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Introduction

Fig.1 An overview of the Thyroid System source: Thyroid Hormones

Thyroid Stimulating Hormone Receptor (TSHR) is a G-Protein Coupled Receptor (GPCR) found in human thyroid follicles. TSHR is activated by the Thyroid Stimulating Hormone (TSH) also known as thyrotropin. Activation of TSHR is initiates a signaling pathway for the production of thyroid hormones such as T₃ and T₄ (Fig 1).

Structure

TSHR forms an active signalling complex with TSH and G_s proteins. This is called the . TSH contains an α and a β subunit. The α subunit is a shared subunit amongst glycoproteins. The β subunit is unique to TSH. TSH binds to the extracellular domain of TSHR ^[3] DOI 10.1038/s41586-022-05173-3</ref>. : Leucine Rich Region Domain (coral), the hinge region (blue-purple), and the transmembrane region(rainbow). The leucine rich region domain is the extracellular TSH ligand domain. The hinge connects the Leucine Rich Repeat Domain and the Transmembrane Region. It provides flexibility for the switch between the active and inactive state of TSHR. The transmembrane region is located within the plasma membrane. Its function transmit the extracellular signal across the membrane to the intracellular G-proteins bound to the N-terminus of the transmembrane region^[3]. Activated G-proteins then signal a robust intracellular signaling cascade.

Transmembrane Region

() is embedded within the cell membrane, like other G-protein receptors, it is composed of a 7-pass helix ^[4] PMID:35940205</ref>. The transmembrane region is surrounded by a "belt" of ^[3]. When cholesterol binding sites are mutated, TSHR activity decreases. These cholesterols are likely important for TSHR function ^[3]. Additionally, at the N-terminus, the transmembrane region binds to the , which are located intracellularly ^[5]. The G-proteins are made up of three subunits: α,β, and γ. When TSHR is activated, it causes the Gα subunit to dissociate from the Gβγ subunits. The Gα subunit is responsible for activating adenylyl cyclase, phospholipase C and ion channels. This sets off the robust intracellular signaling cascade^[5].

=== Leucine Rich Domain===αα

The is part of the extracellular region of TSHR. It is made up of about 280 different residues. Connected to its C-terminus is the Hinge Region. It is made up of an extensive parallel β-sheet. This β-sheet is where TSH binds and is called the binding pocket ^[3].

Hinge Region

The (purple-blue) connects the Transmembrane Region to the Leucine Rich Domain. It is also sometimes referred to as the signaling specificity domain because there is some evidence suggesting that this region is important in both TSH binding and signal transduction. ^[6]. It is made up of two α-helices that are connected via di-sulfide bonds(shown in yellow) and is made up of about 134 residues. Interactions between these two helices and TSH help orient TSH properly. These interactions are essential for TSH binding, however, they are not required for the activation of TSHR. Conformational changes in this region, specifically the orientation of , are responsible for the bringing TSHR into the active state ^[4]

Active vs Inactive State

Figure 2: An overview of the Inactive (pink) vs Active (green) state of TSHR. PDB: 7WX5

Figure 3: A zoomed in view of the Y279 residue in the Hinge Region of TSHR, showing the 6 angstrom move of Y279 during the activation of TSHR. Active TSHR is shown in green (PDB: 7t9i) and inactive TSHR is shown in pink (PDB: 7t9m).

When TSHR is not bound to TSH, it is in the . This is also considered the "down" state because the LRRD is pointing down. When TSH binds to TSHR, steric clashing between TSH and the cell-membrane cause TSHR to take on the (fig 2). During this transition, the Extracellular domains rotate 55° along an axis. This rotation is caused by conformational changes within the , specifically at the . This residue moves 6 angstroms relative to I486, which is a residue located in the Transmembrane Region ^[4] (Fig 3).

Specific Residues

Biological Relevance

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