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

Nat Commun. 2021 Nov 5;12(1):6434. doi: 10.1038/s41467-021-26553-9.

Authors

Lynn Radamaker¹, Sara Karimi-Farsijani¹, Giada Andreotti¹, Julian Baur¹, Matthias Neumann², Sarah Schreiner³, Natalie Berghaus³, Raoul Motika⁴, Christian Haupt¹, Paul Walther⁵, Volker Schmidt², Stefanie Huhn³, Ute Hegenbart⁶, Stefan O Schönland⁶, Sebastian Wiese⁷, Clarissa Read^{5

8}, Matthias Schmidt¹, Marcus Fändrich⁹

Affiliations

¹ Institute of Protein Biochemistry, Ulm University, 89081, Ulm, Germany.
² Institute of Stochastics, Ulm University, 89081, Ulm, Germany.
³ Medical Department V, Section of Multiple Myeloma, Heidelberg University Hospital, 69120, Heidelberg, Germany.
⁴ Department of Asia-Africa-Studies, Middle Eastern History and Culture, University of Hamburg, 20148, Hamburg, Germany.
⁵ Central Facility for Electron Microscopy, Ulm University, 89081, Ulm, Germany.
⁶ Medical Department V, Amyloidosis Center, Heidelberg University Hospital, 69120, Heidelberg, Germany.
⁷ Core Unit Mass Spectrometry and Proteomics, Medical Faculty, Ulm University, 89081, Ulm, Germany.
⁸ Institute of Virology, Ulm University Medical Center, 89081, Ulm, Germany.
⁹ Institute of Protein Biochemistry, Ulm University, 89081, Ulm, Germany. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cryoelectron Microscopy
Glycosylation
Immunoglobulin Light-chain Amyloidosis / genetics
Immunoglobulin Light-chain Amyloidosis / metabolism*
Mutation
Protein Conformation
Protein Folding