Four structural risk factors identify most fibril-forming kappa light chains.
Antibody light chains (LCs) comprise the most structurally diverse family of proteins involved in amyloidosis. Many antibody LCs incorporate structural features that impair their stability and solubility, leading to their assembly into fibrils and to their subsequent pathological deposition when produced in excess during multiple myeloma and primary amyloidosis. The particular amino acid variations in antibody LCs that account for fibril formation and amyloidogenesis have not been identified. This study focuses on amyloidogenesis within the kappa1 family of human LCs. Reanalysis of the current database of primary structures of proteins from more than 100 patients who produced kappa1 LCs, 37 of which were amyloidogenic, reveals apparent structural features that may contribute to amyloidosis. These features include loss of conserved residues or the gain of particular residues through mutation at sites involving a repertoire of approximately 20% of the amino acid positions in the light chain variable domain (V(L)). Moreover 80% of all kappa1 amyloidogenic V(L)s are identifiable by the presence of at least one of three single-site substitutions or the acquisition of an N-linked glycosylation site through mutations. These findings suggest that it is feasible to predict fibril propensity by analysis of primary structure.
Stevens
F J
FJ
Biosciences Division, Argonne National Laboratory, IL 60439-3883 USA. stevens@anlcmb.bim.anl.gov
D000544:Alzheimer Disease / Q000378:metabolism; D019943:Amino Acid Substitution; D000682:Amyloid / Q000737:chemistry*; D000686:Amyloidosis / Q000378:metabolism; D016208:Databases, Factual; D006031:Glycosylation; D006801:Humans; D007145:Immunoglobulin kappa-Chains / Q000737:chemistry* / Q000235:genetics; D009194:Myeloma Proteins / Q000737:chemistry* / Q000235:genetics; D017354:Point Mutation; D011499:Protein Processing, Post-Translational; D012307:Risk Factors
D000682:Amyloid; D007145:Immunoglobulin kappa-Chains; D009194:Myeloma Proteins