Introduction

E-selectin is a member of the selectin family of cell adhesion molecules expressed on the plasma membrane of inflamed endothelium and facilitates initial leukocyte tethering and subsequent cell rolling during the early stages of the inflammatory response via binding to glycoproteins expressing sialyl Lewis^X and sialyl Lewis^A (sLe^X/A). Existing crystal structures of the extracellular lectin/EGF-like domain of E-selectin complexed with sLe^X have revealed that E-selectin can exist in two conformation states, a low affinity (bent) conformation, and a high affinity (extended) conformation. The differentiating characteristic of the two conformations is the interdomain angle between the lectin and the EGF-like domain.

Methods

Using molecular dynamics (MD) simulations we observed that in the absence of tensile force E-selectin undergoes spontaneous switching between the two conformational states at equilibrium. A single amino acid substitution at residue 2 (serine to tyrosine) on the lectin domain favors the extended conformation.

Results

Steered molecular dynamics (SMD) simulations of E-selectin and PSGL-1 in conjunction with experimental cell adhesion assays show a longer binding lifetime of E-selectin (S2Y) to PSGL-1 compared to wildtype protein.

Conclusions

The findings in this study advance our understanding into how the structural makeup of E-selectin allosterically influences its adhesive dynamics.

中文翻译：

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人 E-选择素铰链区的稳定增强了与受力配体的结合亲和力

介绍

E-选择素是在发炎的内皮细胞质膜上表达的细胞粘附分子选择素家族的成员，通过与表达唾液酸路易斯 X 和唾液酸路易斯 X 的糖蛋白结合，在炎症反应的早期阶段促进初始白细胞束缚和随后^的细胞滚动^A (sLe ^X/A )。^{与 sLe X}复合的 E-选择素的细胞外凝集素/EGF 样结构域的现有晶体结构已经揭示E-选择素可以两种构象状态存在，低亲和力（弯曲）构象和高亲和力（延伸）构象。两种构象的区别特征是凝集素和EGF样结构域之间的结构域间角。

方法

使用分子动力学 (MD) 模拟，我们观察到在没有张力的情况下，E-选择素在平衡时会在两种构象状态之间进行自发转换。凝集素结构域上残基 2（丝氨酸到酪氨酸）的单个氨基酸取代有利于扩展构象。

结果

与野生型蛋白相比，E-选择素和 PSGL-1 的转向分子动力学 (SMD) 模拟结合实验性细胞粘附测定显示 E-选择素 (S2Y) 与 PSGL-1 的结合寿命更长。

结论

本研究中的发现促进了我们对 E-选择素的结构组成如何从变构影响其粘附动力学的理解。