bioRxiv [Preprint]. 2026 Aug 28:2026.08.24.746819. doi: 10.64898/2026.08.24.746819.
ABSTRACT
Immunoglobulin light chain (LC) amyloidosis is a debilitating multiorgan disease with limited treatment options. Sequence and structural variability make LC amyloids particularly challenging for therapeutic targeting. We report four cryo-EM structures of λ6-LC amyloid fibrils from four organs of two patients. Fibrils from different patients show different N-terminal conformations expanding known repertoire of λ6-LC amyloid folds. These folds contain a planar β-arch with a flexible linker containing the complementarity-determining region 2, flanked by N- and C-terminal segments in variable patient-specific conformations. The surface location of the structurally frustrated charged segment may contribute to the overrepresentation of the λ6-LC family in amyloidosis. These and other λ6-LC amyloid structures from different patients show different side chain packing. Conversely, cardiac, renal and splenic amyloids from the same patient exhibit similar structures with small peripheral organ-specific variations. Moreover, they show similar "orphan" densities, suggesting collagen-like triple helices bound to a tyrosine ladder along the fibril spine. Mass spectrometry detects collagen type-VI in tissue-extracted amyloids. Molecular dynamics simulations suggest amyloid binds collagen-VI triple helices via mixed interactions facilitated by the geometric complementarity between the layered amyloid structure and the triple helix. Similar interactions may drive formation of other amyloid-collagen complexes, influencing biological properties of amyloids.
PMID:42760916 | PMC:PMC13585027 | DOI:10.64898/2026.08.24.746819