Cryo-EM structure of cardiac amyloid fibrils from an immunoglobulin light chain AL amyloidosis patient.
case_report · Level V
Where this comes from
- Record sourced from PubMed, PMID 30894521.
- Also identified by DOI 10.1038/s41467-019-09133-w and PMC identifier 6427027.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Systemic light chain amyloidosis (AL) is a life-threatening disease caused by aggregation and deposition of monoclonal immunoglobulin light chains (LC) in target organs. Severity of heart involvement is the most important factor determining prognosis. Here, we report the 4.0 Å resolution cryo-electron microscopy map and molecular model of amyloid fibrils extracted from the heart of an AL amyloidosis patient with severe amyloid cardiomyopathy. The helical fibrils are composed of a single protofilament, showing typical 4.9 Å stacking and cross-β architecture. Two distinct polypeptide stretches (total of 77 residues) from the LC variable domain (V<sub>l</sub>) fit the fibril density. Despite V<sub>l</sub> high sequence variability, residues stabilizing the fibril core are conserved through different cardiotoxic V<sub>l</sub>, highlighting structural motifs that may be common to misfolding-prone LCs. Our data shed light on the architecture of LC amyloids, correlate amino acid sequences with fibril assembly, providing the grounds for development of innovative medicines.
Medical subject headings
- Amyloid
- Immunoglobulin Light Chains
- Immunoglobulin Light-chain Amyloidosis
- Myocardium
- Protein Aggregation, Pathological