Sandbox Reserved 1779

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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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spinqualitylabelsall models Thyrotropin Receptor 7T9M Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Introduction Figure 1. TSHR with TSH bound. The extracellular and transmembrane domains of the GPCR are shown in green, the hinge region in cyan, the P10 peptide in pink, and thyrotropin bound in pink and yellow. Thyroid hormones exercise essential functions related to thymocyte activity as well as metabolic processes and oxygen consumption. Misregulation of thyroid hormones is the cause of many disorders related to hypo- or hyperthyroidism. Thus, understanding the signaling of synthesis and release of these hormones is essential to the development therapeutic drugs to combat specific thyroid hormone disorders. The initiation of the synthesis and release of these hormones is caused by the glycoprotein, thyroid stimulating hormone, commonly referred to as TSH or thyrotropin. The thyrotropin receptor (TSHR) is a G-protein coupled receptor that binds TSH and transduces signal to initiate synthesis and release of thyroid hormones. It is important to note that autoantibodies may also bind to this receptor causing inhibition or activation of its desired function. (Figure 1). 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 Structure Overview The thyrotropin receptor has an extracellular domain (ECD) that is composed of a leucine rich repeat domain (LRRD) as well as a hinge region. This hinge region links the ECD to the seven transmembrane helices (7TM domain), which span from the extracellular domain to the intracellular domain . When thyrotropin or an autoantibody binds, it causes a conformational change in the receptor through the transmembrane helices. This causes the thyrotropin receptor to interact differently with its respective G-protein when in the active and inactive states. Leucine Rich Region The Leucine Rich region is part of the extracellular domain (ECD) of TSHR. The highlighted region contains 10-11 Leucine Repeats within the structure. The specific residues from TSHR interacting with TSH are Lys209 and Lys58 . These interact with Glu 98 and Asp 91 in the seatbelt region of TSH forming a salt bridge and initiating the conformational change in the receptor . 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 extracellular domain (ECD) sticks out from the cell membrane into the space outside the cell. The transmembrane domain contains 7 alpha helices that reside within the cell membrane. The TSHR active form 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. 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. 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. . 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. Figure 2: Agonist and antagonist drugs for activating or inactivating the TSHR protein.