Both the environment and somatic mutations govern the aggregation pathway of pathogenic immunoglobulin light chain

lDeposition of monoclonal immunoglobulin light chain (LC) aggregates in tis sues is the hallmark of a class of fatal diseases with no effective treatme nt. In the most prevalent diseases two different types of LC aggregates are observed: fibrillar deposits in LC amyloidosis (AL) and granular aggregate s in LC deposition disease (LCDD). The mechanisms by which a given LC forms either type of aggregate are not understood. Although some LCs are more ag gregation-prone than others, this does not appear to be due to specific seq uence determinants, but more likely from global properties that can be intr oduced by multiple somatic mutations. Moreover, a single LC isotype can som etimes form both fibrillar and granular aggregates within the same patient. To better understand how the different aggregation pathways arise, we deve loped a series of in vitro assays to analyze the formation of distinct aggr egate types. The recombinant kappa IV LC (SMA) assembles into fibrils when agitated. We now show that SMA can also form granular aggregates upon expos ure to copper, and that this aggregation can occur not only in vitro, but a lso in cells. A constellation of somatic mutations, consisting of His89/His 94/Gln96, is sufficient to confer sensitivity to copper on wild-type kappa IV proteins. The formation of both types of aggregates is inhibited by synt hetic peptides derived from the LC variable domain. However, the peptide th at inhibits fibrillar aggregation is different from the peptide that inhibi ts copper-induced aggregation. Thus, distinct molecular surfaces of the LC underly each type of aggregate. We conclude that both the intrinsic propert ies of the sequence and extrinsic conditions govern the aggregation pathway of a LC. (C) 2001 Academic Press.