Domain Interactions Determine the Amyloidogenicity of Antibody Light Chain Mutants

In antibody light chain amyloidosis (AL), mutant light chains (LCs) or their variable domains (V_Ls) form fibrils, which accumulate in organs and lead to their failure. The molecular mechanism of this disease is still poorly understood. One of the key open issues is whether the mutant V_Ls and LCs differ in fibril formation. We addressed this question studying the effects of the V_L mutations S20N and R61A within the isolated V_L domain and in the full-length LC scaffold. Both V_L variants readily form fibrils. Here, we find that in the LC context, the S20N variant is protected from fibril formation while for LC R61A fibril formation is even accelerated compared to V_L R61A. Our analyses revealed that the partially unfolded state of the V_L R61A domain destabilizes the C_L domain by non-native interactions, in turn leading to a further unfolding of the V_L domain. In contrast, the folded mutant V_L S20N and V_L wt form native interactions with C_L. These are beneficial for LC stability and promote amyloid resistance. Thus the effects of specific mutations on the V_L fold can have opposing effects on LC domain interactions, stability and amyloidogenicity.