Local disorder of transthyretin modulates its aggregation-prone propensity

Abstract

Transthyretin (TTR), in its native tetrameric state, is an essential transporter of thyroxine and holo-retinol binding protein for human. However, its dissociation into the mis-folded monomer facilitates abnormal aggregation of TTR, causing deposition of TTR aggregates typically in the peripheral nervous system or in the heart. Although numerous studies were conducted to elucidate the aggregation mechanism of TTR, it is still elusive which structural features are actually responsible for its aggregation. Here, we determined with nuclear magnetic resonance (NMR) spectroscopy the three-dimensional structures of the two TTR variants: amyloidogenic monomeric TTR and its less-amyloidogenic variant, T119M. Distinctive to the native tetrameric state, the misfolded monomer of TTR presented structural features in which the C-terminal beta-strand is released and the neighboring loops are perturbed. On the other hand, introduction of T119M mutation caused non-native rearrangement of the beta-strand structure; it appears that this mutation damped conformational fluctuations of the C-terminal beta-strand, which is known to be important for TTR aggregation. Finally, we also found that Hsp90 interacts with monomeric TTR more strongly than with tetrameric TTR. Taken together, our results provide the atomistic detail to explain the elevated susceptibility of monomeric TTR for aggregation, as well as the novel insight to develop therapeutic strategies for TTR amyloidosis.