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Researchers identify mechanism which ‘turns thyroid on’.

Thyroid disease affects about 12 percent of the U.S. population. While many people with thyroid disease don’t even know they have it, an overactive or underactive thyroid can cause a slew of problems, including weight gain or loss, mood changes and infertility. In children, an underactive thyroid can be fatal, which is why they are tested for a deficiency at birth.  However, despite the prevalence of thyroid disease and its sometimes serious effects, researchers are still unclear as to how the hormone-producing gland is turned on.  Now, a study from researchers at the University of Leipzig has determined the mechanism which triggers normal and abnormal hormone production.  The team state that their findings will aid in the design of therapies for thyroid problems, such as Graves’ disease, and problems with other glands that operate in a similar fashion.  The opensource study is published in the the Journal of Biological Chemistry.

Previous studies show that the thyroid gland is a hormone factory. Under normal conditions the molecule calling the shots is the aptly named thyroid-stimulating hormone, TSH for short.  These glycoprotein hormones (GPHs), attach to  glycoprotein hormone receptors (GPHRs) on the thyroid cell surface, triggering a series of signals that provoke the gland to pump out thyroid hormones.  However, sometimes autoantibodies, essentially posing as TSH, attach to the receptor and trick the thyroid into flooding the body with more hormones than are needed. In addition, sometimes the receptor itself has an inherited or acquired mutation that triggers production of too many or too few hormones.  Meaning the legitimate activator hormone, autoantibodies and mutations are all able to provoke thyroid hormone production. The mechanisms of how these hormones activate GPHRs or how mutations and autoantibodies can alter receptor function are unclear.

The current study identified a small amino acid sequence, which the lab named p10 as it is 10 amino acids long, within the TSH receptor protein. Results show that this sequence functions as activator of the receptor upon binding of the hormone or autoantibodies, in other words, the receptor itself flips the switch, when it should and when it shouldn’t.

The group explain that in most other hormone-receptor systems, the hormone directly activates the receptor protein, offering the example of how adrenalin activates the ß adrenergic receptor.  They go on to add that in the case of glycoprotein hormone receptors (GPHRs), upon binding of the extracellular hormone, the intramolecular activator, p10, induces structural changes of the receptor protein and triggers activation of the intracellular signaling cascade.

The team surmise that their findings in cell studies shows that this family of receptors can essentially flip its own switch, information that can be used to design drugs to prevent that from happening when it shouldn’t. They go on to use the example of Graves’ disease, where autoantibodies directed against the TSH receptor stimulate the thyroid in an uncontrolled fashion, causing hyperthyroidism.  For the future, the researchers state that their findings will promote the development of specific small-molecule drugs useful to treat Graves’ disease and other dysfunctions of GPHRs.

Source: Universität Leipzig

Model of a glycoprotein hormone receptor (white backbone ribbon) with bound hormone and the activating antibody visualizes a potential arrangement and the principle mechanism of glycoprotein hormone receptor activation.  Credit: Journal of Biological Chemistry (doi: 10.1074/jbc.M115.701102).
Model of a glycoprotein hormone receptor (white backbone ribbon) with bound hormone and the activating antibody visualizes a potential arrangement and the principle mechanism of glycoprotein hormone receptor activation. Credit: Journal of Biological Chemistry (doi: 10.1074/jbc.M115.701102).

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