Driving forces in amyloidosis: How does a light chain make a heavy heart?

Light-chain amyloidosis (AL) is a fatal disorder wherein the immunoglobulin light chain misfolds and aggregates, leading to amyloid plaques in various organs. Patient-specific mutations in the light chain variable domain (V) are tightly linked to amyloidosis, but how these mutations drive AL is unknown. In recent work, Rottenaicher et al. analyze five mutations found in the V of a patient with cardiac AL. Their data suggest that decreased V stability and increased flexibility in the core of the V, caused by mutations outside of this core, could be key to aggregation and highlight the delicate balancing act required for antibody maturation to enable antigen recognition while not altering protein biophysics.