Sandbox Reserved 1781: Difference between revisions
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== Structure == | == Structure == | ||
===Overview=== | ===Overview=== | ||
The thyrotropin receptor has an extracellular domain (ECD) that is composed of a <scene name='95/952709/Lrrd_real/2'>leucine rich repeat domain (LRRD)</scene> as well as a hinge region. This <scene name='95/952709/Hinge_region_real/2'>hinge region</scene> links the ECD to the seven transmembrane helices <scene name='95/952709/7tm_helices/4'>(7TM domain)</scene>, which span from the extracellular domain to the intracellular domain <ref name= "Keinau et al.">Kleinau, G., Worth, C. L., Kreuchwig, A., Biebermann, H., Marcinkowski, P., Scheerer, P., & Krause, G. (2017). Structural–functional features of the thyrotropin receptor: A class A G-protein-coupled receptor at work. Frontiers in Endocrinology, 8. https://doi.org/10.3389/fendo.2017.00086</ref>. | The thyrotropin receptor has an extracellular domain (ECD) that is composed of a <scene name='95/952709/Lrrd_real/2'>leucine rich repeat domain (LRRD)</scene> as well as a hinge region. This <scene name='95/952709/Hinge_region_real/2'>hinge region</scene> links the ECD to the seven transmembrane helices <scene name='95/952709/7tm_helices/4'>(7TM domain)</scene>, which span from the extracellular domain to the intracellular domain <ref name= "Keinau et al.">Kleinau, G., Worth, C. L., Kreuchwig, A., Biebermann, H., Marcinkowski, P., Scheerer, P., & Krause, G. (2017). Structural–functional features of the thyrotropin receptor: A class A G-protein-coupled receptor at work. Frontiers in Endocrinology, 8. https://doi.org/10.3389/fendo.2017.00086</ref>. Thyrotropin binding causes a conformational change in the ECD that is transduced through the transmembrane helices. In the active state, the ECD is in the "up" position, while in the inactive state, the ECD is in the "down" state, closer to the cell membrane. A "push-pull" mechanism is proposed to be responsible for the ECD's conformational change between active and inactive states. In the "push" model, TSH binds to the receptor and sterically clashes with the cellular membrane forcing the ECD up away from the membrane. In the pull model, a short α-helix interacts with TSH to pull the ECD up. The active (up) form of the ECD causes a conformation shift in the TMD which causes differential interactions with a heterotrimeric <scene name='95/952709/G_protein/2'>G-protein</scene>, initiating intracellular signaling. | ||
===Hinge Region and P10 Peptide=== | ===Hinge Region and P10 Peptide=== | ||
Several parts of TSHR are very important for the functioning of TSH signaling. The <scene name='95/952709/Hinge_region_real/2'>hinge region</scene> is a scaffold for the attachment of the ECD to the 7TMD. Also, this region, has been found to have impact on the binding potency of TSH as well as intracellular cyclic adenosine monophosphate (cAMP) levels, which are partially mediated by the activation of the GPCR. Several features of this region have been found to be crucial to the potent activation of of the TSHR by TSH.<ref name="Mizutori et al.">Yumiko Mizutori, Chun-Rong Chen, Sandra M. McLachlan, Basil Rapoport, The Thyrotropin Receptor Hinge Region Is Not Simply a Scaffold for the Leucine-Rich Domain but Contributes to Ligand Binding and Signal Transduction, Molecular Endocrinology, Volume 22, Issue 5, 1 May 2008, Pages 1171–1182, https://doi.org/10.1210/me.2007-0407</ref>. The most important feature of the hinge region is the interaction of the <scene name='95/952709/Hinge_helix_rotation/1'>hinge helix</scene> with the <scene name='95/952709/P10_peptide_region/2'>p10 peptide</scene> through disulfides. The p10 peptide is a conserved sequence that spans from the last beta sheet of the LRRD to the first transmembrane helix (TM1)<ref name="Faust et al.">Faust, B., Billesbølle, C.B., Suomivuori, CM. et al. Autoantibody mimicry of hormone action at the thyrotropin receptor. Nature 