Sandbox Reserved 1791: Difference between revisions

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TSHR has 3 main domains</scene>: Leucine Rich Region Domain (coral), the hinge region (blue-purple), and the transmembrane region(rainbow). The leucine rich region domain is the extracellular TSH ligand domain. The hinge connects the Leucine Rich Repeat Domain and the Transmembrane Region. It provides flexibility for the switch between the active and inactive state of TSHR. The transmembrane region is located within the plasma membrane. Its function transmit the extracellular signal across the membrane to the intracellular [https://en.wikipedia.org/wiki/G_protein G-proteins] bound to the N-terminus of the transmembrane region<ref name="Duan"/>. Activated G-proteins then signal a robust intracellular signaling cascade.

=== Leucine Rich Domain===

The <scene name='95/952719/Lrrd/1'>Leucine Rich Repeat Domain (LRRD)</scene> is ~~part of~~ the extracellular region of TSHR. ~~It is made up of about 280 different residues. Connected~~ to its C-terminus ~~is the Hinge Region~~. It is made up of ~~an extensive~~ parallel β-sheet~~. This β-sheet is~~ where TSH binds and is called the binding pocket<ref name="Duan"> DOI 10.1038/s41586-022-05173-3</ref>~~. The <scene name='95/952719/Binding_pocket/7'>binding pocket</scene> is a concave structure with many polar residues~~. This pocket is where the TSH antibody and agonist K1 bind as well as the agonist M22. These structures interact with specific residues to result in a structural change of the molecule. There is a mutation done by N-glycans at asparagine residues that plays a large role in the binding of TSH. The negative charge on these glycans contributes to the polarity of the binding pocket which mediates the binding efficiency of TSH. It has been shown that four of the five N glycan sites must be glycosylated to be in the active form<ref name="Fokina">Fokina, E.F., Shpakov, A.O. Thyroid-Stimulating Hormone Receptor: the Role in the Development of Thyroid Pathology and Its Correction. J Evol Biochem Phys 58, 1439–1454 (2022). [DOI:10.1134/S0022093022050143 https://doi.org/10.1134/S0022093022050143]</ref>.

The <scene name='95/952719/Lrrd/1'>Leucine Rich Repeat Domain (LRRD)</scene> is the extracellular ligand binding region of TSHR. Connects to the Hinge Region at its C-terminus. It is made up of polar residues in a concave parallel β-sheet where TSH binds and is called the <scene name='95/952719/Binding_pocket/7'>binding pocket</scene><ref name="Duan"> DOI 10.1038/s41586-022-05173-3</ref>. This pocket is where the TSH antibody and agonist K1 bind as well as the agonist M22. These structures interact with specific residues to result in a structural change of the molecule. There is a mutation done by N-glycans at asparagine residues that plays a large role in the binding of TSH. The negative charge on these glycans contributes to the polarity of the binding pocket which mediates the binding efficiency of TSH. It has been shown that four of the five N glycan sites must be glycosylated to be in the active form<ref name="Fokina">Fokina, E.F., Shpakov, A.O. Thyroid-Stimulating Hormone Receptor: the Role in the Development of Thyroid Pathology and Its Correction. J Evol Biochem Phys 58, 1439–1454 (2022). [DOI:10.1134/S0022093022050143 https://doi.org/10.1134/S0022093022050143]</ref>.

=== Hinge Region===

The <scene name='95/952719/Hinge_region_spin/3'>Higne Region</scene>(purple-blue) connects the Transmembrane Region to the Leucine Rich Domain. It is sometimes referred to as the signaling specificity domain because there is some evidence suggesting that this region is important in both TSH binding and signal transduction. <ref name="Chen">Chen CR, McLachlan SM, Rapoport B. Thyrotropin (TSH) receptor residue E251 in the extracellular leucine-rich repeat domain is critical for linking TSH binding to receptor activation. Endocrinology. 2010 Apr;151(4):1940-7. doi: 10.1210/en.2009-1430. Epub 2010 Feb 24. PMID: 20181794; PMCID: PMC2851189. [DOI 10.1210/en.2009-1430 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2851189/]</ref>. It is made up of two α-helices that are connected via disulfide bonds(shown in yellow). Interactions between these two helices and TSH help orient TSH properly. These interactions are essential for TSH binding, however, they are not required for the activation of TSHR. Conformational changes in this region, specifically the orientation of <scene name='95/952719/Hinge_region_residues/3'>Y279</scene>(shown in active state), are responsible for bringing TSHR into the active state <ref name="Faust"/>.

