A Thyroid Hormone Binding Motif Is Evolutionarily Conserved in Apolipoproteins

High-density lipoproteins (HDL) are the major lipoprotein (Lp) plasma carriers of thyroid hormones, binding mediated by a specific interaction with their apolipoproteins (A-I, A-II, A-IV, C-I, C-II, C-III and E). The single binding site of these apolipoproteins is encoded by exon 3 (exon 2 for apoA-IV) of the respective gene and has amino acid sequence homology with regions of the three major thyroid hormone plasma transport proteins (TBG, TTR, and albumin) known to contain the corresponding hormone binding site(s). Within the hormone domain, we identified a 5-residue hydrophobic motif "Y, L/I/M, X, X, V/L/I" that is extremely well conserved in apolipoproteins. The exon-3 coded region of human apo E contains a hydrophobic pocket which is formed by Trp 34 and a number of neighboring leucines (residues no. 28, 30, 37 or 43). The location of this pocket overlaps strikingly that of the region (aa 26–40) where the said homology is maximal and where the motif YLRVW (aa 36–40) lies. This hydrophobic pocket should represent the thyroid hormone site of apo E and, because of the said homology, should exist in the other HDL apolipoproteins. Because TBG and/or TTR are not present in all animal species, but Lp are, and because fish HDL bind thyroid hormones, I postulated that thyroid hormone binding to HDL apolipoproteins is conserved through the phylum. To this end, I evaluated the conservation of the 5-residue motif in all the apolipoprotein sequences known (PIR data bank no. 42) and tested the thyroid hormone binding properties of two animal apolipoproteins that were available (bovine apo A-I and rabbit apo E). I found that the conservation does exist and that the binding properties of the two animal apolipoproteins match those of the respective human counterpart. In addition, I found that the 5-residue motif is spared by naturally occurring mutations, which is not the case for other domains. I therefore conclude that the interaction of thyroid hormones with Lp represents the first plasma transport for these hormones that appeared in the animal world and that preservation of the structure of the hormone domain appears to be more important than preservation of other domains.