G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, Prospect 100 let Vladivostoku, 159, Vladivostok, 690022, Russia.
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, Prospect 100 let Vladivostoku, 159, Vladivostok, 690022, Russia.
Int J Biol Macromol. 2018 Feb;107(Pt B):2484-2491. doi: 10.1016/j.ijbiomac.2017.10.133. Epub 2017 Oct 25.
This work is devoted to the ascertainment of serological cross-reactivity between OmpF porin from Yersinia pseudotuberculosis (YpOmpF) and human thyroid-stimulating hormone receptor (hTSHR). Extracts containing hTSHR were isolated from surgical thyroid tissue of patients with clinical and diagnostic signs of diffuse toxic goiter. Monoclonal antibodies to hTSHR (mAbs) were shown to interact both with antigens in thyroid tissue extracts and with YpOmpF. Models of spatial structures of trimer and monomer complexes of YpOmpF with antibodies to hTSHR were also constructed. According to the results of molecular modeling, YpOmpF, being in monomeric form, can, like hTSHR, interact freely with the mAbs. But when the porin trimer is formed the hydrophobic region that comprises in the porin-antibody interaction zone is closed. This circumstance as well as other spatial rearrangement of amino acid residues that determine the efficiency of binding prevents the interaction between YpOmpF trimer and monoclonal antibody to receptor. These in vitro and in silico results confirmed the existence of the phenomenon of molecular mimicry. Thus, an autoimmune disease of the thyroid gland (Graves' disease) that sometimes arises after suffering pseudotuberculosis may be the consequence of the structural and antigenic similarity between YpOmpF and hTSHR.
这项工作致力于确定假结核耶尔森氏菌（YpOmpF）外膜孔蛋白（OmpF）与人类促甲状腺激素受体（hTSHR）之间的血清交叉反应性。从有弥漫性毒性甲状腺肿的临床和诊断特征的手术甲状腺组织中分离出含有 hTSHR 的提取物。抗 hTSHR 的单克隆抗体（mAbs）被证明既与甲状腺组织提取物中的抗原，也与 YpOmpF 相互作用。还构建了 YpOmpF 与抗 hTSHR 的 mAbs 的三聚体和单体复合物的空间结构模型。根据分子建模的结果，单体形式的 YpOmpF 可以像 hTSHR 一样，与 mAbs 自由相互作用。但是，当形成孔蛋白三聚体时，包含在孔蛋白-抗体相互作用区域中的疏水区被封闭。这种情况以及决定结合效率的其他氨基酸残基的空间重排，阻止了 YpOmpF 三聚体与受体的单克隆抗体之间的相互作用。这些体外和计算机模拟的结果证实了分子模拟现象的存在。因此，甲状腺自身免疫性疾病（格雷夫斯病）有时在假结核病后发生，可能是 YpOmpF 和 hTSHR 之间的结构和抗原相似性的结果。
