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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

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)<reference name="Faust et al.">Faust, B., Billesbølle, C.B., Suomivuori, CM. et al. Autoantibody mimicry of hormone action at the thyrotropin receptor. Nature 609, 846–853 (2022). https://doi.org/10.1038/s41586-022-</ref>. These interactions are critical as they link the ECD, where thyrotropin binds, to the TMD, whose conformational changes directly mediate the activation of the receptors complementary G-protein. This being said, the region is not required for the activation of the receptor. In many of the aforementioned misregulations of thyroid hormone release, auto-antibodies are responsible. These auto-antibodies bind to the receptor through alternative interactions which cause conformational changes to the 7TMD without any need for a conformational change or extensive interactions with the hinge region. This is supported by the fact that select autoantibodies are able to bind to the activate the receptor without any contacts.

7 Transmembrane Helices

The thyrotropin receptor is anchored to the membrane through seven transmembrane helices which is characteristic of

Relevance

Structural highlights

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