Transthyretin (TTR) (TTR)

Transthyretin (TTR) is a 55 kDa homotetrameric transport protein composed of 127 amino acid residues per monomer, primarily synthesized in the liver. The protein functions as the major transporter of thyroxine (T4) in plasma and cerebrospinal fluid, and also transports retinol (vitamin A) in complex with retinol-binding protein throughout the body. TTR's tetrameric structure is stabilized by T4 binding at two funnel-shaped sites located at the dimer-dimer interfaces, which maintain protein stability through extensive hydrophobic interactions. Under certain conditions—including genetic mutations (more than 120 identified), aging, or environmental stress—TTR becomes thermodynamically unstable, dissociates into monomers, and misfolds into amyloid fibrils that deposit in cardiac, peripheral nervous, and connective tissues. This pathological process initiates transthyretin amyloidosis (ATTR), a group of diseases including familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), and senile systemic amyloidosis (SSA), characterized by progressive organ dysfunction, inflammation, and cell death. TTR is a well-established therapeutic target for small-molecule drug development, with stabilization of the tetrameric form being the primary strategy to prevent amyloidogenesis. Approved and investigational drugs including bisaryl compounds (diflunisal, flurbiprofen), natural compounds (flavonoids, polychlorinated biphenyls), and novel scaffolds (β-aminoxypropionic acids, crown ethers) work by occupying the T4-binding pockets or stabilizing the protein surface to increase the kinetic barrier for dissociation. TTR amyloid fibrils directly alter cardiac fibroblast structure and function, promoting migration, inflammation, and fibrosis, demonstrating that targeting TTR stabilization may address multiple pathological mechanisms in amyloidosis.

Other names

PrealbuminTransthyretin amyloidAmyloidogenic transthyretinWild-type TTR (wtTTR)Mutant TTR variants (V30M, T119M, R104H, A25T)

Tetramer stabilization - Ligands bind to the two T4-binding sites at dimer-dimer interfaces, preventing dissociation into monomers. Occupancy of halogen-binding pockets - Compounds interact with key residues (Glu54, Lys15, Leu17, Ala108, Thr119, Leu110, Ser117) forming halogen-binding pockets P1, P2, and P3. Hydrophobic interactions - Kinetic stabilization enforced by hydrophobic effect and electrostatic interactions at the weaker dimer-dimer interface. Inhibition of fibril formation - Stabilization prevents monomeric TTR misfolding and oligomerization into amyloid fibrils. Surface binding - Alternative mechanism where some compounds (crown ethers) stabilize the tetramer from the protein surface rather than occupying the T4-binding cavity.