Buchumschlag

Fatal amyloid formation in a patient’s antibody light chain is caused by a single point mutation

In systemic light chain amyloidosis, an overexpressed antibody light chain (LC) forms fibrils which deposit in organs and cause their failure. While it is well-established that mutations in the LC’s VL domain are important prerequisites, the mechanisms which render a patient LC amyloidogenic are ill...

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Bibliographische Detailangaben
Hauptverfasser: Kazman, Pamina (VerfasserIn) , Vielberg, Marie-Theres (VerfasserIn) , Pulido Cendales, María Daniela (VerfasserIn) , Hunziger, Lioba (VerfasserIn) , Weber, Benedikt (VerfasserIn) , Hegenbart, Ute (VerfasserIn) , Zacharias, Martin (VerfasserIn) , Köhler, Rolf (VerfasserIn) , Schönland, Stefan (VerfasserIn) , Groll, Michael (VerfasserIn) , Buchner, Johannes (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 10 March 2020
In: eLife
Year: 2020, Jahrgang: 9
ISSN:2050-084X
DOI:10.7554/eLife.52300
Online-Zugang:Resolving-System, lizenzpflichtig, Volltext: https://doi.org/10.7554/eLife.52300
Volltext
Verfasserangaben:Pamina Kazman, Marie-Theres Vielberg, María Daniela Pulido Cendales, Lioba Hunziger, Benedikt Weber, Ute Hegenbart, Martin Zacharias, Rolf Köhler, Stefan Schönland, Michael Groll, Johannes Buchner
Beschreibung
Zusammenfassung:In systemic light chain amyloidosis, an overexpressed antibody light chain (LC) forms fibrils which deposit in organs and cause their failure. While it is well-established that mutations in the LC’s VL domain are important prerequisites, the mechanisms which render a patient LC amyloidogenic are ill-defined. In this study, we performed an in-depth analysis of the factors and mutations responsible for the pathogenic transformation of a patient-derived λ LC, by recombinantly expressing variants in E. coli. We show that proteolytic cleavage of the patient LC resulting in an isolated VL domain is essential for fibril formation. Out of 11 mutations in the patient VL, only one, a leucine to valine mutation, is responsible for fibril formation. It disrupts a hydrophobic network rendering the C-terminal segment of VL more dynamic and decreasing domain stability. Thus, the combination of proteolytic cleavage and the destabilizing mutation trigger conformational changes that turn the LC pathogenic.
Beschreibung:Gesehen am 11.03.2020
Beschreibung:Online Resource
ISSN:2050-084X
DOI:10.7554/eLife.52300

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