Extended and Structurally Supported Insights into Extracellular Hormone Binding, Signal Transduction and Organization of the Thyrotropin Receptor
Extended and Structurally Supported Insights into Extracellular Hormone Binding, Signal Transduction and Organization of the Thyrotropin Receptor
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DOI：
10.1371/journal.pone.0052920
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发表时间：
2012-12-27
期刊：
影响因子：
3.7
通讯作者：
Kleinau, Gunnar
中科院分区：
文献类型：
--
作者：
Krause, Gerd;Kreuchwig, Annika;Kleinau, Gunnar
促甲状腺激素（TSH）及其受体（TSHR）对甲状腺的生长和功能至关重要。TSHR与促卵泡激素（FSHR）和促黄体激素/绒毛膜促性腺激素（LHR）的受体在进化上相关联，并且它们的序列和结构相似。TSHR的胞外区含有350多个氨基酸，并结合激素和抗体。与TSHR的功能和机制有关的几个重要问题仍然没有得到全面的理解。这些悬而未决的问题的一个主要原因是缺乏任何有关TSHR的胞外段的结构信息，该胞外段连接N-末端富含亮氨酸的重复结构域（LRRD）与跨膜螺旋（TMH）1，铰链区。它已被实验证明，这部分是重要的信号和配体相互作用的微调。最近发表了一种新的晶体结构，其包含与hFSH复合的大部分细胞外hFSHR区域。现在，我们已经将这些新的结构见解应用于同源TSHR，并生成了TSHR LRRD/铰链区/TSH复合物的结构模型。该结构模型与包括激素结合（bTSH、hTSH、甲状腺刺激素）、超激动作用、抗体相互作用和信号调节的实验数据相结合并进行评估。这些研究和重要和非重要氨基酸的考虑导致了TSHR机制的新描述，包括配体诱导的特定铰链区片段的位移。该事件触发LRRD和铰链区的会聚中心处的构象变化，激活靠近跨膜结构域的“分子内激动性单元”。
The hormone thyrotropin (TSH) and its receptor (TSHR) are crucial for the growth and function of the thyroid gland. The TSHR is evolutionary linked with the receptors of follitropin (FSHR) and lutropin/choriogonadotropin (LHR) and their sequences and structures are similar. The extracellular region of TSHR contains more than 350 amino acids and binds hormone and antibodies. Several important questions related to functions and mechanisms of TSHR are still not comprehensively understood. One major reason for these open questions is the lack of any structural information about the extracellular segment of TSHR that connects the N-terminal leucine-rich repeat domain (LRRD) with the transmembrane helix (TMH) 1, the hinge region. It has been shown experimentally that this segment is important for fine tuning of signaling and ligand interactions. A new crystal structure containing most of the extracellular hFSHR region in complex with hFSH has recently been published. Now, we have applied these new structural insights to the homologous TSHR and have generated a structural model of the TSHR LRRD/hinge-region/TSH complex. This structural model is combined and evaluated with experimental data including hormone binding (bTSH, hTSH, thyrostimulin), super-agonistic effects, antibody interactions and signaling regulation. These studies and consideration of significant and non-significant amino acids have led to a new description of mechanisms at the TSHR, including ligand-induced displacements of specific hinge region fragments. This event triggers conformational changes at a convergent center of the LRRD and the hinge region, activating an "intramolecular agonistic unit" close to the transmembrane domain.