The thyroxine-binding proteins

The slow clearance, prolonged half-life, and high serum concentration of thyroxine (T-4) are largely due to strong binding by the principal plasma thyroid hormone-binding proteins, thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin. These proteins, which shield the hydrophobic thyroid hormones from their aqueous environment, buffer a stable free T-4 concentration for cell uptake. Free rather than bound T-4 is subject to homeostatic control by the hypothalamic-pituitary thyroid axis. Although it is not a protease inhibitor, sequence analysis identifies TBG as a member of the serine protease inhibitor (serpin) family of proteins. Proteolytic cleavage of TBG appears to be a mechanism for site-specific release of T-4 independently of homeostatic control. TBG probably facilitates the transport of maternal T-4 and iodide to the fetus, although this remains to be proven. High-affinity cellular binding sites for TTR have been described; however, their function and that of choroid plexus synthesis of TTR and transport of T-4 into the cerebrospinal fluid remain unclear. Albumin, with the lowest T-4 affinity and fastest T-4 release of the major T-4-binding proteins may promote quick exchange of T-4 with tissue sites. The affinity of albumin for T-4 is increased by histidine substitution for arginine 218 in the most common form of dysalbuminemic hyperthyroxinemia. However, proline and alanine substitutions at the same site have a similar effect, suggesting that arginine 218 interferes with T-4 binding.