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. (C) 1996 Academic Press Limited