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 interacti on 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 sequ ence homology with regions of the three major thyroid hormone plasma t ransport proteins (TBG, TTR, and albumin) known to contain the corresp onding hormone binding site(s). Within the hormone domain, we identifi ed a 5-residue hydrophobic motif ''Y, L/I/M, X, X, V/L/I'' that is ext remely well conserved in apolipoproteins. The exon-3 coded region of h uman 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 horm one site of apo E and, because of the said homology, should exist in t he other HDL apolipoproteins. Because TBG and/or TTR are not present i n all animal species, but Lp are, and because fish HDL bind thyroid ho rmones, I postulated that thyroid hormone binding to HDL apolipoprotei ns is conserved through the phylum. To this end, I evaluated the conse rvation of the 5-residue motif in all the apolipoprotein sequences kno wn (PIR data bank no. 42) and tested the thyroid hormone binding prope rties 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-r esidue 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 t han preservation of other domains.