Abstract
Transthyretin (TTR) is an essential transporter of a thyroid hormone and a holo-retinol binding protein, found abundantly in human plasma and cerebrospinal fluid. In addition, this protein is infamous for its amyloidogenic propensity, causing various amyloidoses in humans, such as senile systemic amyloidosis, familial amyloid polyneuropathy, and familial amyloid cardiomyopathy. It has been known for over two decades that decreased stability of the native tetrameric conformation of TTR is the main cause of these diseases. Yet, mechanistic details on the amyloidogenic transformation of TTR were not clear until recent multidisciplinary investigations on various structural states of TTR. In this review, we discuss recent advancements in the structural understanding of TTR misfolding and amyloidosis processes. Special emphasis has been laid on the observations of novel structural features in various amyloidogenic species of TTR. In addition, proteolysis-induced fragmentation of TTR, a recently proposed mechanism facilitating TTR amyloidosis, has been discussed in light of its structural consequences and relevance to acknowledge the amyloidogenicity of TTR.
Highlights
Transthyretin (TTR) is a transporter of thyroxine (T4, a thyroid hormone) and a holoretinol binding protein, from which its name has originated (TRANSporter of THYroxine and RETINol) [1,2,3]
Initial X-ray crystallographic studies focused on revealing the atomic-resolution features of the TTR tetramer. These studies provide critical information for understanding the physiological features of TTR in its native state, and for designing therapeutic molecules, such as tafamidis and diflunisal, that can bind to the T4-binding pocket and stabilize the tetrameric complex, reducing amyloidogenic propensity [26,30]
Advancements have been made in understanding the structural features of non-native and misfolded monomeric, oligomeric, and aggregated TTR species, employing various interdisciplinary techniques, such as solution/solid-state nuclear magnetic resonance (NMR) spectroscopy, force spectroscopy, mass spectrometry, Cryo-electron microscopy (cryo-EM), and computational modeling
Summary
Transthyretin (TTR) is a transporter of thyroxine (T4, a thyroid hormone) and a holoretinol binding protein, from which its name has originated (TRANSporter of THYroxine and RETINol) [1,2,3]. TTR forms a tetrameric complex, giving rise to two hydrophobic pockets for binding T4 (Figure 1) [9,10]. It was reported that a molecule that binds to the T4-binding site could stabilize the tetrameric state and suppress the aggregation of TTR efficiently [23]. By conducting extensive biochemical and biophysical studies on the TTR-ligand complexes, Kelly et al succeeded in developing a ‘kinetic stabilizer’ to stabilize the tetrameric state of TTR and suppress/prevent its aggregation [24,25]. Recent investigations on the structural states of TTR revealed that the protein, either in its stable tetrameric state or in the less stable monomeric state, adopts significant structural heterogeneity, which is strongly associated with many of its physiological and pathological features [31]. We discuss the novel proteolysis-induced aggregation mechanism of TTR and the resultant structural deformation that is directly related to TTR pathology
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