Journal: Nat Commun / Year: 2024 Title: Helical superstructures between amyloid and collagen in cardiac fibrils from a patient with AL amyloidosis. Authors: Tim Schulte / Antonio Chaves-Sanjuan / Valentina Speranzini / Kevin Sicking / Melissa Milazzo / Giulia Mazzini / Paola Rognoni / Serena Caminito / Paolo Milani / Chiara Marabelli / ...Authors: 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 / Stefano Ricagno / 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 ...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.
Aggregation state: FILAMENT / 3D reconstruction method: helical reconstruction
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Sample preparation
Component
Name: Monoclonal immunoglobulin light chains (LC), fibrillar form Type: TISSUE Details: Amyloid fibrils extracted ex vivo from cardiac tissue of AL patient Entity ID: #1 / Source: NATURAL
Source (natural)
Organism: Homo sapiens (human)
Buffer solution
pH: 7
Specimen
Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Vitrification
Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE
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Electron microscopy imaging
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
Microscopy
Model: FEI TALOS ARCTICA
Electron gun
Electron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lens
Mode: BRIGHT FIELD / Nominal magnification: 120000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 500 nm
Image recording
Electron dose: 40 e/Å2 / Detector mode: COUNTING / Film or detector model: FEI FALCON III (4k x 4k) / Num. of real images: 2049
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