Abstract
Transthyretin (TTR) G83R mutation can cause vitreous amyloidosis and severely impair vision. Further understanding of the effect of G83R mutation on the TTR structure and stability will help to understand its pathogenesis. This study investigated the thermodynamic and dynamic stabilities, as well as fibril formation, of TTR G83R and compared them with those of wild-type TTR and V30 M variants. Bioinformatics tools (NetSurfP 3.0, DynaMut2, and Desmond) were used to explore the effect of G83R on the TTR protein structural and dynamic stabilities. We explored the effect of G83R on TTR thermodynamic stability using urea-mediated resveratrol and tryptophan fluorescence. The effect of G83R affects TTR aggregation and fibril formation in acidic environments. Molecular dynamics simulation suggested that the G83R mutation reduces the dynamic stability of TTR by increasing the molecule's flexibility. Regarding thermodynamic stability, the quaternary and tertiary structural stabilities of TTR G83R are significantly lower than those of wild-type TTR but higher than those of TTR V30M. The fibril formation rate of TTR G83R under acidic conditions was between those of wild-type TTR and V30 M variants. In summary, the results from several different analyses in this study consistently demonstrate that the thermodynamic and dynamic stabilities of TTR G83R decrease. The G83R mutation makes TTR tetramers more susceptible to depolymerization and accelerates the formation of amyloid fibers.