Kleinau Gunnar, Jäschke Holger, Neumann Susanne, Lättig Jens, Paschke Ralf, Krause Gerd
Forschungsinstitut für Molekulare Pharmakologie, D-13125 Berlin, Germany.
J Biol Chem. 2004 Dec 3;279(49):51590-600. doi: 10.1074/jbc.M404748200. Epub 2004 Sep 2.
Glycoprotein hormone receptors (GPHRs) differ from the other seven transmembrane receptors mainly through a complex activation mechanism that requires the binding of a large hormone toward a large N-terminal ectodomain. The intramolecular mechanism of the signal transduction to the serpentine domain upon hormone binding at the ectodomain is not understood. To identify determinants at the GPHR ectodomain that may be involved in signal transduction, we first searched for homologous structural features. Based on high sequence similarity to the determined structures of the Nogo-receptor ectodomain and the intermolecular complex of the Interleukin-8 ligand (IL8) and the N-terminal peptide of the IL8 receptor (IL8RA), the hypothesis was developed that portions of the intramolecular components, Cysteine-box-2 and Cysteine-box-3, of the GPHR ectodomain interact and localize at the interface between ectodomain and serpentine domain. Indeed, point mutations within the D403EFN406 motif at Cysteine-box-3 of the thyrotropin receptor resulted in increased basal cAMP levels, suggesting that this motif may be important for transduction of the signal from the ectodomain to the transmembrane domain. New indications are provided about the tight spatial cooperation and relative location of the new epitope and other determinants at the thyrotropin receptor ectodomain, such as the leucine-rich repeat motif Ser281 and the cysteine boxes. According to the high sequence conservation, the results are of general relevance for the signal transduction mechanism of other glycoprotein hormone receptors such as choriogonadotrophic/luteinizing hormone receptor and follicle-stimulating hormone receptor.
糖蛋白激素受体（GPHRs）与其他七跨膜受体的主要区别在于其复杂的激活机制，该机制需要一个大分子激素与一个大的N端胞外域结合。目前尚不清楚激素在胞外域结合后，信号转导至蛇形域的分子内机制。为了确定GPHR胞外域中可能参与信号转导的决定因素，我们首先搜索了同源结构特征。基于与已确定结构的Nogo受体胞外域以及白细胞介素-8配体（IL8）和IL8受体N端肽（IL8RA）的分子间复合物的高度序列相似性，我们提出了一个假设，即GPHR胞外域的分子内组分半胱氨酸盒-2和半胱氨酸盒-3的部分相互作用并定位于胞外域和蛇形域之间的界面。事实上，促甲状腺激素受体半胱氨酸盒-3中D403EFN406基序内的点突变导致基础cAMP水平升高，这表明该基序可能对信号从胞外域转导至跨膜域很重要。关于促甲状腺激素受体胞外域新表位和其他决定因素（如富含亮氨酸的重复基序Ser281和半胱氨酸盒）的紧密空间协作和相对位置，提供了新的线索。根据高度的序列保守性，这些结果对于其他糖蛋白激素受体（如绒毛膜促性腺激素/促黄体生成素受体和促卵泡激素受体）的信号转导机制具有普遍意义。
