Protein Misfolding, Aggregation, and Conformational Diseases

Volume 6 of the series Protein Reviews pp 259-283

Transthyretin and the Transthyretin Amyloidoses

  • Joel N. BuxbaumAffiliated withDivision of Research Rheumatology Department of Molecular and Experimental Medicine, The Scripps Research Institute

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Transthyretin is a normal serum protein that carries the secondary thyroid hormone thyroxine and retinol binding protein when it is loaded with retinol. It is synthesized primarily in the liver but there is also significant production in the choroid plexus and the retina. Both message and protein are found in the kidney but that site does not appear to contribute to the serum level in any meaningful way. The protein is a homotetramer composed of the 14-kDa monomer with the thyroxine binding sites in the central groove. The structure is highly conserved particularly in the regions responsible for ligand binding, suggesting that its carrier function has been retained over the millennia. More than 80 mutations at 55 different positions in the gene encoding the protein are the primary cause of a set of human disorders collectively known as the familial amyloidotic polyneuropathies and cardiomyopathies. In these diseases, the soluble protein becomes insoluble under physiologic conditions resulting in functional compromise in the organs in which the protein is deposited. Peripheral nerves, heart, kidneys, gastrointestinal tract, and the leptomeninges have all been described as sites of deposition. It is possible that particular syndromes are associated with particular sets of mutations but, because of the rarity of some of the mutations, it is uncertain if the relationship between any mutation and any clinical syndrome is absolute. Further, it is also clear that the wild-type protein can deposit in tissues with subsequent dysfunction, particularly in the heart and carpal tunnel. Biophysical studies in vitro indicate that the process leading from soluble tetramer to insoluble aggregates involves monomer release, misfolding, oligomerization, and extension and lateral aggregation apparently as a downhill polymerization to a more stable lower energy state. How this is modulated in vivo is not known, although accessory molecules appear to be involved in the process. The early, albeit incomplete, understanding of the processes have led to potential therapies directed at stabilizing the tetramer or interfering with the interaction with other molecules as well as replacing the offending gene by liver transplantation.