Sandbox Reserved 1781

This Sandbox is Reserved from February 27 through August 31, 2023 for use in the course CH462 Biochemistry II taught by R. Jeremy Johnson at the Butler University, Indianapolis, USA. This reservation includes Sandbox Reserved 1765 through Sandbox Reserved 1795.

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spinqualitylabelsall models Thyrotropin receptor 7UTZ Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D This is a default text for your page '. Click above on edit this page' to modify. Be careful with the < and > signs. You may include any references to papers as in: the use of JSmol in Proteopedia or to the article describing Jmol to the rescue. Introduction File:Surface of tshr.png Figure 1. TSHR with TSH bound. The extracellular and transmembrane domains of the GPCR are shown in green, the hinge region in cyan, the P10 peptide in pink, and thyrotropin bound in pink and yellow. Thyroid hormones exercise essential functions related to activity of thyroid cells as well as metabolic processes and oxygen consumption. Misregulation of thyroid hormone levels is the cause of many disorders related to hypo- or hyperthyroidism. Thus, understanding the signaling of synthesis and release of these hormones will have applications in treating thyroid hormone disorders. The initiation of the synthesis and release of these hormones is caused by the glycoprotein, thyroid stimulating hormone (TSH), which is released by the anterior pituitary gland. The release of TSH from the anterior pituitary is regulated by thyroid-releasing hormone (TRH) which is released by the hypothalamus. When stimulated by TRH, the anterior pituitary releases TSH. When stimulated by TSH, the thyroid gland will produce and release the the thyroid hormones T4 and T3. T3 is the "active form" of the hormone, however it accounts for only 20% of the thyroid hormone that is released after stimulus by TSH. The T4 that predominates in release from the thyroid will be converted to T3 in the bloodstream. High levels of T3 and T4 can negatively regulate the release of TSH from the anterior pituitary, constituting a negative feedback loop . The thyrotropin receptor (TSHR) is a G-protein coupled receptor that binds TSH and transduces signal to initiate synthesis and release of thyroid hormones. It is important to note that autoantibodies may also bind to this receptor causing inhibition or activation of its desired function. (Figure 1) Structure Overview The thyrotropin receptor has an extracellular domain (ECD) that is composed of a leucine rich repeat domain (LRRD) as well as a hinge region. This hinge region links the ECD to the seven transmembrane helices (7TM domain), which span from the extracellular domain to the intracellular domain . When thyrotropin or an autoantibody binds, it causes a conformational change in the receptor through the transmembrane helices. This causes the thyrotropin receptor to interact differently with its respective G-protein when in the active and inactive states. Hinge Region and P10 Peptide Several parts of TSHR are very important for the functioning of TSH signaling. The hinge region is a scaffold for the attachment of the ECD to the 7TMD. Also, this region, has been found to have impact on the binding potency of TSH as well as intracellular cyclic adenosine monophosphate (cAMP) levels, which are partially mediated by the activation of the GPCR. Several features of this region have been found to be crucial to the potent activation of of the TSHR by TSH.. The most important feature of the hinge region is the interaction of the hinge helix with the p10 peptide through disulfides. The p10 peptide is a conserved sequence that spans from the last beta sheet of the LRRD to the first transmembrane helix (TM1). These disulfides are critical as they link the ECD, where thyrotropin binds, to the TMD, whose conformational changes directly mediate the activation of the receptor's complementary G-protein. Movement of the ECD, caused by TSH binding, will cause rotation of the hinge helix and subsequent movement of the p10 peptide leading to movement of the transmembrane helices which will cause activation of the G-protein. In addition to activation, the hinge region plays an important role in tightly binding TSH. Residues 382-390 of the hinge region adopt a short helix containing Y385 and D386. Y385 is buried into a hydrophobic region of TSH while D386 forms a salt bride with R386 of the hormone. Together, these interactions assist in facilitating the stable binding of TSH to the TSHR . This being said, it is important to acknowledge, the hinge region itself is not required for the activation of the receptor. In many of the aforementioned misregulations of thyroid hormone release, auto-antibodies are responsible. These auto-antibodies bind to the receptor through alternative interactions which cause conformational changes to the 7TMD without any need for a conformational change or extensive interactions with the hinge region. 7 Transmembrane Helices The thyrotropin receptor is anchored to the membrane through seven transmembrane helices which is characteristic of GPCRs. Conformational changes in this region of the receptor are responsible for the activation of associated G protein. In thyrotropin binding, changes to this region are mediated by movements in the afforementioned p10 peptide. When the hinge helix rotates, it causes p10 peptide displacement that allows the seventh helix of the transmembrane domain to migrate towards the center of the 7TMD to increase van der waals contacts. In addition, lysine 660 of TM7 forms an ionic interaction with glutamate 409 of the p10 region. This interaction assists in the stabilization of the active state of 7TMD. In addition, the movement of the hinge helix has been found to bee associated with movement of a tyrosine residue relative to and isoleucine residue on the neighboring extracellular loop 1 (ECL1) helix. The identity of these residues has been found to be an important predictor in the activation of the thyrotropin receptor. For instance, structurally guided mutagenic studies have shown that the mutation of the isoleucine to a more sizeable phenylalanine decreases TSH signaling potency.In addition to these conformational changes, the sixth transmembrane helix of TSHR is also moved outward from the center of the 7TMD to facilitate alpha helix 5 of the alpha subunit of the G protein, which is the domain that becomes activated. Relevance Glu 98 and Asp 91 M22 bound to TSHR Structural highlights This is a sample scene created with SAT to color by Group, and another to make a transparent representation of the protein. 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