Evolution of thyroid hormone binding by transthyretins in birds and mammals

Abstract

Transthyretin, a protein synthesized and secreted by the choroid plexus and liver, binds thyroid hormones in extracellular compartments. This binding prevents accumulation of thyroid hormones in the lipids of membranes, establishing extracellular thyroid hormone pools for the distribution of the hormones throughout the body and brain. The N-termini of the transthyretin subunits are longer and more hydrophobic in chicken than in eutherian transthyretins. Here, we show that this is a general structural feature of avian transthyretins. Systematic changes of protein structure during evolution result from selection pressure leading to changes in function. The evolution of transthyretin function, namely, the binding of thyroid hormones, was studied in nine vertebrate species. The affinity of thyroxine binding to transthyretin is lowest in avians (mean K(d) of about 30 nM), intermediate in metatherians (mean K(d) of about 17 nM) and highest in eutherians (mean K(d) of about 11 nM). The affinity for 3,5,3'-triiodothyronine shows an opposite trend, being four times higher for avian transthyretins than for mammalian transthyretins.