Cryo-EM of cardiac AL-224L amyloid reveals shared features in {lambda}6 light chain fibril folds

Hicks, C. W.; Prokaeva, T.; Spencer, B.; Jayaraman, S.; Huda, N.; Wong, S.; Chen, H.; Sanchorawala, V.; Lavatelli, F.; Gursky, O.

doi:10.1101/2025.06.25.661559

bioRxiv · 10.1101/2025.06.25.661559

Cryo-EM of cardiac AL-224L amyloid reveals shared features in {lambda}6 light chain fibril folds

Hicks, C. W.·Prokaeva, T.·Spencer, B.·Jayaraman, S.·Huda, N.·Wong, S.·Chen, H.·Sanchorawala, V.·Lavatelli, F.·Gursky, O.

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Abstract

In amyloid light chain (AL) amyloidosis, aberrant monoclonal antibody light chains (LCs) deposit in vital organs causing organ damage. Each AL patient features a unique LC. Previous cryogenic electron microscopy (cryo-EM) studies revealed different amyloid structures in different AL patients. How LC mutations influence amyloid structures remains unclear. We report a cryo-EM structure of cardiac AL-224L amyloid (2.92 [A] resolution) from {lambda}6-LC family, which is overrepresented in amyloidosis. Comparison with {lambda}6-LC structures from two other patients reveals similarities in amyloid folds. Mutation-induced structural differences in AL-224L include altered C-terminal conformation with an exposed ligand-binding surface; an enlarged hydrophilic pore with orphan density; and altered steric zipper registry with backbone flipping, which likely represent general adaptive mechanisms in amyloids. The results suggest shared features in {lambda}6-LC amyloid folds and reveal how mutation-induced structural changes influence amyloid-ligand interactions in a patient-specific manner.

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Hicks, C. W., Prokaeva, T., Spencer, B., Jayaraman, S., Huda, N., Wong, S., Chen, H., Sanchorawala, V., Lavatelli, F., Gursky, O.. 2025-06-27. Cryo-EM of cardiac AL-224L amyloid reveals shared features in {lambda}6 light chain fibril folds. https://doi.org/10.1101/2025.06.25.661559

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