Sandbox 27

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TSH Receptor in complex with the thyroid-stimulating autoantibody M22

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The thyrotropin receptor (or TSH receptor or TSHR) is a member of the G protein-coupled receptor superfamily of integral membrane proteins and is coupled to the Gs protein. It is on the surface of thyroid follicular cells. Once stimulated by TSH (Thyroid-Stimulating Hormone), THSR activates the production of thyroid hormones: thyroxine (T4) and triiodothyronine (T3).

TSH and M22

TSH is a hormone also known as "thyrotropin". It is a member of the glycoprotein family (like LH, FSH or hCG). TSH regulates growth and function of thyroid follicular cells, and the gonadotropins LH/CG and FSH play an important role in human reproduction. Therefore, this class of receptors is central to medical, pharmaceutical, and biological research.

The studies on the structure of TSH receptor are based upon its binding to an antibody called M22. Crystals suitable for X-Ray diffraction analysis were obtained and the structure solved at 2.55 A resolution. Further crystallographic information is available from Pubmed

M22 is a thyroid stimulating human monoclonal antibody prepared using lymphocytes from a patient with Graves’ disease. It is an antibody to the TSHR. It mimics closely the binding of TSH on its receptor, so it stimulates the receptor and inhibits the binding of TSH to give rise to full activation of receptor mediated signal transduction.

Signalling pathway

Structure of the TSH Receptor

This receptor is evolutionary classified as rhodopsin-like receptors of family A. It is consisted of three different domains:

• An extracellular domain consisting of ten leucine-rich repeats (leucine rich domain or LRD), with a N-terminal tail linked by disulfide bonds. This ectodomain forms a concave surface (also with some contribution from the CD), it is responsible for the high affinity and selective binding of the corresponding hormones.
• A cleavage domain (or CD), containing six half-cystines. This domain is cleaved out upon maturation in the case of the TSHR.
• A transmembrane domain (also called "serpentine"), containing seven helixes connected by three extra- and three intracellular loops (ECL1-3; ICL1-3) and a C-terminal intracellular domain.

Full information about the LRD domain from Hot Thyroidology Journal

Here is a scheme of the THS bound to its receptor TSRH: Media:http://www.hotthyroidology.com/editorial_pics/editorial15_figure1.jpg

Structure of the complexe TSHR – M22

 : M22 Light chain (fragment or Fab)

 : Autoantibody M22 Heavy chain (fragment or Fab) Chain C: Fragment Leucine Rich Repeat Domain (Segment 22-260) of Thyrotropin Receptor

M22 binds to the concave surface of the LRD domain. The binding results of several interactions between TSHR and M22, most of them are hydrogen bonds and salt bridges. The heavy chain (HC) of M22 has more interactions with the LRD than has the light chain (respectively 14 and 8 interactions). [1]

The binding of M22 to the LRD must induce changes in the receptor conformation, which cause signal induction, but the nature of these changes are not currently known. Indeed no movement of the atoms of M22 is observed after its binding to the receptor. This conformational change may occur also with TSH binding.

Although the two ligands of TSHR (M22 and TSH) have different structures, there are similar types of interaction. The M22 LC interacts with the LCD in a very close way to the beta-chain of TSH. And it’s the same case with M22 HC and TSH alpha-chain.

However we can remark that the M22–TSHR complex involves more strong interactions and fewer hydrophobic interactions than the TSH–TSHR complex. That can explain the effects of autoantibody like M22 binding with the TSHR. (diseases)

Diseases

Like M22 other autoantibodies can bind to the TSHR and be responsible for diseases:

• antibodies binding to the receptor TSH (also called TRACK)

The disease of Basedow ou Graves Basedow is an autoimmune disease consisting of a hyperthyroidism. The sick person produces abnormal antibodies against the follicular cells of the thyroid. Theses antibodies imitate the effects of TSH and thus over-stimulate continually the production of thyroidal hormones. That causes a hypertrophy of thyroid with formation of a goiter. This disease is more frequent in woman than man; the symptoms are in particular an acceleration of basal metabolism, diaphorese, cardiac arhythmy, increasing of nervosity, ophtalmopathy...

• Another case of hyperthyroidism: linked to hCG

hCG is the chorionic gonadotrope hormone produced during the pregnancy. This hormone has structural homologies with TSH and thus can be a low agonist of the receptor. Secreted in high concentrations, it can cause hyperthyroidism too.

The comprehension of the interactions between the autoantibody and their receptor can be useful for designing a new generation of drugs which will control for example thyroid function by targeting the actions of these autoantibodies responsible for autoimmune diseases.

External ressources

References

Proteopedia Page Contributors and Editors

Nathalie FAGGIANELLI and Meriam ANNANI