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
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TSHR Activation
Hinge Motion
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This shows the TSHR hinge movement.
This shows the TSHR hinge movement.
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- Image:TSHR MorphBetterAngle.mp4
Stabilizing Interactions in the Hinge
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Ligand Binding
Ligand-induced Conformation Change
Describe how TSH binds in the upright conformation here.
Ligand Recognition
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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
