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Introduction
Figure 1. TSHR with TSH bound. The extracellular and transmembrane domains of the GPCR are shown in green, the hinge region in cyan, the P10 peptide in pink, and thyrotropin bound in pink and yellow.
Thyroid hormones exercise essential functions related to thymocyte activity as well as metabolic processes and oxygen consumption. Misregulation of thyroid hormones is the cause of many disorders related to hypo- or hyperthyroidism. Thus, understanding the signaling of synthesis and release of these hormones is essential to the development therapeutic drugs to combat specific thyroid hormone disorders[3]. The initiation of the synthesis and release of these hormones is caused by the glycoprotein, thyroid stimulating hormone, commonly referred to as TSH or thyrotropin. The thyrotropin receptor is a G-protein coupled receptor that binds TSH and transduces signal to initiate synthesis and release of thyroid hormones. It is important to note that autoantibodies may also bind to this receptor causing inhibition or activation of its desired function. (Figure 1)[4][5]
Structure
Overview
The thyrotropin receptor has an extracellular domain (ECD) that is composed of a as well as a hinge region. This links the ECD to the seven transmembrane helices , which span from the extracellular domain to the intracellular domain [6]. When thyrotropin or an autoantibody binds, it causes a conformational change in the receptor through the transmembrane helices. This causes the thyrotropin receptor to interact differently with its respective when in the active and inactive states.
Hinge Region and P10 Peptide
Several parts of TSHR are very important for the functioning of TSH signaling. The is a scaffold for the attachment of the ECD to the 7TMD. Also, this region, has been found to have impact on the binding potency of TSH as well as intracellular cyclic adenosine monophosphate (cAMP) levels, which are partially mediated by the activation of the GPCR. Several features of this region have been found to be crucial to the potent activation of of the TSHR by TSH.[7]. The most important feature of the hinge region is the interaction of the hinge helix with the p10 peptide through disulfides. The p10 peptide is a conserved sequence that spans from the last beta sheet of the LRRD to the first transmembrane helix (TM1)[8]. These disulfides are critical as they link the ECD, where thyrotropin binds, to the TMD, whose conformational changes directly mediate the activation of the receptor's complementary G-protein. Movement of the ECD, caused by TSH binding, will cause rotation of the hinge helix and subsequent movement of the p10 peptide leading to movement of the transmembrane helices which will cause activation of the G-protein. In addition to activation, the hinge region plays an important role in tightly binding TSH. Residues 382-390 of the hinge region adopt a short helix containing Y385 and D386. Y385 is buried into a hydrophobic region of TSH while D386 forms a salt bride with R386 of the hormone. Together, these interactions assist in facilitating the stable binding of TSH to the TSHR [9]
