Fig. 4

Proposed model of mutational effect on TTR stability. Shorter arrows indicate a lower propensity to association/folding. Red arrows reflect the qualitative change in reaction rates for the mutants with respect to WT-TTR. a The S52P mutation increases the likelihood of partial and full unfolding of TTR monomeric units. This, in turn, also leads to a lower stability of TTR multimeric assemblies; hence partially unfolded dimers and monomers, and fully unfolded monomers, are generated at a higher rate. Some or all of these species are then removed from solution via the formation of amyloid fibrils. b In contrast to S52P, the T119M mutation stabilises the folded monomeric forms of TTR. Most importantly, this mutation has a large stabilising effect on TTR tetramers, which are believed not to form fibrils. Furthermore, it is proposed that the higher stability of the tetramer also has the effect of further stabilising the monomer fold