A spatio-temporal model reveals self-limiting Fc ɛ RI cross-linking by multivalent antigens
A spatio-temporal model reveals self-limiting Fc ɛ RI cross-linking by multivalent antigens
复制标题
时空模型揭示了多价抗原的自限性 Fc E RI 交联
DOI：
10.1098/rsos.180190
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发表时间：
2018
影响因子：
3.5
通讯作者：
Barua, Dipak
中科院分区：
文献类型：
--
作者：
Shahinuzzaman, Md;Khetan, Jawahar;Barua, Dipak
多价抗原聚集细胞表面受体蛋白是免疫细胞信号传递的重要早期步骤。在过去的一些实验和模型研究中，已经研究了肥大细胞质膜上多价配体介导的Ig E受体聚集(Fc、ɛ、RI)。然而，对FcɛRI聚集机制的了解仍不完全。实验报告表明，FcɛRI在多价配体的刺激下形成相对较小的有限大小的团簇。相比之下，模拟研究表明，通过三价配体进行受体交联会导致大的受体超聚集体的形成，这可能会潜在地引起细胞过度活跃的反应。在这项工作中，我们发展了一个基于布朗动力学的时空模型来分析三价抗原对FcɛRI聚集的影响。与实现非空间模拟方法的现有模型不同，我们的模型显式地考虑了多价物种(分子和络合物)的粗粒度位置特定特征。该模型包含了膜扩散、空间碰撞和任意结构随时间演化的物种的亚纳米尺度的特定位置相互作用。利用该模型，我们研究了物种的时间演化及其扩散系数。与最近的一份实验报告一致，我们的模型预测了由多价抗原交织的反应受体在质膜上的物种迁移率急剧下降。我们表明，由于物种流动性的这种衰退，刺激后受体聚集可能变得自我限制。我们的分析揭示了一种潜在的调节机制，抑制免疫细胞对多价抗原的过度激活。
Aggregation of cell surface receptor proteins by multivalent antigens is an essential early step for immune cell signalling. A number of experimental and modelling studies in the past have investigated multivalent ligand-mediated aggregation of IgE receptors (FcɛRI) in the plasma membrane of mast cells. However, understanding of the mechanisms of FcɛRI aggregation remains incomplete. Experimental reports indicate that FcɛRI forms relatively small and finite-sized clusters when stimulated by a multivalent ligand. By contrast, modelling studies have shown that receptor cross-linking by a trivalent ligand may lead to the formation of large receptor superaggregates that may potentially give rise to hyperactive cellular responses. In this work, we have developed a Brownian dynamics-based spatio-temporal model to analyse FcɛRI aggregation by a trivalent antigen. Unlike the existing models, which implemented non-spatial simulation approaches, our model explicitly accounts for the coarse-grained site-specific features of the multivalent species (molecules and complexes). The model incorporates membrane diffusion, steric collisions and sub-nanometre-scale site-specific interaction of the time-evolving species of arbitrary structures. Using the model, we investigated temporal evolution of the species and their diffusivities. Consistent with a recent experimental report, our model predicted sharp decay in species mobility in the plasma membrane in response receptor cross-linking by a multivalent antigen. We show that, due to such decay in the species mobility, post-stimulation receptor aggregation may become self-limiting. Our analysis reveals a potential regulatory mechanism suppressing hyperactivation of immune cells in response to multivalent antigens.