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Glycan-mediated functional assembly of IL-1RI: structural insights into completion of the current description for immune response
Journal of Biomolecular Structure and Dynamics ( IF 2.7 ) Pub Date : 2020-10-30 , DOI: 10.1080/07391102.2020.1841027
Maryam Azimzadeh Irani 1 , Mohammad Reza Ejtehadi 2
Affiliation  

Abstract

Interleukin 1 Receptor type I (IL-1RI) is a multi-domain transmembrane receptor that triggers the inflammatory response. Understanding its detailed mechanism of action is crucial for treating immune disorders. IL-1RI is activated upon formation of its functional assembly that occurs by binding of the IL-1 cytokine and the accessory protein (Il-1RAcP) to it. X-ray crystallography, small-Angle X-ray Scattering and molecular dynamics simulation studies showed that IL-1RI adopts two types of ‘compact’ and ‘extended’ conformational states in its dynamical pattern. Furthermore, glycosylation has shown to play a critical role in its activation process. Here, classical and accelerated atomistic molecular dynamics were carried out to examine the role of full glycosylation of IL-1RI and IL-1RAcP in arrangement of the functional assembly. Simulations showed that the ‘compact’ and ‘extended’ IL-1RI form two types of ‘cytokine-inaccessible-non-signaling’ and ‘cytokine-accessible-signaling’ assemblies with the IL-1RacP, respectively that are both abiding in the presence of glycans. Suggesting that the cytokine binding to IL-1RI is not required for the formation of IL-1RI-IL-1RAcP complex and the ‘compact’ complex could act as a down-regulatory mechanism. The ‘extended’ complex is maintained by formation of several persistent hydrogen bonds between the IL-1RI-IL-1RAcP inter-connected glycans. Taken together, it was shown that full glycosylation regulates formation of the IL-1RI functional assembly and play critical role in cytokine biding and triggering the IL-1RI involved downstream pathways in the cell.

Communicated by Ramaswamy H. Sarma



中文翻译:

聚糖介导的 IL-1RI 功能组装:完成当前免疫反应描述的结构见解

摘要

I 型白细胞介素 1 受体 (IL-1RI) 是一种多域跨膜受体,可触发炎症反应。了解其详细的作用机制对于治疗免疫疾病至关重要。IL-1RI 在其功能组装形成时被激活,该组装通过 IL-1 细胞因子和辅助蛋白 (Il-1RAcP) 与其结合而发生。X 射线晶体学、小角 X 射线散射和分子动力学模拟研究表明,IL-1RI 在其动力学模式中采用“紧凑”和“扩展”两种构象状态。此外,糖基化已显示在其活化过程中起关键作用。在这里,进行了经典和加速的原子分子动力学,以检查 IL-1RI 和 IL-1RAcP 的完全糖基化在功能组装排列中的作用。模拟表明,“紧凑型”和“扩展型”IL-1RI 分别与 IL-1RacP 形成两种类型的“细胞因子不可接近 - 非信号传导”和“细胞因子可接近 - 信号传导”组件,它们都存在于存在聚糖。这表明细胞因子与 IL-1RI 的结合对于 IL-1RI-IL-1RAcP 复合物的形成不是必需的,并且“紧凑”复合物可以作为一种下调机制。通过在 IL-1RI-IL-1RAcP 相互连接的聚糖之间形成几个持久的氢键来维持“扩展”复合物。总之,显示完全糖基化调节 IL-1RI 功能组装的形成,并在细胞因子结合和触发 IL-1RI 参与细胞中的下游途径中起关键作用。

由 Ramaswamy H. Sarma 传达

更新日期:2020-10-30
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