IL-1RI is the signaling receptor for the IL-1 family of cytokines that are involved in establishment of the innate and acquired immune systems. Glycosylated extracellular (EC) domain of the IL-1RI binds to agonist such as IL-1β or antagonist ligands and the accessory protein to form the functional signaling complex. Dynamics and ligand binding of the IL-1RI is influenced by presence of the glycosaminoglycans (GAGs) of the EC matrix. Here a combination of molecular dockings and molecular dynamics simulations of the unglycosylated, partially N-glycosylated and fully N-glycosylated IL-1RI EC domain in the apo, GAG-bound and IL-1β-bound states were carried out to explain the co-occurring dynamical effect of receptor’s glycosylation and GAGs. It was shown that the IL-1RI adopts two types of “extended” and “locked” conformations in its dynamical pattern, and glycosylation maintains the receptor in the latter form. Maintaining the receptor in the locked conformation disfavors IL-1β binding by burying its two binding site on the IL-1RI EC domain. Glycosylation disfavors GAG binding to the extended IL-1RI EC domain by sterically limiting the GAGs degrees of freedom in targeting its binding site, while it favors GAG binding to the locked IL-1RI by favorable packing interactions.

中文翻译：

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GAG在IL-1RI上的定位；糖基化双重作用调节的机制

IL-1RI是涉及先天和后天免疫系统建立的细胞因子IL-1家族的信号受体。IL-1RI的糖基化细胞外（EC）结构域与激动剂（例如IL-1β或拮抗剂配体）和辅助蛋白结合，形成功能性信号复合物。IL-1RI的动力学和配体结合受EC基质中糖胺聚糖（GAG）的存在影响。在这里，结合了apo，GAG结合和IL-1β结合状态中未糖基化，部分N-糖基化和完全N-糖基化的IL-1RI EC域的分子对接和分子动力学模拟，以解释共-发生受体糖基化和GAG的动力学作用。结果表明，IL-1RI在其动态模式中采用“扩展”和“锁定”两种构型，糖基化将受体维持在后一种形式。通过将受体的两个结合位点掩埋在IL-1RI EC结构域上，将受体维持在锁定构象会不利于IL-1β结合。糖基化在空间上限制了靶向其结合位点的GAG的自由度，从而不利于GAG与扩展的IL-1RI EC结构域的结合，而糖化则有利于GAG通过有利的包装相互作用与锁定的IL-1RI结合。