The effect of G83R mutation on transthyretin protein structural stability

Transthyretin (TTR) G83R mutation can cause vitreous amyloidosis and severely impair vision. Further understanding of the effect of G83R mutation on TTR structure and stability will help to understand its pathogenesis. This study investigated the thermodynamic and dynamic stability and fibril formation of TTR G83R and compared it with wild-type TTR and V30M variants. The bioinformatics tools (NetSurfP 3.0, DynaMut, and Desmond) were used to explore the effect of G83R on TTR protein structural and dynamic stability. Explored the effect of G83R on TTR thermodynamic stability using urea-mediated resveratrol and tryptophan fluorescence. And the effect of G83R on 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 flexibility. In the thermodynamic stability, the quaternary and tertiary structural stability of TTR G83R is lower than wild-type TTR but significantly higher than TTR V30M. The fibril formation rate of TTR G83R under acidic conditions was between that of wild-type TTR and V30M variants. In summary, results from several different analyses in this study consistently demonstrate the thermodynamic and dynamic stability of G83R TTR decreases. The G83R mutation causes TTR tetramers to be more susceptible to depolymerisation and accelerates the formation of amyloid fibres.