Sandbox Reserved 1774

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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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1 Thyroid Stimulating Hormone Receptor (TSHR) Structure and Function

Thyroid Stimulating Hormone Receptor (TSHR) Structure and Function

Introduction

In humans, the hypothalamic-pituitary-thyroid (HPT) signaling axis regulates functions including metabolism, growth, organ development, and neural differentiation ^[1]. In this pathway, the thyroid stimulating hormone receptor (TSHR) activates transcription of thyroid hormones in response to ligand binding by thyroid stimulating hormone (TSH). After a brief introduction to the biological significance of TSHR, this page explores the structure of TSHR and its significance to TSH binding and receptor activation.

Biological Significance of TSHR

The HPT signaling axis involves the brain, thyroid gland, and bloodstream circulation. In the first step of the pathway, thyrotropin releasing hormone (TRH) is secreted by the hypothalamus, which in turn stimulates the anterior pituitary gland to produce TSH ^[1]. TSH binds to TSHR on the surface of thyroid cells and triggers the production of thyroid hormones thyroxine (T3) and triiodothyronine (T4) through G-protein coupled receptor (GPCR) signaling ^[2]. T3 and T4 circulate in the bloodstream and enter cells via thyroid hormone transporters to regulate metabolic functions. Additionally, T3 and T4 act in a negative feedback loop to inhibit further TSH production ^[1].

Dysregulation of TSHR can lead to disease. In Grave's disease, antibody analogs of TSH cause overactivation of TSHR, leading to clinical symptoms of hyperthyroidism ^[2]. In contrast, congenital mutations which inactivate TSHR can lead to hypothyroidism, which results in growth retardation and neurologic impairment if left untreated ^[1].

Structural Overview of TSHR

Describe the domains here.

TSHR Activation

Hinge Motion

Describe the hinge motion and biological function here. This shows the TSHR hinge movement. This shows the TSHR hinge movement. .

Image:TSHR MorphBetterAngle.mp4

Stabilizing Interactions in the Hinge

Describe important structural features of the hinge here.

Ligand Binding

Ligand-induced Conformation Change

Describe how TSH binds in the upright conformation here.

Ligand Recognition

Describe seatbelt and hinge important to ligand recognition here.

References

↑ ^1.0 ^1.1 ^1.2 ^1.3 Brent GA. Mechanisms of thyroid hormone action. J Clin Invest. 2012;122(9):3035-3043. DOI: 10.1172/JCI60047
↑ ^2.0 ^2.1 Chu YD, Yeh CT. The Molecular Function and Clinical Role of Thyroid Stimulating Hormone Receptor in Cancer Cells. Cells. 2020;9(7):1730. DOI:10.3390/cells9071730

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 == Biological Significance of TSHR ==
-[[Image:HPT Axis.jpg|200 px|right|thumb|Figure 1: TSHR binds TSH in the HPT signaling axis pathway, which regulates metabolism and growth.]]
+[[Image:HPT Axis.jpg|300 px|right|Figure 1: TSHR binds TSH in the HPT signaling axis pathway, which regulates metabolism and growth.]]
 The HPT signaling axis involves the brain, thyroid gland, and bloodstream circulation. In the first step of the pathway, thyrotropin releasing hormone (TRH) is secreted by the hypothalamus, which in turn stimulates the anterior pituitary gland to produce TSH <ref name="Brent" />. TSH binds to TSHR on the surface of thyroid cells and triggers the production of thyroid hormones thyroxine (T3) and triiodothyronine (T4) through G-protein coupled receptor (GPCR) signaling <ref name="Chu">Chu YD, Yeh CT. The Molecular Function and Clinical Role of Thyroid Stimulating Hormone Receptor in Cancer Cells. Cells. 2020;9(7):1730. [https://doi.org/10.3390/cells9071730 DOI:10.3390/cells9071730]</ref>. T3 and T4 circulate in the bloodstream and enter cells via thyroid hormone transporters to regulate metabolic functions. Additionally, T3 and T4 act in a negative feedback loop to inhibit further TSH production <ref name="Brent" />.