Cryo-EM structure of cardiac amyloid fibrils from an immunoglobulin light chain AL amyloidosis patient

Paolo Swuec, Francesca Lavatelli, Masayoshi Tasaki, Cristina Paissoni, Paola Rognoni, Martina Maritan, Francesca Brambilla, Paolo Milani, Pierluigi Mauri, Carlo Camilloni, Giovanni Palladini, Giampaolo Merlini, Stefano Ricagno () and Martino Bolognesi ()
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Paolo Swuec: Università degli Studi di Milano
Francesca Lavatelli: University of Pavia
Masayoshi Tasaki: University of Pavia
Cristina Paissoni: Università degli Studi di Milano
Paola Rognoni: University of Pavia
Martina Maritan: Università degli Studi di Milano
Francesca Brambilla: Institute for Biomedical Technologies-CNR
Paolo Milani: University of Pavia
Pierluigi Mauri: Institute for Biomedical Technologies-CNR
Carlo Camilloni: Università degli Studi di Milano
Giovanni Palladini: University of Pavia
Giampaolo Merlini: University of Pavia
Stefano Ricagno: Università degli Studi di Milano
Martino Bolognesi: Università degli Studi di Milano

Nature Communications, 2019, vol. 10, issue 1, 1-9

Abstract: 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 (Vl) fit the fibril density. Despite Vl high sequence variability, residues stabilizing the fibril core are conserved through different cardiotoxic Vl, 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.

Date: 2019
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DOI: 10.1038/s41467-019-09133-w

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