Decreased Thermodynamic Stability as a Crucial Factor for Familial Amyloidotic Polyneuropathy

Abstract A single mutation in the wild-type transthyretin (WT TTR) such as V30M causes a familial amyloidotic polyneuropathy disease. Comparison of the three-dimensional crystal structures of WT and V30M does not tell much about the reason. High-pressure NMR revealed that at neutral pH both WT and V30M exist as equilibrium between the native tetramer and the dissociated/unfolded monomer. The native tetramer is highly stable in WT ( Δ G 0 =104 kJ/mol at 37 °C, pH 7.1), but the stability is significantly reduced in V30M ( ΔΔ G 0 =−18 kJ/mol ), increasing the fraction of the unfolded monomer by a 1000-fold. Significant reduction of thermodynamic stability of WT TTR by mutation could be a crucial factor for familial amyloidotic polyneuropathy.