Sandbox 27
From Proteopedia
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 located 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).
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TSH and M22
TSH is a hormone also known as "thyrotropin". It is a member of the Glycoprotein Hormone Family or GHF(like hormones LH, FSH or hCG). TSH regulates the growth and the function of thyroid follicular cells by stimulating the secretion of thyroid hormones T3 and T4. These play an important role in human reproduction, metabolism and cellular development. Therefore, this class of receptors is central to medical, pharmaceutical, and biological research.
Studies on the structure of TSH receptor are based upon its binding to an antibody called M22. TSH - M22 complex can be studied by crystallography and X-Ray diffraction analysis at 2.55 A resolution. Zinc ions are used as cristallisation additive (there is no specific interaction with the protein). Further information is available from Pubmed [1]
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
TSH hormone or in our case the autoantibody M22 binds to its receptor (more precisely to LRD). This binding actives the receptor and then small G-proteins coupled to the receptor. The alpha subunit stimulates enzymes of the cellular membrane. A cascade of reactions and second messengers pathways are involved and result in the stimulation and the synthesis of thyroid hormones T3 and T4.
Structure of the TSH Receptor
This receptor is evolutionary classified as rhodopsin-like receptors of family A. It is constituted of five different domains (as represented on the opposite scheme)
- An extracellular domain or ectodomain: it consists of ten leucine-rich repeats, so also called leucine rich domain or LRD, or LRRs. This ectodomain has a shape of slightly curved helical tube (also with some contribution from the CD), it is responsible for the high affinity and selective binding of TSH or M22.
- A N-Terminal tail: it contains four half-cystines linked by disulfide bonds to the first of ten repeats of the LRD.
- A cleavage domain (or CD, or CR for cleaved region): it contains six half-cystines and it is cleaved out upon maturation.
- A transmembrane domain (also called "serpentine" or TMD): it contains seven helixes connected by three extra- and three intracellular loops (ECL1-3; ICL1-3).
- A C-terminal intracellular domain
Full information about the LRD domain from : Hot Thyroidology Journal [2]
One of models for the receptor’s activation explains that interactions between ectodomain and extracellular loops would inhibit the activity of serpentine domain in the absence of stimulation. But when TSH is binding to LRD, the ectodomain would have a change of conformation which activates the transduction of signal. [3]
Structure of the complexe TSHR – M22
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| 3g04, resolution 2.55Å () | |||||||||
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| Ligands: | , | ||||||||
| Gene: | TSHR (Homo sapiens) | ||||||||
| Related: | 1xwd | ||||||||
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| Resources: | FirstGlance, OCA, RCSB, PDBsum | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
M22 binds to the concave surface of the LRD domain (only a fragment of this domain is represented on the pdb structure: residues 22 to 260 of TSHR)
The binding results of several interactions between TSHR and M22, most of them are hydrogen bonds and salt bridges. The (HC, or Chain B) of M22 has more interactions with the than has the (LC, or Chain A), respectively 14 and 8 interactions. [4]
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 the binding of autoantibody like M22. So the idendification of interaction residues and understanding of the mechanism may be useful for developing means of inhibiting TSHR autoantibodies binding.
Other 3D structure of complexes between TSHR and autoantibodies from pdb: 2xwt
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.
References
- ↑ J. Sanders and co Crystal, Structure of the TSH Receptor in Complex with a Thyroid-Stimulating Autoantibody, THYROID Volume 17, Number 5, 2007 PMID:17542669
- ↑ B R Smith, J Sanders, J Furmaniak, The TSH receptor – a new cristal structure, Hot Thyroidology Journal, article n°175
- ↑ V Vlaeminck-Guillem, G Vassart et S Costagliola, Un modèle d’activation du récepteur de la TSH / A THS receptor activation model, M/S : médecine sciences, vol. 18, n° 12, 2002, p. 1184-1186.[[1]]
- ↑ J. Sanders and co Crystal, Structure of the TSH Receptor in Complex with a Thyroid-Stimulating Autoantibody, THYROID Volume 17, Number 5, 2007 PMID:17542669
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