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; Marcus Fändrich

doi:10.1038/s41467-021-26553-9

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, Marcus Fändrich^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	6434
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-26553-9
Publication status	Published - 1 Dec 2021
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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Radamaker, L., Karimi-Farsijani, S., Andreotti, G., Baur, J., Neumann, M., Schreiner, S., Berghaus, N., Motika, R., Haupt, C., Walther, P., Schmidt, V., Huhn, S., Hegenbart, U., Schönland, S. O., Wiese, S., Read, C., Schmidt, M., & Fändrich, M. (2021). Role of mutations and post-translational modifications in systemic AL amyloidosis studied by cryo-EM. Nature Communications, 12(1), Article 6434. https://doi.org/10.1038/s41467-021-26553-9

Radamaker, L, Karimi-Farsijani, S, Andreotti, G, Baur, J, Neumann, M, Schreiner, S, Berghaus, N, Motika, R, Haupt, C, Walther, P, Schmidt, V, Huhn, S, Hegenbart, U, Schönland, SO, Wiese, S, Read, C, Schmidt, M & Fändrich, M 2021, 'Role of mutations and post-translational modifications in systemic AL amyloidosis studied by cryo-EM', Nature Communications, vol. 12, no. 1, 6434. https://doi.org/10.1038/s41467-021-26553-9

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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.",

author = "Lynn Radamaker and Sara Karimi-Farsijani and Giada Andreotti and Julian Baur and Matthias Neumann and Sarah Schreiner and Natalie Berghaus and Raoul Motika and Christian Haupt and Paul Walther and Volker Schmidt and Stefanie Huhn and Ute Hegenbart and Sch{\"o}nland, {Stefan O.} and Sebastian Wiese and Clarissa Read and Matthias Schmidt and Marcus F{\"a}ndrich",

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AU - Radamaker, Lynn

AU - Karimi-Farsijani, Sara

AU - Andreotti, Giada

AU - Baur, Julian

AU - Neumann, Matthias

AU - Schreiner, Sarah

AU - Berghaus, Natalie

AU - Motika, Raoul

AU - Haupt, Christian

AU - Walther, Paul

AU - Schmidt, Volker

AU - Huhn, Stefanie

AU - Hegenbart, Ute

AU - Schönland, Stefan O.

AU - Wiese, Sebastian

AU - Read, Clarissa

AU - Schmidt, Matthias

AU - Fändrich, Marcus

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AB - 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.

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JO - Nature Communications

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

Abstract

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