Sandbox Reserved 1791: Difference between revisions

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TSHR forms an active signaling complex with TSH and G<sub>s</sub> proteins. This is called the <scene name=scene name='95/952720/Tsh-tshr-gs_complex/3'>TSH-TSHR-Gs Complex</scene>. TSH contains an α and a β subunit. The α subunit is a shared subunit amongst glycoproteins. The β subunit is unique to TSH. TSH binds to the extracellular domain of TSHR <ref name="Duan"> DOI 10.1038/s41586-022-05173-3</ref>.

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.

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 transmits 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 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 composed of leucine-rich repeats 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>. The LRRD concave surface is where the TSH antibody antagonist, K1, binds as well as the agonist M22. Two specific LYS residues interact with the substrate to result in a structural change of the molecule. N-glycans attached to asparagine residues play a large role in the binding of TSH. Negative charge on these N glycans contributes to the polarity of the binding pocket which mediates the binding efficiency of TSH. Four of the five N glycan sites must be glycosylated for TSHR 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 composed of leucine-rich repeats 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>. The LRRD concave surface is where the TSH antibody antagonist, K1, binds as well as the agonist M22. Two specific LYS residues interact with the substrate to result in a structural change of the molecule. [https://pubmed.ncbi.nlm.nih.gov/35536965/ N glycans] attached to asparagine residues play a large role in the binding of TSH. Negative charge on these N glycans contributes to the polarity of the binding pocket which mediates the binding efficiency of TSH. TSHR can be glycosylated at residues 77, 99, 113, 177, 198, and 302<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>. Four of the five N glycan sites must be glycosylated for TSHR 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. Also referred to as the signaling specificity domain the hinge region plays a dual role 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>. The hinge region is made up of two α-helices connected via disulfide bonds. The disulfide bonds are important for transmitting the signal to the Transmembrane region. The two helices help orient TSH properly for LRRD binding. It is proposed that the <scene name='95/952720/Hinge_tsh_residue/1'>Hinge Region residues</scene> Asp386, Tyr385, and Tyr387 create a negative-charged region on the Helix. This negatively charged region interacts with the positively charged region of TSH created by residue Arg54. These interactions are essential for TSH binding, however, they are not required for the activation of TSHR. This is known because the M22 antibody is able to activate TSHR even though it does not have an Arg54 residue Conformational changes in this hinge region, specifically the orientation of <scene name='95/952719/Hinge_region_residues/4'>Y279</scene>, which is located in the hinge region, are responsible for the bringing TSHR into the active state <ref name="Faust"/>.

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@@ Line 9: / Line 9: @@
 TSHR forms an active signaling complex with TSH and G<sub>s</sub> proteins. This is called the <scene name=scene name='95/952720/Tsh-tshr-gs_complex/3'>TSH-TSHR-Gs Complex</scene>. TSH contains an α and a β subunit. The α subunit is a shared subunit amongst glycoproteins. The β subunit is unique to TSH. TSH binds to the extracellular domain of TSHR <ref name="Duan"> DOI 10.1038/s41586-022-05173-3</ref>.
 <scene name=scene name='95/952720/Structure_overview_spins/3'>
-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.
+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 transmits 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 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 composed of leucine-rich repeats 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>. The LRRD concave surface is where the TSH antibody antagonist, K1, binds as well as the agonist M22. Two specific LYS residues interact with the substrate to result in a structural change of the molecule.  N-glycans attached to asparagine residues play a large role in the binding of TSH. Negative charge on these N glycans contributes to the polarity of the binding pocket which mediates the binding efficiency of TSH. Four of the five N glycan sites must be glycosylated for TSHR 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 composed of leucine-rich repeats 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>. The LRRD concave surface is where the TSH antibody antagonist, K1, binds as well as the agonist M22. Two specific LYS residues interact with the substrate to result in a structural change of the molecule. [https://pubmed.ncbi.nlm.nih.gov/35536965/ N glycans] attached to asparagine residues play a large role in the binding of TSH. Negative charge on these N glycans contributes to the polarity of the binding pocket which mediates the binding efficiency of TSH. TSHR can be glycosylated at residues 77, 99, 113, 177, 198, and 302<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>. Four of the five N glycan sites must be glycosylated for TSHR 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. Also referred to as the signaling specificity domain the hinge region plays a dual role 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>. The hinge region is made up of two α-helices connected via disulfide bonds. The disulfide bonds are important for transmitting the signal to the Transmembrane region. The two helices help orient TSH properly for LRRD binding. It is proposed that the <scene name='95/952720/Hinge_tsh_residue/1'>Hinge Region residues</scene> Asp386, Tyr385, and Tyr387 create a negative-charged region on the Helix. This negatively charged region interacts with the positively charged region of TSH created by residue Arg54.  These interactions are essential for TSH binding, however, they are not required for the activation of TSHR. This is known because the M22 antibody is able to activate TSHR even though it does not have an Arg54 residue  Conformational changes in this hinge region, specifically the orientation of <scene name='95/952719/Hinge_region_residues/4'>Y279</scene>, which is located in the hinge region, are responsible for the bringing TSHR into the active state <ref name="Faust"/>.