications
Year: 2021, Jahrgang: 12, Pages: 1-11
ISSN:2041-1723
DOI:10.1038/s41467-021-26553-9
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41467-021-26553-9
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41467-021-26553-9
Volltext
Verfasserangaben:Lynn Radamaker, Sara Karimi-Farsijani, Giada Andreotti, Julian Baur, Matthias Neumann, Sarah Schreiner, Natalie Berghaus, Raoul Motika, Christian Haupt, Paul Walther, Volker Schmidt, Stefanie Huhn, Ute Hegenbart, Stefan O. Schönland, Sebastian Wiese, Clarissa Read, Matthias Schmidt, Marcus Fändrich
Beschreibung
Zusammenfassung:Systemic AL amyloidosis is a rare disease that is caused by the misfolding of immunoglobulin light chains (LCs). Potential drivers of amyloid formation in this disease are post-translational modifications (PTMs) and the mutational changes that are inserted into the LCs by somatic hypermutation. Here we present the cryo electron microscopy (cryo-EM) structure of an ex vivo λ1-AL amyloid fibril whose deposits disrupt the ordered cardiomyocyte structure in the heart. The fibril protein contains six mutational changes compared to the germ line and three PTMs (disulfide bond, N-glycosylation and pyroglutamylation). Our data imply that the disulfide bond, glycosylation and mutational changes contribute to determining the fibril protein fold and help to generate a fibril morphology that is able to withstand proteolytic degradation inside the body.
Beschreibung:Gesehen am 06.12.2021
Beschreibung:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-021-26553-9

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