The destabilization of transthyretin (TTR) tetramers underlies the pathogenesis of ATTR amyloidosis, a disease manifesting in form of toxic amyloid deposits. Here we investigate two clinically relevant TTR variants, H88R and I107V, found among ATTR patients in the Carpathian Basin. While the I107V mutation exerts only a mild effect on tetramer assembly and monomer stability, it decreases the denaturation midpoint and enhances aggregation propensity at physiological pH, against both wild-type and monomeric TTR (MTTR) backgrounds. Structural analysis revealed that the absence of the methyl group of residue 107 perturbs the hydrophobic trapping of F87 across the primary tetramerization interface. We also found that the far more disruptive H88R mutation that fully abolishes tetramer formation and yields a highly amyloidogenic monomer also acts through the disarray of the F87-centered inter-chain contact. Its equilibrium ensemble includes unfolded components and displays reduced denaturation entropy, traits suggestive of a primed aggregation-prone state. Simulations reveal that the H88R mutation leads to the partial disordering of the EF helix/loop, which in wild-type TTR participates in a Trp-cage-like architecture (centered on W79) shielding the hydrophobic core of the monomeric form. Our results suggest that the H88R variant may serve as a more physiologically relevant model of aggregation-prone TTR than the widely used MTTR double mutant, which does not show amyloidogenic propensity at physiological pH. Based on their physicochemical properties and position with respect to the determined interaction loci, we offer explanation for the phenotypic presentation of D18G, A25T, and Y114H and H88R monomerizing mutations.
Bódy et al. (Sat,) studied this question.