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

ABSTRACT: The dataset contains a .raw file of the total mass analysis of FOR001, 23 .raw/MzXML files of protease digested FOR001 used for PEAKS X investigations and eight .raw files of protease digested FOR001 used for PEAKS AB de novo sequencing.

INSTRUMENT(S): LTQ Orbitrap Velos Pro, LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Julian Baur

PROVIDER: MSV000089773 | MassIVE | Thu Jun 30 05:07:00 BST 2022

REPOSITORIES: MassIVE

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

Project description: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. Systemic AL amyloidosis is caused by misfolding of immunoglobulin light chains (LCs) but how post-translational modifications (PTMs) of LCs influence amyloid formation is not well understood. Here, the authors present the cryo-EM structure of an AL amyloid fibril derived from the heart tissue of a patient that is partially pyroglutamylated, N-glycosylated and contains an intramolecular disulfide bond. Based on their structure and biochemical experiments the authors conclude that the mutational changes, disulfide bond and glycosylation determine the fibril protein fold and that glycosylation protects the fibril core from proteolytic degradation.

| S-EPMC8571268 | biostudies-literature

Cryo-EM fibril structures from systemic AA amyloidosis reveal the species complementarity of pathological amyloids.

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Cryo-EM reveals structural breaks in a patient-derived amyloid fibril from systemic AL amyloidosis.

Project description:Systemic AL amyloidosis is a debilitating and potentially fatal disease that arises from the misfolding and fibrillation of immunoglobulin light chains (LCs). The disease is patient-specific with essentially each patient possessing a unique LC sequence. In this study, we present two ex vivo fibril structures of a λ3 LC. The fibrils were extracted from the explanted heart of a patient (FOR005) and consist of 115-residue fibril proteins, mainly from the LC variable domain. The fibril structures imply that a 180° rotation around the disulfide bond and a major unfolding step are necessary for fibrils to form. The two fibril structures show highly similar fibril protein folds, differing in only a 12-residue segment. Remarkably, the two structures do not represent separate fibril morphologies, as they can co-exist at different z-axial positions within the same fibril. Our data imply the presence of structural breaks at the interface of the two structural forms.

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Identification of AL proteins from 10 lambda AL amyloidosis patients by mass spectrometry extracted from abdominal fat and heart tissue

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inSPIRE Spectral Rescoring Tool

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