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TSH Receptor in complex with the thyroid-stimulating autoantibody M22 | '''TSH Receptor in complex with the thyroid-stimulating autoantibody M22''' | ||
PLEASE do NOT change this sandbox. It is currently reserved | |||
''PLEASE do NOT change this sandbox. It is currently reserved for a Proteopedia Project (ESBS Strasbourg)'' | |||
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). | 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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Studies on the structure of TSH receptor are based upon its binding to an antibody called M22. | 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 [http://www.ncbi.nlm.nih.gov/pubmed/17542669 Pubmed] <ref> 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 </ref> | 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 [http://www.ncbi.nlm.nih.gov/pubmed/17542669 Pubmed] <ref> J. Sanders and co Crystal, Structure of the TSH Receptor in Complex with a Thyroid-Stimulating Autoantibody, THYROID Volume 17, Number 5, 2007 [http://www.liebertonline.com/doi/abs/10.1089/thy.2007.0034?journalCode=thy PMID:17542669] </ref> | ||
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. | 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 == | == Signalling pathway == | ||
[[Image:TSHR 1.jpg | thumb | right]] | |||
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. | |||
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== Structure of the TSH Receptor == | == Structure of the TSH Receptor == | ||
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Full information about the LRD domain from : [http://www.hotthyroidology.com/editorial_175.html Hot Thyroidology Journal] <ref> B R Smith, J Sanders, J Furmaniak, The TSH receptor – a new cristal structure, Hot Thyroidology Journal, article n°175</ref> | Full information about the LRD domain from : [http://www.hotthyroidology.com/editorial_175.html Hot Thyroidology Journal] <ref> B R Smith, J Sanders, J Furmaniak, The TSH receptor – a new cristal structure, Hot Thyroidology Journal, article n°175</ref> | ||
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. <ref> 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. </ref> | 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. <ref> 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.[[http://www.erudit.org/revue/MS/2002/v18/n12/000588ar.pdf]] </ref> | ||
== Structure of the complexe TSHR – M22 == | == Structure of the complexe TSHR – M22 == | ||
{{STRUCTURE_3g04| PDB=3g04 | SCENE= | size='500'}} | |||
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) | 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 <scene name='Sandbox_27/Chaine_b/3'>heavy chain</scene> (HC, or Chain B) of M22 has more interactions with the <scene name='Sandbox_27/Chaine_c/1'>LRD</scene> than has the <scene name='Sandbox_27/Chaine_a/2'>light chain</scene> (LC, or Chain A), respectively 14 and 8 interactions. [http://www. | The binding results of several interactions between TSHR and M22, most of them are hydrogen bonds and salt bridges. The <scene name='Sandbox_27/Chaine_b/3'>heavy chain</scene> (HC, or Chain B) of M22 has more interactions with the <scene name='Sandbox_27/Chaine_c/1'>LRD</scene> than has the <scene name='Sandbox_27/Chaine_a/2'>light chain</scene> (LC, or Chain A), respectively 14 and 8 interactions. <ref> J. Sanders and co Crystal, Structure of the TSH Receptor in Complex with a Thyroid-Stimulating Autoantibody, THYROID Volume 17, Number 5, 2007 [http://www.ncbi.nlm.nih.gov/pubmed/19221175 PMID:17542669] </ref> | ||
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. | 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. | ||
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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. | 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 | 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: [http://www.rcsb.org/pdb/explore/explore.do?structureId=2XWT 2xwt] | |||
== Diseases == | == Diseases == | ||
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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. | 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 == | ||
<references /> | |||
== Proteopedia Page Contributors and Editors == | == Proteopedia Page Contributors and Editors == | ||
Nathalie FAGGIANELLI and Meriam ANNANI | Nathalie FAGGIANELLI and Meriam ANNANI | ||