Cryo-EM reveals patient- versus organ-specific structural diversity and bound ligands in lambda-6 light chain amyloids

Huda, N.; Spencer, B.; Hicks, C. W.; JAYARAMAN, S.; Pantelopulos, G. A.; Wong, S.; Chen, H.; Best, R.; Sanchorawala, V.; Lavatelli, F.; Prokaeva, T.; Gursky, O.

doi:10.64898/2026.08.24.746819

bioRxiv · 10.64898/2026.08.24.746819

Cryo-EM reveals patient- versus organ-specific structural diversity and bound ligands in lambda-6 light chain amyloids

Huda, N.·Spencer, B.·Hicks, C. W.·JAYARAMAN, S.·Pantelopulos, G. A.·Wong, S.·Chen, H.·Best, R.·Sanchorawala, V.·Lavatelli, F.·Prokaeva, T.·Gursky, O.

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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 lambda6-LC amyloid fibrils from four organs of two patients. Fibrils from different patients show different N-terminal conformations expanding known repertoire of lambda6-LC amyloid folds. These folds contain a planar beta-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 lambda6-LC family in amyloidosis. These and other lambda6-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.

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Huda, N., Spencer, B., Hicks, C. W., JAYARAMAN, S., Pantelopulos, G. A., Wong, S., Chen, H., Best, R., Sanchorawala, V., Lavatelli, F., Prokaeva, T., Gursky, O.. 2026-08-25. Cryo-EM reveals patient- versus organ-specific structural diversity and bound ligands in lambda-6 light chain amyloids. https://doi.org/10.64898/2026.08.24.746819

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