biostudies-literatureUnknownHicks CWNIGMS NIH HHSNIH HHSIn 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 Å resolution) from λ6-LC family, which is overrepresented in amyloidosis. Comparison with λ6-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 λ6-LC amyloid folds and reveal how mutation-induced structural changes influence amyloid-ligand interactions in a patient-specific manner.bioRxiv : the preprint server for biology2025.06.25.661559https://www.ebi.ac.uk/biostudies/studies/S-EPMC12236830biostudies-literatureCryo-EM of cardiac AL-224L amyloid reveals shared features in λ6 light chain fibril folds.PMC12236830S10 OD032253R01 GM135158R01 GM067260Hicks CWWong SHuda NProkaeva TGursky OLavatelli FJayaraman SChen HSpencer BSanchorawala VfalseCryo-EM of cardiac AL-224L amyloid reveals shared features in λ6 light chain fibril folds.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 Å resolution) from λ6-LC family, which is overrepresented in amyloidosis. Comparison with λ6-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 λ6-LC amyloid folds and reveal how mutation-induced structural changes influence amyloid-ligand interactions in a patient-specific manner.2025-01-01T00:00:00Z2025 Jul2025-08-23T03:09:19.317Z2025-08-23T03:09:19.317ZS-EPMC122368304063113110.1101/2025.06.25.661559