Acceleration of carbonic anhydrase amyloid aggregation leads to a decrease in the fibrils toxicity.

Cells damage by protein aggregates is one of the causes of amyloid diseases. This study aimed to explore the structural features of cytotoxic amyloid fibrils and to find strategies to reduce their damaging effect. Bovine carbonic anhydrase B (BCAB) was chosen for this work due to high toxicity of its amyloid fibrils. The kinetics of amyloid formation, structural features and cytotoxicity of mature fibrils and early globular aggregates formed by wild type protein and six mutant variants have been investigated. The results showed that an increase in residue hydrophobicity accelerates amyloid aggregation, but the formed fibrils have a reduced content of cross-β-structure and are non-toxic to cells. On the contrary, a decrease in hydrophobicity due to the L139A substitution and slowing the initiation of aggregation leads to the formation of highly toxic oligomers during the lag-period. Thus, the data obtained conclude that accelerating amyloid formation can alter the structure of amyloid aggregates and decrease their cytotoxicity.