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

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 and Marcus Fändrich ()
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Lynn Radamaker: Institute of Protein Biochemistry, Ulm University
Sara Karimi-Farsijani: Institute of Protein Biochemistry, Ulm University
Giada Andreotti: Institute of Protein Biochemistry, Ulm University
Julian Baur: Institute of Protein Biochemistry, Ulm University
Matthias Neumann: Institute of Stochastics, Ulm University
Sarah Schreiner: Medical Department V, Section of Multiple Myeloma, Heidelberg University Hospital
Natalie Berghaus: Medical Department V, Section of Multiple Myeloma, Heidelberg University Hospital
Raoul Motika: Middle Eastern History and Culture, University of Hamburg
Christian Haupt: Institute of Protein Biochemistry, Ulm University
Paul Walther: Central Facility for Electron Microscopy, Ulm University
Volker Schmidt: Institute of Stochastics, Ulm University
Stefanie Huhn: Medical Department V, Section of Multiple Myeloma, Heidelberg University Hospital
Ute Hegenbart: Medical Department V, Amyloidosis Center, Heidelberg University Hospital
Stefan O. Schönland: Medical Department V, Amyloidosis Center, Heidelberg University Hospital
Sebastian Wiese: Core Unit Mass Spectrometry and Proteomics, Medical Faculty, Ulm University
Clarissa Read: Central Facility for Electron Microscopy, Ulm University
Matthias Schmidt: Institute of Protein Biochemistry, Ulm University
Marcus Fändrich: Institute of Protein Biochemistry, Ulm University

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-26553-9

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