Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, 10019, New York, USA.
Thyroid Research Unit, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, 10019, New York, USA.
Endocrinology. 2024 Aug 27;165(10). doi: 10.1210/endocr/bqae099.
The TSH receptor (TSHR) and its many forms are the primary antigens of Graves' disease as evidenced by the presence of TSHR antibodies of differing biological activity. The TSH holoreceptor undergoes complex posttranslational changes including cleavage of its ectodomain and oligomer formation. We have previously shown that the TSHR exists in both monomeric and dimeric structures in the thyroid cell membrane and have demonstrated, by modeling, that the transmembrane domains (TMD) can form stable dimeric structures. Based on these earlier simulations of the TSHR-TMD structure and our most recent model of the full-length TSHR, we have now built models of full-length TSHR multimers with and without TSH ligand in addition to multimers of the extracellular leucine-rich domain, the site of TSH and autoantibody binding. Starting from these models we ran molecular dynamics simulations of the receptor oligomers solvated with water and counterions; the full-length oligomers also were embedded in a dipalmitoylphosphatidylcholine bilayer. The full-length TSHR dimer and trimer models stayed in the same relative orientation and distance during 2000 ns (or longer) molecular dynamics simulation in keeping with our earlier report of TMD dimerization. Simulations were also performed to model oligomers of the leucine-rich domain alone; we found a trimeric complex to be even more stable than the dimers. These data provide further evidence that different forms of the TSHR add to the complexity of the immune response to this antigen that, in patients with autoimmune thyroid disease, generate an autoantibody reactome with multiple types of autoantibody to the TSHR.
促甲状腺激素受体 (TSHR) 及其多种形式是格雷夫斯病的主要抗原，这一点可以从存在不同生物活性的 TSHR 抗体得到证明。TSH 全受体经历复杂的翻译后变化，包括其胞外结构域的裂解和寡聚体形成。我们之前已经表明，TSHR 存在于甲状腺细胞膜的单体和二聚体结构中，并通过建模证明跨膜结构域 (TMD) 可以形成稳定的二聚体结构。基于这些早期 TSHR-TMD 结构的模拟以及我们最近的全长 TSHR 模型，我们现在构建了全长 TSHR 三聚体模型，包括有和没有 TSH 配体的模型，以及细胞外富含亮氨酸的结构域三聚体，该结构域是 TSH 和自身抗体结合的位点。从这些模型开始，我们对水和反离子溶剂化的受体寡聚体进行了分子动力学模拟；全长寡聚体也被嵌入二棕榈酰磷脂酰胆碱双层中。全长 TSHR 二聚体和三聚体模型在 2000ns（或更长时间）的分子动力学模拟中保持相同的相对取向和距离，这与我们之前关于 TMD 二聚化的报告一致。还进行了模拟来构建富含亮氨酸的结构域的寡聚体；我们发现三聚体复合物比二聚体更稳定。这些数据进一步证明了 TSHR 的不同形式增加了对这种抗原的免疫反应的复杂性，在自身免疫性甲状腺疾病患者中，产生了具有多种 TSHR 自身抗体的自身抗体反应组。
