Helical superstructures between amyloid and collagen VI in heart-derived fibrils from a patient with Light Chain Amyloidosis

Authors

Ricagno S, Schulte T, Chaves-Sanjuan A, Speranzini V, Sicking K, Mazzini G, Rognoni P, Caminito S, Milani P, Marabelli C, Corbelli A, Diomede L, Fiordaliso F, Anastasia L, Pappone C, Merlini G, Bolognesi M, Nuvolone M, Fernandez-Busnadiego R, Palladini G

Journal

Research Square

Citation

Research Square 2023. 20 Nov 2023.

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. Its structure displays a stable core and two flexible segments adopting alternative conformations. Two confirmations are sterically incompatible and typically distributed on separate fibrils. Noteworthy, the fibril core 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 the first structural evidence of interactions between amyloid and collagen, potentially signifying a novel pathophysiological mechanism of amyloid deposits.

DOI

10.21203/rs.3.rs-3625869/v1