Sandbox Reserved 1779: Difference between revisions

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TSHR exists in dynamic equilibrium between two states: active and inactive (Figure 2). In the active form, the extracellular portion is rotated 55° away from the cell membrane. TSH will bind and keep the active state in the up position as a result of clashes between bound TSH and the cell membrane.<ref name="Faust" />. <scene name='95/952708/Tsh_7t9i/5'>Glycolysations of an N52 residue</scene> on the <scene name='95/952707/Tsh_7t9i/1'>α-subunit of TSH</scene> cause this clash.

===Structural Overview===

The thyrotropin receptor has an extracellular domain (ECD) that is composed of a <scene name='95/952709/Lrrd_real/3'>leucine rich repeat domain (LRRD)</scene> as well as a hinge region. The <scene name='95/952709/Hinge_region_real/6'>hinge region</scene> links the ECD to the seven transmembrane helices <scene name='95/952709/7tm_helices/5'>(7TM domain)</scene>, which span from the ECD to the intracellular loops <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 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<ref name="Duan et al.">PMID:35940204</ref>.

The thyrotropin receptor has an extracellular domain (ECD) that is composed of a <scene name='95/952709/Lrrd_real/3'>leucine rich repeat domain (LRRD)</scene> as well as a hinge region. The <scene name='95/952709/Hinge_region_real/6'>hinge region</scene> links the ECD to the seven transmembrane helices <scene name='95/952709/7tm_helices/5'>(7TM domain)</scene>, which span from the ECD to the intracellular loops <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 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/3'>G-protein</scene>, initiating intracellular signaling<ref name="Duan et al.">PMID:35940204</ref>.

=== Leucine Rich Repeats ===

The Leucine Rich Repeat Domain (LRRD) is part of the <scene name='95/952708/Tshr_chainr_ecd/1'>ECD</scene> of TSHR and contains <scene name='95/952707/Lrr/5'>10-11 Leucine Rich Repeats</scene>. A unique feature of this region is that it is composed entirely of β-pleated sheets. These β-pleated sheets of the LRRD provide a concave binding surface for TSH, including the residues <scene name='95/952707/Interactions_with_thyrotropin/4'>K209 and K58</scene> <ref name="Duan et al.">PMID: 35940204</ref>. These interact with <scene name='95/952707/Interactions_with_thyrotropin/4'>N91 and E98</scene> in the seatbelt region of TSH forming a salt bridge and assisting in binding TSH <ref name="Faust">PMID: 35940205</ref>. This interaction is specific to TSH and TSHR. When other agonists or antagonists bind to the receptor, the change in conformation is a result of different residues interacting, as explained later in the page. The LRRD acts as a probe to receive information from the extracellular environment.

Sandbox Reserved 1779: Difference between revisions

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@@ Line 10: / Line 10: @@
 TSHR exists in dynamic equilibrium between two states: active and inactive (Figure 2). In the active form, the extracellular portion is rotated 55° away from the cell membrane. TSH will bind and keep the active state in the up position as a result of clashes between bound TSH and the cell membrane.<ref name="Faust" />. <scene name='95/952708/Tsh_7t9i/5'>Glycolysations of an N52 residue</scene> on the <scene name='95/952707/Tsh_7t9i/1'>α-subunit of TSH</scene> cause this clash.
 ===Structural Overview===
-The thyrotropin receptor has an extracellular domain (ECD) that is composed of a <scene name='95/952709/Lrrd_real/3'>leucine rich repeat domain (LRRD)</scene> as well as a hinge region. The <scene name='95/952709/Hinge_region_real/6'>hinge region</scene> links the ECD to the seven transmembrane helices <scene name='95/952709/7tm_helices/5'>(7TM domain)</scene>, which span from the ECD to the intracellular loops <ref name= "Keinau et al.">Kleinau, G., Worth, C. L., Kreuchwig, A., Biebermann, H., Marcinkowski, P., Scheerer, P., &amp; 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 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<ref name="Duan et al.">PMID:35940204</ref>.
+The thyrotropin receptor has an extracellular domain (ECD) that is composed of a <scene name='95/952709/Lrrd_real/3'>leucine rich repeat domain (LRRD)</scene> as well as a hinge region. The <scene name='95/952709/Hinge_region_real/6'>hinge region</scene> links the ECD to the seven transmembrane helices <scene name='95/952709/7tm_helices/5'>(7TM domain)</scene>, which span from the ECD to the intracellular loops <ref name= "Keinau et al.">Kleinau, G., Worth, C. L., Kreuchwig, A., Biebermann, H., Marcinkowski, P., Scheerer, P., &amp; 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 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/3'>G-protein</scene>, initiating intracellular signaling<ref name="Duan et al.">PMID:35940204</ref>.
 === Leucine Rich Repeats ===
 The Leucine Rich Repeat Domain (LRRD) is part of the <scene name='95/952708/Tshr_chainr_ecd/1'>ECD</scene> of TSHR and contains <scene name='95/952707/Lrr/5'>10-11 Leucine Rich Repeats</scene>. A unique feature of this region is that it is composed entirely of β-pleated sheets. These β-pleated sheets of the LRRD provide a concave binding surface for TSH, including the residues <scene name='95/952707/Interactions_with_thyrotropin/4'>K209 and K58</scene> <ref name="Duan et al.">PMID: 35940204</ref>. These interact with <scene name='95/952707/Interactions_with_thyrotropin/4'>N91 and E98</scene> in the seatbelt region of TSH forming a salt bridge and assisting in binding TSH <ref name="Faust">PMID: 35940205</ref>. This interaction is specific to TSH and TSHR. When other agonists or antagonists bind to the receptor, the change in conformation is a result of different residues interacting, as explained later in the page. The LRRD acts as a probe to receive information from the extracellular environment.