The thyrotropin receptor 25 years after its discovery: new insight after its molecular cloning

The molecular cloning and functional expression of the TSH receptor has led to rapid advances in understanding the structure and function of the molecule. Knowledge of its genomic structure provides information on the evolutionary origin of the TSH receptor as well as on the functional organization of its extracellular domain, which is responsible for ligand binding. A beginning has been made in defining the discontinuous contact points for TSH in this extracellular region, but determination of all of the amino acids involved will be difficult. The binding sites of TSH receptor autoantibodies do not appear to be identical to the TSH binding site. Two of the six potential glycosylation sites in the extracellular domain are important in the expression of a functional receptor. Disulfide bonding contributes toward maintenance of the three-dimensional structure of the receptor. Recent evidence suggests that the TSH receptor exists as a single polypeptide chain without subunits. Significant progress has been made in understanding the intracellular regions of the TSH receptor that are involved in signal transduction. Although still in the distant future, we are closer to the goal of understanding precisely how TSH interacts with and activates its receptor. More importantly from the clinical perspective, we are closer to defining the B cell, and ultimately T cell, epitopes on the TSH receptor that are recognized by the immune system. This information may ultimately facilitate the development of immunological approaches to treating Graves' disease, which will be an improvement over thyroid gland destruction and consequent hypothyroidism, the most common form of therapy at the present time.