Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
J Immunol. 2010 Sep 15;185(6):3268-76. doi: 10.4049/jimmunol.1000326. Epub 2010 Aug 23.
The term serial engagement was introduced to describe the ability of a single peptide, bound to a MHC molecule, to sequentially interact with TCRs within the contact region between a T cell and an APC. In addition to ligands on surfaces, soluble multivalent ligands can serially engage cell surface receptors with sites on the ligand, binding and dissociating from receptors many times before all ligand sites become free and the ligand leaves the surface. To evaluate the role of serial engagement in Syk activation, we use a detailed mathematical model of the initial signaling cascade that is triggered when FcepsilonRI is aggregated on mast cells by multivalent Ags. Although serial engagement is not required for mast cell signaling, it can influence the recruitment of Syk to the receptor and subsequent Syk phosphorylation. Simulating the response of mast cells to ligands that serially engage receptors at different rates shows that increasing the rate of serial engagement by increasing the rate of dissociation of the ligand-receptor bond decreases Syk phosphorylation. Increasing serial engagement by increasing the rate at which receptors are cross-linked (for example by increasing the forward rate constant for cross-linking or increasing the valence of the ligand) increases Syk phosphorylation. When serial engagement enhances Syk phosphorylation, it does so by partially reversing the effects of kinetic proofreading. Serial engagement rapidly returns receptors that have dissociated from aggregates to new aggregates before the receptors have fully returned to their basal state.
术语“连续结合”被引入以描述单个肽与 MHC 分子结合，能够在 T 细胞与 APC 之间的接触区域内与 TCR 连续相互作用。除了表面上的配体之外，可溶性多价配体可以与配体上的细胞表面受体连续结合，在所有配体结合位点都变为游离且配体离开表面之前，多次结合和解离受体。为了评估连续结合在 Syk 激活中的作用，我们使用了一个详细的数学模型，该模型描述了 FcepsilonRI 在多价抗原作用下在肥大细胞上聚集时引发的初始信号级联反应。虽然连续结合不是肥大细胞信号所必需的，但它可以影响 Syk 向受体的募集以及随后的 Syk 磷酸化。模拟肥大细胞对以不同速率连续结合受体的配体的反应表明，通过增加配体-受体键的解离速率来增加连续结合速率会降低 Syk 磷酸化。通过增加受体交联的速率（例如，通过增加交联的正向速率常数或增加配体的价数）来增加连续结合会增加 Syk 磷酸化。当连续结合增强 Syk 磷酸化时，它通过部分逆转动力学校对的作用来实现。连续结合会在受体完全恢复到基础状态之前，将从聚集物中解离的受体快速重新结合到新的聚集物上。
