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

Light chain amyloidosis (AL) is a fatal disorder wherein immunoglobulin light chain misfolds and aggregates, leading to amyloid plaques in various organs. Patient-specific mutations in the antibody VL domain 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 variable (VL ) domain of a cardiac AL patient. Their data suggest that decreased VL stability and increased flexibility in the core of VL , 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.