Sandbox 27: Difference between revisions
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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 == | ||
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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. | 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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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 == | ||
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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. <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> | 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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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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== References == | == References == | ||
<references /> | |||
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== Proteopedia Page Contributors and Editors == | == Proteopedia Page Contributors and Editors == | ||
Nathalie FAGGIANELLI and Meriam ANNANI | Nathalie FAGGIANELLI and Meriam ANNANI | ||