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Thyroid Stimulating Hormone Receptor (TSHR)

spinqualitylabelsall models The Human Thyroid Stimulating Hormone Receptor and G-Protein Complex. TSHR is colored based off of its domains. The Leucine Rich Repeat Region (LRRD) is shown in coral. The Hinge Region is shown in bluepurple. The transmembrane region is colored from N to C terminus in a rainbow spectrum. TSH is in navy. And the G-proteins are shown in grey. PDB: 7xw5 Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D This is a default text for your page '. Click above on edit this page' to modify. Be careful with the < and > signs. You may include any references to papers as in: the use of JSmol in Proteopedia or to the article describing Jmol to the rescue. 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 Gs proteins. This is called the TSH-TSHR-Gs Complex. 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 . TSHR has 3 main domains: 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. Activated G-proteins then signal a robust intracellular signaling cascade. Transmembrane Region The Transmembrane Region (top-view) is embedded within the cell membrane, like other G-protein receptors, it is composed of a 7-pass helix . The transmembrane region is surrounded by a "belt" of 15 cholesterols. When cholesterol binding sites are mutated, TSHR activity decreases. These cholesterols are likely important for TSHR function . Additionally, at the N-terminus, the transmembrane region binds to the G-protein, which are located intracellularly . 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. Leucine Rich Domain The Leucine Rich Repeat Domain (LRRD) is the extracellular ligand binding 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 . Hinge Region The Hinge Region (purple-blue) connects the Transmembrane Region to the Leucine Rich Domain. Also referred to as the signaling specificity domain the hinge region plays a dual role in both TSH binding and signal transduction. . The hinge region is made up of two α-helices connected via di-sulfide bonds. These two helices help orient TSH properly for LRRD binding. It is proposed that the residues Asp386, Tyr385, and Tyr387 create a negative-charged region on the Helix. This negatively charged region interacts with the positively charged region of TSH created by residue Arg54. 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 Y279 residue, are responsible for the bringing TSHR into the active state Active vs Inactive State Figure 2: An overview of the Inactive (pink) vs Active (green) state of TSHR embedded in the plasma membrane. PDB: 7t9m and 7t9i 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 inactive state. 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 active or "up" state (fig 2). During this transition, the Extracellular domains rotate 55° along an axis. This rotation is caused by conformational changes within the Hinge Region, specifically at the Y279 residue. This residue moves 6 angstroms relative to I486, which is a residue located in the Transmembrane Region (Fig 3). Biological Relevance This is a sample scene created with SAT to color by Group, and another to make a transparent representation of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

Student Contributors

• Alex Kem
• Grace Lane