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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, View ORCID ProfileMartino Bolognesi
doi: https://doi.org/10.1101/444901
Paolo Swuec
1Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy.
2Centro di Ricerca Pediatrica Romeo ed Enrica Invernizzi, Università degli Studi di Milano, 20133 Milano, Italy.
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Francesca Lavatelli
3Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, and Department of Molecular Medicine, University of Pavia, 27100, Pavia, Italy.
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Masayoshi Tasaki
3Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, and Department of Molecular Medicine, University of Pavia, 27100, Pavia, Italy.
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Cristina Paissoni
1Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy.
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Paola Rognoni
3Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, and Department of Molecular Medicine, University of Pavia, 27100, Pavia, Italy.
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Martina Maritan
1Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy.
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Francesca Brambilla
4Institute for Biomedical Technologies (ITB-CNR), 20090 Segrate, Italy.
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Paolo Milani
3Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, and Department of Molecular Medicine, University of Pavia, 27100, Pavia, Italy.
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Pierluigi Mauri
4Institute for Biomedical Technologies (ITB-CNR), 20090 Segrate, Italy.
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Carlo Camilloni
1Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy.
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Giovanni Palladini
3Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, and Department of Molecular Medicine, University of Pavia, 27100, Pavia, Italy.
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Giampaolo Merlini
3Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, and Department of Molecular Medicine, University of Pavia, 27100, Pavia, Italy.
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Stefano Ricagno
1Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy.
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  • For correspondence: stefano.ricagno@unimi.it martino.bolognesi@unimi.it
Martino Bolognesi
1Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy.
2Centro di Ricerca Pediatrica Romeo ed Enrica Invernizzi, Università degli Studi di Milano, 20133 Milano, Italy.
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  • ORCID record for Martino Bolognesi
  • For correspondence: stefano.ricagno@unimi.it martino.bolognesi@unimi.it
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Abstract

Systemic light chain (AL) amyloidosis 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 (cryo-EM) map and structural model of amyloid fibrils extracted from the heart of an AL patient affected by severe amyloid cardiomyopathy. The fibrils are composed of one asymmetric protofilament, showing typical 4.9 Å stacking and parallel cross-β architecture. Two distinct polypeptide stretches belonging to the LC variable domain (Vl) could be modelled in the density (total of 77 residues), stressing the role of the Vl domain in fibril assembly and LC aggregation. Despite high levels of Vl sequence variability, residues stabilising the observed fibril core are conserved through several Vl domains, highlighting structural motifs that may be common to misfolded LCs. Our data shed first light on the architecture of life-threatening LC amyloid deposits, and provide a rationale for correlating LC amino acid sequences and fibril structures.

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Posted October 17, 2018.
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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, Martino Bolognesi
bioRxiv 444901; doi: https://doi.org/10.1101/444901
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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, Martino Bolognesi
bioRxiv 444901; doi: https://doi.org/10.1101/444901

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