Kleinau Gunnar, Worth Catherine L, Kreuchwig Annika, Biebermann Heike, Marcinkowski Patrick, Scheerer Patrick, Krause Gerd
Institute of Experimental Pediatric Endocrinology, Charité-Universitätsmedizin, Berlin, Germany.
Group Protein X-Ray Crystallography and Signal Transduction, Institute of Medical Physics and Biophysics, Charité-Universitätsmedizin, Berlin, Germany.
Front Endocrinol (Lausanne). 2017 Apr 24;8:86. doi: 10.3389/fendo.2017.00086. eCollection 2017.
The thyroid-stimulating hormone receptor (TSHR) is a member of the glycoprotein hormone receptors, a sub-group of class A G-protein-coupled receptors (GPCRs). TSHR and its endogenous ligand thyrotropin (TSH) are of essential importance for growth and function of the thyroid gland and proper function of the TSH/TSHR system is pivotal for production and release of thyroid hormones. This receptor is also important with respect to pathophysiology, such as autoimmune (including ophthalmopathy) or non-autoimmune thyroid dysfunctions and cancer development. Pharmacological interventions directly targeting the TSHR should provide benefits to disease treatment compared to currently available therapies of dysfunctions associated with the TSHR or the thyroid gland. Upon TSHR activation, the molecular events conveying conformational changes from the extra- to the intracellular side of the cell across the membrane comprise reception, conversion, and amplification of the signal. These steps are highly dependent on structural features of this receptor and its intermolecular interaction partners, e.g., TSH, antibodies, small molecules, G-proteins, or arrestin. For better understanding of signal transduction, pathogenic mechanisms such as autoantibody action and mutational modifications or for developing new pharmacological strategies, it is essential to combine available structural data with functional information to generate homology models of the entire receptor. Although so far these insights are fragmental, in the past few decades essential contributions have been made to investigate in-depth the involved determinants, such as by structure determination X-ray crystallography. This review summarizes available knowledge (as of December 2016) concerning the TSHR protein structure, associated functional aspects, and based on these insights we suggest several receptor complex models. Moreover, distinct TSHR properties will be highlighted in comparison to other class A GPCRs to understand the molecular activation mechanisms of this receptor comprehensively. Finally, limitations of current knowledge and lack of information are discussed highlighting the need for intensified efforts toward TSHR structure elucidation.
促甲状腺激素受体（TSHR）是糖蛋白激素受体家族的成员，属于A类G蛋白偶联受体（GPCR）亚组。TSHR及其内源性配体促甲状腺激素（TSH）对于甲状腺的生长和功能至关重要，TSH/TSHR系统的正常功能对于甲状腺激素的产生和释放至关重要。该受体在病理生理学方面也很重要，例如自身免疫性（包括眼病）或非自身免疫性甲状腺功能障碍以及癌症发展。与目前可用的与TSHR或甲状腺相关功能障碍的治疗方法相比，直接靶向TSHR的药物干预应为疾病治疗带来益处。TSHR激活后，信号从细胞外侧跨膜传递到细胞内侧所涉及的分子事件包括信号的接收、转换和放大。这些步骤高度依赖于该受体及其分子间相互作用伙伴（例如TSH、抗体、小分子、G蛋白或抑制蛋白）的结构特征。为了更好地理解信号转导、自身抗体作用和突变修饰等致病机制或开发新的药理策略，将可用的结构数据与功能信息相结合以生成整个受体的同源模型至关重要。尽管到目前为止这些见解还不完整，但在过去几十年中，已经做出了重要贡献来深入研究相关的决定因素，例如通过X射线晶体学确定结构。本综述总结了截至2016年12月关于TSHR蛋白质结构、相关功能方面的现有知识，并基于这些见解提出了几种受体复合物模型。此外，将与其他A类GPCR相比突出TSHR的独特特性，以全面了解该受体的分子激活机制。最后，讨论了当前知识的局限性和信息的缺乏，强调了加强对TSHR结构阐明的努力的必要性。
