The effect of G83R mutation on transthyretin protein structural stability

Transthyretin (TTR) G83R mutation can cause vitreous amyloidosis and severely impair vision. TTR variant aggregation and amyloid formation are known to be associated with transthyretin amyloidosis. However, the mechanism underlying the pathological aggregation process of TTR G83R remains elusive. Further understanding of the effect of G83R mutation on TTR structure and stability will help to understand its pathogenesis. This study investigated thermodynamic and dynamic stability and fibril formation of TTR G83R and compared it with WT TTR and V30M variant. The results show that the quaternary and tertiary structural stability of TTR G83R is lower than WT TTR but significantly higher than TTR V30M. The fibril formation rate of TTR G83R under acidic conditions was between that of WT TTR and V30M variants. Molecular dynamics simulation suggested that G83R mutation mainly affected the stability of TTR tetramer, especially in an acidic environment. In summary, results from several different analyses in this study consistently demonstrate the thermodynamic and kinetic instability of G83R TTR in denaturant and acidic environments. The effect of G83R mutation on TTR stability is mainly tetramer dissociation, which may accelerate the aggregation of monomers to a certain extent. These results strongly suggest that the G83R mutation increases the amyloidosis potential inherent in TTR.