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

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.
Authors	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, Martino Bolognesi
Journal	Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 1269 (03 20 2019) ISSN: 2041-1723 [Electronic] England
PMID	30894521 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Amyloid Immunoglobulin Light Chains
Topics	Aged Amino Acid Sequence Amyloid (immunology, metabolism, ultrastructure) Autopsy Cryoelectron Microscopy Humans Immunoglobulin Light Chains (immunology, metabolism, ultrastructure) Immunoglobulin Light-chain Amyloidosis (diagnosis, immunology, metabolism, pathology) Male Myocardium (immunology, metabolism, pathology, ultrastructure) Protein Aggregation, Pathological (diagnosis, immunology, metabolism, pathology) Protein Conformation, beta-Strand Protein Folding Sequence Alignment Sequence Homology, Amino Acid Severity of Illness Index

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