Specificity of abnormal assembly in immunoglobulin light chain deposition disease and amyloidosis

Although both light chain amyloidosis (AL) and deposition disease (LCDD) involve the aggregation of light chain V(L) domains into highly insoluble deposits, the factors which determine both disease onset and type (amyloid fibrils (AL) or granular deposits (LCDD)) are not clear. Previously, we showed that the AL-associated replacement Arg61 --> Asn, introduced as a point mutation into the kappa V(L) domain REI, greatly destabilizes the domain and renders it susceptible to the formation of ordered, fibril-like aggregates in vitro. The importance of Arg61 for stability may be due to the role of this residue in making a key, conserved salt bridge with Asp82 located on an adjacent loop. Here we show that an Asp82 --> Ile replacement, recently identified in a V(L) associated with LCDD, also highly destabilizes REI as a point mutation and makes it susceptible to in vitro aggregate formation. The D82I aggregate, however, is dramatically different in morphology from aggregates obtained from amyloid-associated mutants, suggesting that specific amino acid residue changes can control not only the onset of aggregation disease but also aggregate morphology and disease type.