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

Schulte T, Chaves-Sanjuan A, Speranzini V, Sicking K, Milazzo M, 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, Fernández-Busnadiego R, Palladini G, Ricagno S

Nat Commun 15 (1) 6359 [2024-07-28; online 2024-07-28]

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.

PubMed 39069558

DOI 10.1038/s41467-024-50686-2

Crossref 10.1038/s41467-024-50686-2

pmc: PMC11284220
pii: 10.1038/s41467-024-50686-2
GENBANK: OR567864
PDB: AL59
PDB: 9FAA