Sandbox Reserved 1792

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Revision as of 21:35, 24 March 2023

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)

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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

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

An overview of the Thyroid System source: Thyroid Hormones

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. 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

() is embedded within the cell membrane. Like other G-proteins, 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

Hinge Region

The (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 , 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

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 , specifically at the Y279 residue. 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 13: / Line 13: @@
 TSHR forms a complex with TSH and G<sub>s</sub> proteins. This is called the <scene name='95/952720/Tsh-tshr-gs_complex/1'>TSH-TSHR-G<sub>s</sub> Complex</scene>.
-<scene name='95/952720/Structure_overview/2'>TSHR has 3 main domains</scene>: 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.
+<scene name='95/952720/Structure_overview/2'>TSHR has 3 main domains</scene>: 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===
 <scene name='95/952720/Transmembrane_region_spin/1'>The Transmembrane Region</scene> (<scene name='95/952720/Transmembrane_region_top-view/1'>top-view</scene>) is embedded within the cell membrane. Like other G-proteins, 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/1'>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
@@ Line 26: / Line 26: @@
 == 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 <ref name="Faust"/>
+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 <scene name='95/952720/Hinge_region_spin/1'>Hinge Region</scene>, specifically at the Y279 residue. This residue moves 6 angstroms relative to I486, which is a residue located in the Transmembrane Region <ref name="Faust"/>
 == Specific Residues ==