Four structural risk factors identify most fibril-forming kappa light chains

Antibody light chains (LCs) comprise the most structurally diverse family o f proteins involved in amyloidosis. Many antibody LCs incorporate structura l features that impair their stability and solubility, leading to their ass embly into fibrils and to their subsequent pathological deposition when pro duced in excess during multiple myeloma and primary amyloidosis. The partic ular amino acid variations in antibody LCs that account for fibril formatio n and amyloidogenesis have not been identified. This study focuses on amylo idogenesis within the kappa 1 family of human LCs. Reanalysis of the curren t database of primary structures of proteins from more than 100 patients wh o produced kappa 1 LCs, 37 of which were amyloidogenic, reveals apparent st ructural features that may contribute to amyloidosis. These features includ e loss of conserved residues or the gain of particular residues through mut ation at sites involving a repertoire of approximately 20% of the amino aci d positions in the light chain variable domain (V-L). Moreover, 80% of all kappa 1 amyloidogenic V(L)s are identifiable by the presence of at least on e of three single-site substitutions or the acquisition of an N-linked glyc osylation site through mutations. These findings suggest that it is feasibl e to predict fibril propensity by analysis of primary structure.