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.
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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