| Transthyretin, also known as prealbumin for its electrophoretic migration ahead of albumin, is a homotetrameric transport protein synthesized primarily by the liver and also by the choroid plexus, assembling from four identical beta-sheet-rich subunits arranged as a dimer of dimers around a central hydrophobic channel. This channel forms two funnel-shaped binding pockets at the dimer-dimer interface that accommodate thyroxine, and TTR additionally presents four surface-exposed binding sites for retinol-binding protein, two per dimer, though steric hindrance permits only two RBP molecules to engage a single tetramer at once, and because circulating RBP levels remain lower than TTR levels, typically only one RBP molecule is bound at a given time; formation of this TTR-RBP complex is required to prevent renal filtration of the smaller RBP-retinol complex, allowing vitamin A to remain in circulation and reach target tissues. Thyroxine binding to the two T4 pockets exerts a stabilizing effect on the tetramer through ligand-induced kinetic stabilization, extending the tetramer's structural half-life from hours to days and directly slowing the rate-limiting dissociation step that initiates the amyloidogenic pathway; the two T4 binding sites additionally show negative cooperativity, so that ligand occupancy at one pocket structurally influences binding at the other rather than the two sites functioning as fully independent pockets. Amyloid fibril formation proceeds only after this tetramer first dissociates into partially unfolded monomers, which then self-associate into soluble oligomers and ultimately insoluble amyloid fibrils, and structural mapping of the aggregation-prone regions of the monomer identifies beta-strands F and H as specifically required for this self-association step, a finding that has enabled design of non-natural peptide inhibitors that block aggregation by targeting these two structural elements directly rather than by stabilizing the tetramer indirectly through the T4 pocket. Point mutations in the TTR gene destabilize the tetrameric structure, accelerating the dissociation step and producing hereditary forms of transthyretin amyloidosis, while wild-type TTR retains an intrinsic, lower-grade amyloidogenic potential that manifests with aging and underlies non-hereditary systemic amyloidosis in older individuals; depending on the specific destabilizing mutation, the resulting misfolded protein deposits preferentially in peripheral nerves, producing familial amyloid polyneuropathy, or in the myocardium, producing familial amyloid cardiomyopathy. |