609, 846–853 (2022). https://doi.org/10.1038/s41586-022-</ref>. These disulfides are critical as they link the ECD, where thyrotropin binds, to the TMD, whose conformational changes directly mediate the activation of the receptor's complementary G-protein. Movement of the ECD, caused by TSH binding, will cause rotation of the hinge helix and subsequent movement of the p10 peptide leading to movement of the transmembrane helices which will cause activation of the G-protein. In addition to activation, the hinge region plays an important role in tightly binding TSH. Residues 382-390 of the hinge region adopt a short helix containing Y385 and D386. Y385 is buried into a hydrophobic region of TSH while D386 forms a salt bride with R386 of the hormone. Together, <scene name='95/952709/Binding_interactions_hinge/1'>these interactions</scene> assist in facilitating the stable binding of TSH to the TSHR <ref name="Duan et al.">PMID:35940204</ref>. This being said, it is important to acknowledge, the hinge region itself is not required for the activation of the receptor<ref name="Faust et al.">Faust, B., Billesbølle, C.B., Suomivuori, CM. et al. Autoantibody mimicry of hormone action at the thyrotropin receptor. Nature 609, 846–853 (2022). https://doi.org/10.1038/s41586-022-</ref>. | Several parts of TSHR are very important for the functioning of TSH signaling. The <scene name='95/952709/Hinge_region_real/2'>hinge region</scene> is a scaffold for the attachment of the ECD to the 7TMD. Also, this region, has been found to have impact on the binding potency of TSH as well as intracellular cyclic adenosine monophosphate (cAMP) levels, which are partially mediated by the activation of the GPCR. Several features of this region have been found to be crucial to the potent activation of of the TSHR by TSH.<ref name="Mizutori et al.">Yumiko Mizutori, Chun-Rong Chen, Sandra M. McLachlan, Basil Rapoport, The Thyrotropin Receptor Hinge Region Is Not Simply a Scaffold for the Leucine-Rich Domain but Contributes to Ligand Binding and Signal Transduction, Molecular Endocrinology, Volume 22, Issue 5, 1 May 2008, Pages 1171–1182, https://doi.org/10.1210/me.2007-0407</ref>. The most important feature of the hinge region is the interaction of the <scene name='95/952709/Hinge_helix_rotation/1'>hinge helix</scene> with the <scene name='95/952709/P10_peptide_region/2'>p10 peptide</scene> through disulfides. The p10 peptide is a conserved sequence that spans from the last beta sheet of the LRRD to the first transmembrane helix (TM1)<ref name="Faust et al.">Faust, B., Billesbølle, C.B., Suomivuori, CM. et al. Autoantibody mimicry of hormone action at the thyrotropin receptor. Nature 609, 846–853 (2022). https://doi.org/10.1038/s41586-022-</ref>. These disulfides are critical as they link the ECD, where thyrotropin binds, to the TMD, whose conformational changes directly mediate the activation of the receptor's complementary G-protein. Movement of the ECD, caused by TSH binding, will cause rotation of the hinge helix and subsequent movement of the p10 peptide leading to movement of the transmembrane helices which will cause activation of the G-protein. In addition to activation, the hinge region plays an important role in tightly binding TSH. Residues 382-390 of the hinge region adopt a short helix containing Y385 and D386. Y385 is buried into a hydrophobic region of TSH while D386 forms a salt bride with R386 of the hormone. Together, <scene name='95/952709/Binding_interactions_hinge/1'>these interactions</scene> assist in facilitating the stable binding of TSH to the TSHR <ref name="Duan et al.">PMID:35940204</ref>. This being said, it is important to acknowledge, the hinge region itself is not required for the activation of the receptor<ref name="Faust et al.">Faust, B., Billesbølle, C.B., Suomivuori, CM. et al. Autoantibody mimicry of hormone action at the thyrotropin receptor. Nature 609, 846–853 (2022). https://doi.org/10.1038/s41586-022-</ref>. | ||
