Prealbumin and the thyroid hormone nuclear receptor.
The thyroid hormones exhibit a wide range of biological activities, which are now thought to be mediated by a specific receptor molecule in the nucleus of the target cells. This receptor appears to promote the production of new mRNA molecules, leading to the synthesis of proteins, but the precise mode of action of the receptor and the nature of the gene products are not known at present. Thyroid hormone binding proteins are also present in the blood plasma; in humans there are two distinct binding proteins, thyroxine binding globulin (TBG) and prealbumin (PA), sometimes known as thyroxine binding (TBPA). In addition to its hormone binding function PA is also involved in vitamin A transport through a protein-protein interaction with the specific vitamin A binding protein in plasma, retinol-binding protein (RBP). Prealbumin has been subjected to an extensive X-ray analysis of its molecular structure and interactions with the thyroid hormones. The PA molecule is a tetramer of 55 000 relative molecular mass, composed of identical subunits. The structure of the subunit is essentially an eight-stranded beta-barrel. The subunits are organized in the tetramer by extensive hydrogen-bond and hydrophobic contacts, giving rise to a prealbumin molecule with a channel running right through its centre, and two deep cylindrical-helical depressions in its outer surface. The central channel contains two identical binding sites for the thyroid hormones, which closely match the shape and chemistry of the iodothyronine nucleus of the hormones. The two deep surface depressions have found to be structurally complementary to the DNA double helix. This structural information on prealbumin may be appropriate to the nuclear receptor in the light of recent studies that suggest a considerable degree of functional similarity between the two molecules. In particular, the receptor appears to be composed of two units: a thyroid hormone binding unit, or core receptor, and a regulatory unit that modulates the hormone binding; this latter protein may be a histone. Separating the hormone binding unit from the holoreceptor radically changes the binding affinity for the thyroid hormones and their analogues, with the pattern of binding in the core receptor showing a striking similarity to the pattern in prealbumin. These and other similarities between the two proteins are examined, and possible relationships are considered.
D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D011228:Prealbumin / Q000378:metabolism*; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone; D012709:Serum Albumin / Q000378:metabolism*; D014284:Triiodothyronine / Q000378:metabolism
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D011228:Prealbumin; D011956:Receptors, Cell Surface; D011988:Receptors, Thyroid Hormone; D012709:Serum Albumin; D014284:Triiodothyronine; D004247:DNA