Cryo-EM of Cardiac AL-224L Amyloid Reveals Shared Structural Motifs and Mutation-induced Differences in λ6 Light Chain Fibrils.

In light chain amyloidosis (AL), 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 à resolution) from λ6-LC family, which is overrepresented in AL amyloidosis. Comparison with λ6-LC structures from two other patients reveals similarities in amyloid folds, along with major differences caused by specific mutations. Differences in AL-224L include altered C-terminal conformation with an exposed surface forming an apparent ligand-binding site; 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 reveal shared features in λ6-LC amyloid folds and suggest how mutation-induced structural changes influence amyloid-ligand interactions in a patient-specific manner.