Sandbox Reserved 1779

Introduction

Grave's Disease

Grave’s disease is an autoimmune disease that is a result of hyperthyroidism. Hyperthyroidism indicates that the body is producing too much Thyroid Stimulating Hormone (TSH). The binding of TSH to TSHR results in the receptor remaining in its active conformation. This is important as the thyroid gland controls metabolism in the body and overstimulation can lead to many side effects. This is including but not limited to: eye and skin problems, weight loss, fatigue, muscle weakness, trouble tolerating heat/ profuse sweating, enlarged thyroid glands (goiter). This disease effects 1 in 100 Americans and especially women or people older than 30 years of age. Grave's Disease

Hypothyroidism

Hypothyroidism is the converse of Grave’s Disease as there is not enough TSH produced in the body with this disease. The most common cause of Hypothyroidism is Hashimoto’s disease. Without enough TSH to bind TSHR, the pathway remains inactive and thus metabolic processes are inhibited in this pathway. This results in many symptoms including, but not limited to fatigue, cold sensitivity, weight gain, irregular/heavy menstrual cycle, thinning of hair, and depression. This disease effects women and those older than the age of 60. This disease can also occur in infancy. Hypothyroidism

Structural Overview

Leucine Rich Region

The Leucine Rich region is part of the of TSHR. The highlighted region contains within the structure. The specific residues from TSHR interacting with TSH are ^[1]. These interact with Asp91 and Glu98 in the seatbelt region of TSH forming a salt bridge and initiating the conformational change in the receptor ^[2]. This interaction is specific to TSH and TSHR. When other agonists or antagonists bind to the receptor, the interaction is a result of different residues interacting. The Leucine residues likely play a role in how the ECD folds and which residues are located on the exterior protein. As Leucine is hydrophobic, it would be forced into the interior of the protein during folding exposing other residues that are more hydrophobic to the surface.

Active and Inactive Form

Figure 1: Inactive form of the thyrotropin receptor shown in blue. Active form of the thyrotropin receptor shown in green.

The TSHR protein exists in two states, active and inactive (Figure 1). The sticks out from the cell membrane into the space outside the cell. The contains 7 alpha helices that reside within the cell membrane. The exists when bound to the thyroid stimulating hormone (TSH) (GREEN LINK). One proposed mechanism for the transition from the active to inactive describes that in its natural state, the TSHR ECD can spontaneously transition to the up state, leading to constitutive activity. In this active state, TSH will bind and keep the active state in the up position because of clash with the cell membrane.^[3] Conformational change of ECD allows for signal transduction through the TM and into the cell. The ECD rotates 55 degrees up in the active form. ^[3]

TSHR Agonists and Antagonists

Chemical agonists are found in many living systems and serve as a way to activate receptors or pathways that are necessary for a wide array of biological processes. Chemical antagonists block or inhibit biological processes. Different types of agonists/antagonists exist within the body including hormones, antibodies, and neurotransmitters. The body naturally produces autoantibodies that can act as agonists and mimic the activating mechanism of the natural hormone. Isolating these antibodies in patients with diseases can lead researches to uncover the mechanism of binding for the receptor.

M22 Agonist

M22 is a monoclonal antibody that was isolated from a patient with Graves' Disease. In Graves' disease TSHR autoantibodies like M22 mimic TSH function and cause thyroid overactivity. ^[4]. The M22 autoantibody activates TSHR by causing a membrane clash with the ECD and cell membrane, therefore keeping the TSHR in the activate state by preventing the TSHR from rotating to the inactive state (Figure 2). This autoantibody mimics TSH action and binding to TSHR resulting in a potent activator for TSHR. ^[3]

Figure 2: Agonist and antagonist drugs for activating or inactivating the TSHR protein.