We apologize for Proteopedia being slow to respond. For the past two years, a new implementation of Proteopedia has been being built. Soon, it will replace this 18-year old system. All existing content will be moved to the new system at a date that will be announced here.

Sandbox Reserved 1791

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Revision as of 04:11, 31 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.

To get started:

Click the edit this page tab at the top. Save the page after each step, then edit it again.
show the Scene authoring tools, create a molecular scene, and save it. Copy the green link into the page.
Add a description of your scene. Use the buttons above the wikitext box for bold, italics, links, headlines, etc.

More help: Help:Editing

Thyroid Stimulating Hormone Receptor (TSHR)

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 ^[1] or to the article describing Jmol ^[2] to the rescue.

1 Introduction
2 Structure
3 Active vs. Inactive State
4 Specific Residues and Interactions
5 Biological Relevance
- 5.1 Hyperthyroidism
- 5.2 Hypothyroidism

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. 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

The is a concave structure with many polar residues. This pocket is where the TSH antibody and agonist K1 bind as well as the agonist M22. These structures interact with specific residues to result in a structural change of the molecule.

Active vs. Inactive State

The active form of TSHR is found when bound by TSH or M22. The structure can be seen as straight.
The inactive form of TSHR is found when bound with K1. The overall structure of the molecule when K1 is bound is bent.
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 and Interactions

There are two in the binding pocket of TSHR that are the main contributors to the binding of the antibodies.
When in the inactive form, Lys 209 does not interact with any residue but Lys 58 has interaction with Glu 118 and this interaction pulls the molecule into the bent position.
The binding pocket allows a tight interaction with the antibodies. These antibodies make tight interactions with a lot of intermolecular forces at play.
LYS 58 interacts with Glu 118 on the antibodies to make a salt bridge interaction
LYS 209 interacts with Asp 11 on the antibodies to make a salt bridge interaction
When in the inactive form, Lys 209 does not interact with any residue but Lys 58 has interaction with Glu 118 and this interaction pulls the molecule into the bent position.
Specifically the two residues make an ionic interaction. The interaction is not close enough to make a hydrogen bond. Instead, the interaction between the Lys residues with the Asp or Glu residues is a salt bridge interaction. This is the main bond that holds these two molecules together.

Biological Relevance

The thyroid plays an essential role in the body's metabolism. The body's metabolism affects things like heart rate, digestion, temperature regulation, and many more things. When TSH is bound to TSHR, a signal is sent to produce T3 and T4. Those hormones then go impact cells in your body to increase or decrease your metabolism.

Hyperthyroidism

Hyperthyroidism is when the thyroid is overactive. When the M22 antibody is bound it keeps TSHR in the active conformation. This overstimulates the body's metabolism. Symptoms of hyperthyroidism include fast or irregular heartbeats, tiredness, increased hunger, sleep problems, enlarged thyroid gland, sensitivity to heat, and many other symptoms. Grave's disease is the most common cause of hyperthyroidism. This is an autoimmune disorder that causes your body to attack the thyroid gland. Grave's Disease

Hypothyroidism

Hypothyroidism is when the thyroid is underactive. When the K1 antibody is bound it does not allow the TSHR to go into the upright, active, position. This does not allow for the signaling of the T3 and T4 hormones to upregulate the metabolism. The symptoms of this slow or irregular heartbeats, tiredness, muscle aches, memory problems, jaundice sensitivity to cold, and many other symptoms. Hypothyroidism

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 Contributions

Alex Kem
Grace Lane

Retrieved from "http://52.214.119.220/wiki/index.php/Sandbox_Reserved_1791"

@@ Line 28: / Line 28: @@
 *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 ==
+== Specific Residues and Interactions==
-*LYS 58 interacts with Glu 118 on each of the antibodies
+*There are two <scene name='95/952719/Specific_residues/3'>lysine residues</scene> in the binding pocket of TSHR that are the main contributors to the binding of the antibodies.
-*LYS 209 interacts with Asp 11 on each of the antibodies
 *When in the inactive form, Lys 209 does not interact with any residue but Lys 58 has interaction with Glu 118 and this interaction pulls the molecule into the bent position.
 *<scene name='95/952719/Specific_residues/1'>LYS Residues</scene>
 *<scene name='95/952719/Specific_residues/2'>LYS closer look</scene>
 *<scene name='95/952719/Specific_residues/3'>LYS w/ label</scene>
-=== Interactions ===
+*The binding pocket allows a tight interaction with the antibodies. These antibodies make tight interactions with a lot of intermolecular forces at play. <scene name='95/952719/Lock_and_key/1'>Tight interaction</scene>
-*The binding pocket allows a tight interaction with the antibodies. These antibodies make tight interactions with a lot of IMFs at play. <scene name='95/952719/Lock_and_key/1'>Tight interaction</scene>
+*LYS 58 interacts with Glu 118 on the antibodies to make a salt bridge interaction
+*LYS 209 interacts with Asp 11 on the antibodies to make a salt bridge interaction
+*When in the inactive form, Lys 209 does not interact with any residue but Lys 58 has interaction with Glu 118 and this interaction pulls the molecule into the bent position.
 *Specifically the two residues make an ionic interaction. The interaction is not close enough to make a hydrogen bond. Instead, the interaction between the Lys residues with the Asp or Glu residues is a salt bridge interaction. This is the main bond that holds these two molecules together. <scene name='95/952719/K---d_interaction/1'>LYS ASP interaction</scene>
 *<scene name='95/952719/K---e_interaction/1'>LYS GLU interaction</scene>