Title:Nearly 200 X-Ray Crystal Structures of Transthyretin: What Do They Tell Us About This Protein and the Design of Drugs for TTR Amyloidoses?
Volume: 19
Issue: 15
Author(s): S. K. Palaninathan
Affiliation:
Keywords:
Amyloidosis, crystal structure, inhibitor complex, native state kinetic stabilization, protein misfolding, retinol binding protein,
thyroxine (T4), transthyretin (TTR)
Abstract: Transthyretin (TTR), a β-strand rich tetrameric protein present in human serum and cerebrospinal fluid is involved in the
transport of thyroxine and retinol binding protein:retinol complex (holo-RBP). TTR forms two T4 binding sites at the center of the
dimer-dimer interface and contains holo-RBP binding sites on both faces of the tetramer. Dissociation of TTR tetramers followed by
misfolding and misassembly results in amyloid fibril formation, the causative agent of four neurodegenerative diseases. Misfolding of
wild type TTR in humans over 60 years of age is linked to a sporadic amyloid disease called senile systemic amyloidosis. Single point
mutations enhance the amyloidogenicity of TTR, causing familial amyloid cardiomyopathy, familial amyloid polyneuropathy, and central
nervous system selective amyloidosis. To date, nearly 200 X-ray crystal structures of TTR and their complexes have been solved. They
have provided potential insights into its structure-function relationships with molecular partners, and its interactions with small molecule
ligands that inhibit tetramer destabilization and amyloid formation. This review will focus on the key findings of the structural studies of
TTR that provided atomic level description of its architecture, the mechanistic role of structural components involved in its function and
misfolding, and the progress and limitations towards the design of selective inhibitors for TTR amyloidoses.