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 A 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 A 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. Immunoglobulin Light Chain Amyloidosis (AL) is the most common systemic amyloidosis occurring in Western countries. Here the authors present the 4.0 A cryo-EM structure of light chain AL55 fibrils that were isolated from the heart of an AL systemic amyloidosis patient.
Highlights
Systemic light chain amyloidosis (AL) is a life-threatening disease caused by aggregation and deposition of monoclonal immunoglobulin light chains (LC) in target organs
We show that the ex vivo fibrils are composed of an asymmetric protofilament hosting 77 residues from the LC variable domain (Vl) domain, coupled to two low-order regions that comprise about one-third of the Vl domain and portions of the Cl domain
Fibrils were isolated from left ventricle specimens acquired during autopsy from a male patient affected by AL λ amyloidosis, with severe amyloid cardiomyopathy
Summary
Systemic light chain amyloidosis (AL) is a life-threatening disease caused by aggregation and deposition of monoclonal immunoglobulin light chains (LC) in target organs. We present the cryo-EM structure, at 4.0 Å overall resolution, of ex vivo LC fibrils extracted from the heart of a patient affected by severe AL cardiac amyloidosis.
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