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@@ Line 11: / Line 11: @@
 TSHR has 3 main domains</scene>: Leucine Rich Region Domain (coral), the hinge region (blue-purple), and the transmembrane region(rainbow). The leucine rich region domain is the extracellular TSH ligand domain. The hinge connects the Leucine Rich Repeat Domain and the Transmembrane Region. It provides flexibility for the switch between the active and inactive state of TSHR. The transmembrane region is located within the plasma membrane. Its function transmit the extracellular signal across the membrane to the intracellular [https://en.wikipedia.org/wiki/G_protein G-proteins] bound to the N-terminus of the transmembrane region<ref name="Duan"/>. Activated G-proteins then signal a robust intracellular signaling cascade.
 === Leucine Rich Domain===
-The <scene name='95/952719/Lrrd/1'>Leucine Rich Repeat Domain (LRRD)</scene> is part of the extracellular region of TSHR. It is made up of about 280 different residues. Connected to its C-terminus is the Hinge Region. It is made up of an extensive parallel β-sheet. This β-sheet is where TSH binds and is called the binding pocket<ref name="Duan"> DOI 10.1038/s41586-022-05173-3</ref>. The <scene name='95/952719/Binding_pocket/7'>binding pocket</scene> is a concave structure with many polar residues. This pocket is where the TSH antibody and agonist K1 bind as well as the agonist M22. These structures interact with specific residues to result in a structural change of the molecule. There is a mutation done by N-glycans at asparagine residues that plays a large role in the binding of TSH. The negative charge on these glycans contributes to the polarity of the binding pocket which mediates the binding efficiency of TSH. It has been shown that four of the five N glycan sites must be glycosylated to be in the active form<ref name="Fokina">Fokina, E.F., Shpakov, A.O. Thyroid-Stimulating Hormone Receptor: the Role in the Development of Thyroid Pathology and Its Correction. J Evol Biochem Phys 58, 1439–1454 (2022). [DOI:10.1134/S0022093022050143 https://doi.org/10.1134/S0022093022050143]</ref>.
+The <scene name='95/952719/Lrrd/1'>Leucine Rich Repeat Domain (LRRD)</scene> is the extracellular ligand binding region of TSHR. Connects to the Hinge Region at its C-terminus. It is made up of polar residues in a concave parallel β-sheet where TSH binds and is called the <scene name='95/952719/Binding_pocket/7'>binding pocket</scene><ref name="Duan"> DOI 10.1038/s41586-022-05173-3</ref>. This pocket is where the TSH antibody and agonist K1 bind as well as the agonist M22. These structures interact with specific residues to result in a structural change of the molecule. There is a mutation done by N-glycans at asparagine residues that plays a large role in the binding of TSH. The negative charge on these glycans contributes to the polarity of the binding pocket which mediates the binding efficiency of TSH. It has been shown that four of the five N glycan sites must be glycosylated to be in the active form<ref name="Fokina">Fokina, E.F., Shpakov, A.O. Thyroid-Stimulating Hormone Receptor: the Role in the Development of Thyroid Pathology and Its Correction. J Evol Biochem Phys 58, 1439–1454 (2022). [DOI:10.1134/S0022093022050143 https://doi.org/10.1134/S0022093022050143]</ref>.
 === Hinge Region===
 The <scene name='95/952719/Hinge_region_spin/3'>Higne Region</scene>(purple-blue) connects the Transmembrane Region to the Leucine Rich Domain. It is sometimes referred to as the signaling specificity domain because there is some evidence suggesting that this region is important in both TSH binding and signal transduction. <ref name="Chen">Chen CR, McLachlan SM, Rapoport B. Thyrotropin (TSH) receptor residue E251 in the extracellular leucine-rich repeat domain is critical for linking TSH binding to receptor activation. Endocrinology. 2010 Apr;151(4):1940-7. doi: 10.1210/en.2009-1430. Epub 2010 Feb 24. PMID: 20181794; PMCID: PMC2851189. [DOI 10.1210/en.2009-1430 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2851189/]</ref>. It is made up of two α-helices that are connected via disulfide bonds(shown in yellow). Interactions between these two helices and TSH help orient TSH properly. These interactions are essential for TSH binding, however, they are not required for the activation of TSHR.  Conformational changes in this region, specifically the orientation of <scene name='95/952719/Hinge_region_residues/3'>Y279</scene>(shown in active state), are responsible for bringing TSHR into the active state <ref name="Faust"/>.