Helical superstructures between amyloid and collagen in cardiac fibrils from a patient with AL amyloidosis

Tim Schulte, Antonio Chaves-Sanjuan, Valentina Speranzini, Kevin Sicking, Melissa Milazzo, Giulia Mazzini, Paola Rognoni, Serena Caminito, Paolo Milani, Chiara Marabelli, Alessandro Corbelli, Luisa Diomede, Fabio Fiordaliso, Luigi Anastasia, Carlo Pappone, Giampaolo Merlini, Martino Bolognesi, Mario Nuvolone, Rubén Fernández-Busnadiego, Giovanni Palladini and Stefano Ricagno ()
Additional contact information
Tim Schulte: IRCCS Policlinico San Donato
Antonio Chaves-Sanjuan: Università degli Studi di Milano
Valentina Speranzini: Università degli Studi di Milano
Kevin Sicking: Institute for Neuropathology
Melissa Milazzo: Università degli Studi di Milano
Giulia Mazzini: Università Degli Studi di Pavia
Paola Rognoni: Università Degli Studi di Pavia
Serena Caminito: Università Degli Studi di Pavia
Paolo Milani: Università Degli Studi di Pavia
Chiara Marabelli: Università degli Studi di Milano
Alessandro Corbelli: Istituto di Ricerche Farmacologiche Mario Negri IRCCS
Luisa Diomede: Istituto di Ricerche Farmacologiche Mario Negri IRCCS
Fabio Fiordaliso: Istituto di Ricerche Farmacologiche Mario Negri IRCCS
Luigi Anastasia: IRCCS Policlinico San Donato
Carlo Pappone: IRCCS Policlinico San Donato
Giampaolo Merlini: Università Degli Studi di Pavia
Martino Bolognesi: Università degli Studi di Milano
Mario Nuvolone: Università Degli Studi di Pavia
Rubén Fernández-Busnadiego: Institute for Neuropathology
Giovanni Palladini: Università Degli Studi di Pavia
Stefano Ricagno: IRCCS Policlinico San Donato

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract Systemic light chain (LC) amyloidosis (AL) is a disease where organs are damaged by an overload of a misfolded patient-specific antibody-derived LC, secreted by an abnormal B cell clone. The high LC concentration in the blood leads to amyloid deposition at organ sites. Indeed, cryogenic electron microscopy (cryo-EM) has revealed unique amyloid folds for heart-derived fibrils taken from different patients. Here, we present the cryo-EM structure of heart-derived AL amyloid (AL59) from another patient with severe cardiac involvement. The double-layered structure displays a u-shaped core that is closed by a β-arc lid and extended by a straight tail. Noteworthy, the fibril harbours an extended constant domain fragment, thus ruling out the variable domain as sole amyloid building block. Surprisingly, the fibrils were abundantly concatenated with a proteinaceous polymer, here identified as collagen VI (COLVI) by immuno-electron microscopy (IEM) and mass-spectrometry. Cryogenic electron tomography (cryo-ET) showed how COLVI wraps around the amyloid forming a helical superstructure, likely stabilizing and protecting the fibrils from clearance. Thus, here we report structural evidence of interactions between amyloid and collagen, potentially signifying a distinct pathophysiological mechanism of amyloid deposits.

Date: 2024
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DOI: 10.1038/s41467-024-50686-2

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