Sandbox Reserved 1791: Difference between revisions

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<scene name='95/952720/Transmembrane_region_spin/5'>The Transmembrane Region</scene> (<scene name='95/952720/Transmembrane_region_top-view/2'>top-view</scene>) is embedded within the cell membrane. Like other G-protein receptors, it is made up of a 7-pass helix <ref name="Faust"> DOI 10.1038/s41586-022-05159-1</ref>. It is made up of about 284 residues. The transmembrane region is surrounded by a "belt" of <scene name='95/952719/Tmd_cholesterol_spin/3'>15 cholesterols</scene>. When cholesterol binding sites are mutated such that they are unfunctional, TSHR activity decreases. Thus, the cholesterols are important for TSHR function <ref name="Duan"> DOI 10.1038/s41586-022-05173-3</ref>. Additionally, at the N-terminus, the transmembrane region binds to the <scene name='95/952719/Tsh-tshr-gs_complex/2'>G-Proteins</scene>, which are located intracellularly.

=== 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/4'>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 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>.

=== 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 12: / Line 12: @@
 <scene name='95/952720/Transmembrane_region_spin/5'>The Transmembrane Region</scene> (<scene name='95/952720/Transmembrane_region_top-view/2'>top-view</scene>) is embedded within the cell membrane. Like other G-protein receptors, it is made up of a 7-pass helix <ref name="Faust"> DOI 10.1038/s41586-022-05159-1</ref>. It is made up of about 284 residues. The transmembrane region is surrounded by a "belt" of <scene name='95/952719/Tmd_cholesterol_spin/3'>15 cholesterols</scene>. When cholesterol binding sites are mutated such that they are unfunctional, TSHR activity decreases. Thus, the cholesterols are important for TSHR function <ref name="Duan"> DOI 10.1038/s41586-022-05173-3</ref>. Additionally, at the N-terminus, the transmembrane region binds to the <scene name='95/952719/Tsh-tshr-gs_complex/2'>G-Proteins</scene>, which are located intracellularly.
 === 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/4'>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 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>.
 === 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"/>.