Sandbox Reserved 1792

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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)

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

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You may include any references to papers as in: the use of JSmol in Proteopedia ^[1] or to the article describing Jmol ^[2] to the rescue.

1 Introduction
2 Structure
3 Active vs Inactive State
4 Specific Residues
5 Biological Relevance

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 G_s proteins. This is called the . : Leucine Rich Region Domain (coral), the hinge region (blue-purple), and the transmembrane region(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 at the N-terminus.

Transmembrane Region

() is embedded within the cell membrane. Like other G-protein receptors, it is made up of a 7-pass helix ^[3]. The transmembrane region is surrounded by a "belt" of . When cholesterol binding sites are mutated such that they are unfunctional, TSHR activity decreases. Thus, the cholesterols are important for TSHR function (reference). Additionally, at the N-terminus, the transmembrane region binds to the .

Hinge Region

The (purple-blue) connects the Transmembrane Region to the Leucine Rich Domain. It is made up of two α-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 , are responsible for the bringing TSHR into the active state ^[3]

Leucine Rich Domain

The 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^[4].

Binding Pocket

Active vs Inactive State

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

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 . 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 ^[3]

Specific Residues

Biological Relevance

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References

↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
↑ ^3.0 ^3.1 ^3.2 Faust B, Billesbolle CB, Suomivuori CM, Singh I, Zhang K, Hoppe N, Pinto AFM, Diedrich JK, Muftuoglu Y, Szkudlinski MW, Saghatelian A, Dror RO, Cheng Y, Manglik A. Autoantibody mimicry of hormone action at the thyrotropin receptor. Nature. 2022 Aug 8. pii: 10.1038/s41586-022-05159-1. doi:, 10.1038/s41586-022-05159-1. PMID:35940205 doi:http://dx.doi.org/10.1038/s41586-022-05159-1
↑ Duan J, Xu P, Luan X, Ji Y, He X, Song N, Yuan Q, Jin Y, Cheng X, Jiang H, Zheng J, Zhang S, Jiang Y, Xu HE. Hormone- and antibody-mediated activation of the thyrotropin receptor. Nature. 2022 Aug 8. pii: 10.1038/s41586-022-05173-3. doi:, 10.1038/s41586-022-05173-3. PMID:35940204 doi:http://dx.doi.org/10.1038/s41586-022-05173-3

Student Contributors

Alex Kem
Grace Lane

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@@ Line 12: / Line 12: @@
 <scene name=scene name='95/952720/Structure_overview_spins/3'>TSHR has 3 main domains</scene>: Leucine Rich Region Domain (coral), the hinge region (blue-purple), and the transmembrane region(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 at the N-terminus.
 === Transmembrane Region===
-<scene name='95/952720/Transmembrane_region_spin/3'>The Transmembrane Region</scene> (<scene name='95/952720/Transmembrane_region_top-view/2'>top-view</scene>) is embedded within the cell membrane. Like other G-protein receptors, it is made up of a 7-pass helix <ref name="Faust"> DOI 10.1038/s41586-022-05159-1</ref>. The transmembrane region is surrounded by a "belt" of <scene name='95/952720/Tmd_cholesterol_spin/2'>15 cholesterols</scene>. When cholesterol binding sites are mutated such that they are unfunctional, TSHR activity decreases. Thus, the cholesterols are important for TSHR function (reference). Additionally, at the N-terminus, the transmembrane region binds to the <scene name='95/952720/Transmembrane_region_spin/4'>G-proteins</scene>.
+<scene name='95/952720/Transmembrane_region_spin/5'>The Transmembrane Region</scene> (<scene name='95/952720/Transmembrane_region_top-view/2'>top-view</scene>) is embedded within the cell membrane. Like other G-protein receptors, it is made up of a 7-pass helix <ref name="Faust"> DOI 10.1038/s41586-022-05159-1</ref>. The transmembrane region is surrounded by a "belt" of <scene name='95/952720/Tmd_cholesterol_spin/2'>15 cholesterols</scene>. When cholesterol binding sites are mutated such that they are unfunctional, TSHR activity decreases. Thus, the cholesterols are important for TSHR function (reference). Additionally, at the N-terminus, the transmembrane region binds to the <scene name='95/952720/Transmembrane_region_spin/4'>G-proteins</scene>.
 === Hinge Region===