INTERACTION BETWEEN GLYCOSAMINOGLYCANS AND IMMUNOGLOBULIN LIGHT-CHAINS

Amyloidosis is a pathological process in which normally soluble protei ns polymerize to form insoluble fibrils (amyloid), Amyloid formation i s found in a number of diseases, including Alzheimer's disease, adult- onset diabetes, and light-chain-associated amyloidosis. No pharmaceuti cal methods currently exist to prevent this process or to remove the f ibrils from tissue. The search for treatment and prevention methods is hampered by a limited understanding of the biophysical basis of amylo id formation. Glycosaminoglycans (GAGs) are long, unbranched heteropol ysaccharides composed of repeating disaccharide subunits and are known to associate with amyloid fibrils. The interaction of amyloid-associa ted free light chains with GAGs was tested by both size-exclusion high -performance liquid chromatography and sodium dodecyl sulfate-polyacry lamide gel electrophoresis experiments, The results indicated that hep arin 16 000 and chondroitin sulfate B and C precipitated both human in tact light chains and recombinant light chain variable domains. Althou gh all light chains interacted with heparin, the strongest interaction s were obtained with proteins that had formed amyloid. Molecular model ing indicated the possibility of interaction between heparin and the c onserved saddlelike surface of the light chain dimer opposite the comp lementarity-determining segments that form part of the antigen-binding site of a functional antibody. This suggestion might offer a new path to block the aggregation of amyloid-associated light chain proteins, by design of antagonists based on properties of GAG binding. A hexasac charide was modeled as the basis for a possible antagonist.