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.

~~=== Transmembrane Region===~~

<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 composed of a 7-pass helix <ref name="Faust"> DOI:10.1038/s41586-022-05159-1</ref>. 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, TSHR activity decreases. These cholesterols are likely important for TSHR function <ref name="Duan"/>. Additionally, at the N-terminus, the transmembrane region binds to the <scene name='95/952719/Tsh-tshr-gs_complex/3'>G-Proteins</scene>, which are located intracellularly <ref name="GOEL"/>. The G-proteins are made up of four subunits: α, β, γ, and Nb35. Nb35 is used to stabilize the structure by binding between the Gα and Gβ interface<ref name="Maeda"> DOI: 10.1038/s41467-018-06002-w</ref>. When TSHR is activated, it causes the Gα subunit to dissociate from the Gβγ subunits. The Gα subunit is responsible for activating [https://en.wikipedia.org/wiki/Adenylyl_cyclase adenylyl cyclase], [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [https://en.wikipedia.org/wiki/Ion_channel ion channels]. This sets off the robust intracellular signaling cascade<ref name="GOEL"> PMID:24255551</ref>.

=== 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>.

=== 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"/>.

=== Transmembrane Region===

<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 composed of a 7-pass helix <ref name="Faust"> DOI:10.1038/s41586-022-05159-1</ref>. 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, TSHR activity decreases. These cholesterols are likely important for TSHR function <ref name="Duan"/>. Additionally, at the N-terminus, the transmembrane region binds to the <scene name='95/952719/Tsh-tshr-gs_complex/3'>G-Proteins</scene>, which are located intracellularly <ref name="GOEL"/>. The G-proteins are made up of four subunits: α, β, γ, and Nb35. Nb35 is used to stabilize the structure by binding between the Gα and Gβ interface<ref name="Maeda"> DOI: 10.1038/s41467-018-06002-w</ref>. When TSHR is activated, it causes the Gα subunit to dissociate from the Gβγ subunits. The Gα subunit is responsible for activating [https://en.wikipedia.org/wiki/Adenylyl_cyclase adenylyl cyclase], [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [https://en.wikipedia.org/wiki/Ion_channel ion channels]. This sets off the robust intracellular signaling cascade<ref name="GOEL"> PMID:24255551</ref>.

== Antibodies ==

[https://my.clevelandclinic.org/health/body/22971-antibodies Antibodies] are an important part of the thyroid response. These proteins are made in an immune system response to get rid of unwanted antigens in the body. [https://www.btf-thyroid.org/thyroid-antibodies-explained Thyroid antibodies] are made when the body attacks the thyroid tissues. These antibodies are made to mimic [https://my.clevelandclinic.org/health/articles/23524-thyroid-stimulating-hormone-tsh-levels TSH (Thyroid Stimulating Hormone)]. TSH is released from the pituitary gland to bind to TSHR and stimulate the thyroid to make T3 and T4 hormones to regulate the metabolism. These thyroid antibodies bind to the concave surface of the LRD.

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@@ Line 10: / Line 10: @@
 <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.
-=== Transmembrane Region===
-<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 composed of a 7-pass helix <ref name="Faust"> DOI:10.1038/s41586-022-05159-1</ref>. 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, TSHR activity decreases. These cholesterols are likely important for TSHR function <ref name="Duan"/>. Additionally, at the N-terminus, the transmembrane region binds to the <scene name='95/952719/Tsh-tshr-gs_complex/3'>G-Proteins</scene>, which are located intracellularly <ref name="GOEL"/>. The G-proteins are made up of four subunits: α, β, γ, and Nb35. Nb35 is used to stabilize the structure by binding between the Gα and Gβ interface<ref name="Maeda"> DOI: 10.1038/s41467-018-06002-w</ref>. When TSHR is activated, it causes the Gα subunit to dissociate from the Gβγ subunits. The Gα subunit is responsible for activating [https://en.wikipedia.org/wiki/Adenylyl_cyclase adenylyl cyclase], [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [https://en.wikipedia.org/wiki/Ion_channel ion channels]. This sets off the robust intracellular signaling cascade<ref name="GOEL"> PMID:24255551</ref>.
 === 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>.
 === 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"/>.
+=== Transmembrane Region===
+<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 composed of a 7-pass helix <ref name="Faust"> DOI:10.1038/s41586-022-05159-1</ref>. 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, TSHR activity decreases. These cholesterols are likely important for TSHR function <ref name="Duan"/>. Additionally, at the N-terminus, the transmembrane region binds to the <scene name='95/952719/Tsh-tshr-gs_complex/3'>G-Proteins</scene>, which are located intracellularly <ref name="GOEL"/>. The G-proteins are made up of four subunits: α, β, γ, and Nb35. Nb35 is used to stabilize the structure by binding between the Gα and Gβ interface<ref name="Maeda"> DOI: 10.1038/s41467-018-06002-w</ref>. When TSHR is activated, it causes the Gα subunit to dissociate from the Gβγ subunits. The Gα subunit is responsible for activating [https://en.wikipedia.org/wiki/Adenylyl_cyclase adenylyl cyclase], [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [https://en.wikipedia.org/wiki/Ion_channel ion channels]. This sets off the robust intracellular signaling cascade<ref name="GOEL"> PMID:24255551</ref>.
 == Antibodies ==
 [https://my.clevelandclinic.org/health/body/22971-antibodies Antibodies] are an important part of the thyroid response. These proteins are made in an immune system response to get rid of unwanted antigens in the body. [https://www.btf-thyroid.org/thyroid-antibodies-explained Thyroid antibodies] are made when the body attacks the thyroid tissues. These antibodies are made to mimic [https://my.clevelandclinic.org/health/articles/23524-thyroid-stimulating-hormone-tsh-levels TSH (Thyroid Stimulating Hormone)]. TSH is released from the pituitary gland to bind to TSHR and stimulate the thyroid to make T3 and T4 hormones to regulate the metabolism. These thyroid antibodies bind to the concave surface of the LRD.