Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-019-09133-w
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Funding
- University of Milano
- Fondazione Romeo and Enrica Invernizzi
- Fondazione Cariplo [2015-0591, 2016-0489]
- Associazione Italiana per la Ricerca sul Cancro special program 5 per mille [9965]
- Italian Ministry of Health [RF-2013-02355259, RF-2016-02361756]
- Italian Medicines Agency [AIFA-2016-02364602]
- E-Rare JTC 2016 grant ReDox
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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 angstrom 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 angstrom stacking and cross-beta architecture. Two distinct polypeptide stretches (total of 77 residues) from the LC variable domain (V-l) fit the fibril density. Despite Vl high sequence variability, residues stabilizing the fibril core are conserved through different cardiotoxic V-l, 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.
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