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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.

Specific Residues

• LYS 58 interacts with Glu 118 on each 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.

Interactions

• The binding pocket allows a tight interaction with the antibodies. These antibodies make tight interactions with a lot of IMFs at play.
• 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.

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.