InterPro domain: IPR036817

This entry includes transthyretin that is a thyroid hormone-binding protein that transports thyroxine from the bloodstream to the brain. However, most of the sequences listed in this entry do not bind thyroid hormones. They are actually enzymes of the purine catabolism that catalyse the conversion of 5-hydroxyisourate (HIU) to OHCU [ 1 , 2 ]. HIU hydrolysis is the original function of the family and is conserved from bacteria to mammals; transthyretins arose by gene duplications in the vertebrate lineage [ 3 , 4 ]. HIUases are distinguished in the alignment from the conserved C-terminal YRGS sequence.

Transthyretin (formerly prealbumin) is one of 3 thyroid hormone-binding proteins found in the blood of vertebrates [ 5 ]. It is produced in the liver and circulates in the bloodstream, where it binds retinol and thyroxine (T4) [ 6 ]. It differs from the other 2 hormone-binding proteins (T4-binding globulin and albumin) in 3 distinct ways: (1) the gene is expressed at a high rate in the brain choroid plexus; (2) it is enriched in cerebrospinal fluid; and (3) no genetically caused absence has been observed, suggesting an essential role in brain function, distinct from that played in the bloodstream [ 7 ]. The protein consists of around 130 amino acids, which assemble as a homotetramer that contains an internal channel in which T4 is bound. Within this complex, T4 appears to be transported across the blood-brain barrier, where, in the choroid plexus, the hormone stimulates further synthesis of transthyretin. The protein then diffuses back into the bloodstream, where it binds T4 for transport back to the brain [ 7 ]. Structurally, it consists of a sandwich fold with seven strands arranged in two sheets and a greek-key topology.

1. Transthyretin-related proteins function to facilitate the hydrolysis of 5-hydroxyisourate, the end product of the uricase reaction. FEBS Lett. 579, 4769-74
2. Completing the uric acid degradation pathway through phylogenetic comparison of whole genomes. Nat. Chem. Biol. 2, 144-8
3. Structure of zebra fish HIUase: insights into evolution of an enzyme to a hormone transporter. J. Mol. Biol. 363, 1-9
4. The x-ray crystal structure refinements of normal human transthyretin and the amyloidogenic Val-30-->Met variant to 1.7-A resolution. J. Biol. Chem. 268, 2416-24
5. Isolation, characterization, cDNA cloning and gene expression of an avian transthyretin. Implications for the evolution of structure and function of transthyretin in vertebrates. Eur. J. Biochem. 200, 679-87
6. Structure of the chromosomal gene for human serum prealbumin. Gene 37, 191-7