Dynamic of beta(2)-microglobulin fibril formation and reabsorption: The role of proteolysis

Dialysis-related amyloidosis (DRA) is caused by the deposition, in target t issues, of beta (2)-microglobulin (beta M-2) in fibrillar conformation. Sev eral reports indicate that fibrillar beta M-2 is chemically heterogeneous a nd such heterogeneity is partially related to the presence of truncated spe cies of the protein. In association with the full-length species, a beta M- 2 isoform lacking six N-terminal residues is present in all the samples of our collection of ex vivo fibrils. The pattern of proteolytic cleavage in a myloidosis and in other diseases is completely different, as demonstrated b y the absence in fibrillar beta M-2 of the cleavage at lysine 58, which is contrary to that described in rheumatoid arthritis and other diseases. The role of limited proteolysis of beta M-2 in the pathogenesis of the disease is uncertain. However, we have shown that the apparently minor modification of the intact protein, such as the removal of N-terminal hexapeptide, is c apable of dramatically affecting its stability, protection from proteolytic digestion, and enhance its capacity to make in vitro amyloid fibrils. The structure, folding dynamic, and function of the truncated species of beta M -2, peculiar of DRA, could shed new light on the mechanism of beta M-2 fibr il formation and reabsorption.