Sandbox Reserved 1792

This Sandbox is Reserved from February 27 through August 31, 2023 for use in the course CH462 Biochemistry II taught by R. Jeremy Johnson at the Butler University, Indianapolis, USA. This reservation includes Sandbox Reserved 1765 through Sandbox Reserved 1795.

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Thyroid Stimulating Hormone Receptor (TSHR)

spinqualitylabelsall models The Human Thyroid Stimulating Hormone Receptor 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 An overview of the Thyroid System source: Thyroid Hormones Thyroid Stimulating Hormone Receptor (TSHR) is a type of G-Protein Coupled Receptor (GPCR) found in human thyroid follicles. It is activated by the Thyroid Stimulating Hormone (TSH) which is known as thyrotropin. Activation of TSHR is neccessary for activating a signaling pathway for the production of thyroid hormones such as T3 and T4 Structure TSHR forms a complex with TSH and Gs proteins. This is called the TSH-TSHR-G<sub>s</sub> Complex. TSHR has 3 main domains: Leucine Rich Region Domain (coral), the hinge region (blue-purple), and the transmembrane region. The (rainbow). The leucine rich region domain is located on the outside of the cell. This is where TSH will bind. The hinge region is also extracellular. Conformational changes in this region are responsible for the switch between the active vs inactive state. Finally, the transmembrane region is located within the plasma membrane. Its function is to hold the receptor into the membrane. This domain is also bound to the G-proteins. Transmembrane Region The Transmembrane Region (top-view) is embedded within the cell membrane. Like other G-proteins, it is made up of a 7-pass helix . The transmembrane region is surrounded by a "belt" of 15 cholesterols. When cholesterol binding sites are mutated such that they are unfunctional, TSHR activity decreases. Thus, the cholesterols are important for TSHR function Hinge Region The Hinge Region (purple-blue) connects the Transmembrane Region to the Leucine Rich Domain. It is made up of two <math>α</math>-helices that are connected via di-sulfide bonds(shown in yellow). 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 Y279 residue, are responsible for the bringing TSHR into the active state Leucine Rich Domain The Leucine Rich Repeat Domain (LRRD) is part of the extracellular region of TSHR. 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. Active vs Inactive State 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. 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 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