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(L)s) 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(L)s 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. (C) 2020 Elsevier Ltd. All rights reserved.