Platelet endothelial cell adhesion molecule 1 (PECAM-1) and its interactions with glycosaminoglycans: 1. Molecular modeling studies.
Platelet endothelial cell adhesion molecule 1 (PECAM-1) and its interactions with glycosaminoglycans: 1. Molecular modeling studies.
复制标题
血小板内皮细胞粘附分子1（PECAM-1）及其与糖胺聚糖的相互作用：1.分子模型研究。
作者：
Neha S. Gandhi;D. R. Coombe;R. Mancera
血小板内皮细胞黏附分子1(PECAM-1)具有多种功能，包括作为炎症反应的一部分在白细胞外渗中的作用，以及通过促进内皮细胞与细胞间的黏附来维持血管完整性。PECAM-1已被证明通过亲性结合事件来调节细胞间的黏附，该结合事件涉及PECAM-1分子的结构域1与相邻细胞之间的相互作用。然而，也有人提出了PECAM-1的各种亲异型配体。PECAM-1与糖胺多聚糖(GAG)可能的相互作用是本研究的重点。采用同源建模法和穿线法构建了PECAM-1细胞外免疫球蛋白(Ig)结构域的三维结构。根据它们的氨基酸共同序列以及与已知的硫酸盐结合蛋白结构的比较，预测了潜在的肝素/肝素硫酸盐结合位点。肝素和其他GAG片段已被对接，以研究它们与蛋白质结合的特异性和选择性的结构决定因素。该模型预测了PECAM-1中似乎与肝素低聚糖结合的两个区域。在Ig结构域2和3上有一个高亲和力结合位点，在Ig结构域5和6上有一个低亲和力结合位点。这些Gag结合区不同于参与PECAM-1亲和性相互作用的区域。
Platelet endothelial cell adhesion molecule 1 (PECAM-1) has many functions, including its roles in leukocyte extravasation as part of the inflammatory response and in the maintenance of vascular integrity through its contribution to endothelial cell-cell adhesion. PECAM-1 has been shown to mediate cell-cell adhesion through homophilic binding events that involve interactions between domain 1 of PECAM-1 molecules on adjacent cells. However, various heterophilic ligands of PECAM-1 have also been proposed. The possible interaction of PECAM-1 with glycosaminoglycans (GAGs) is the focus of this study. The three-dimensional structure of the extracellular immunoglobulin (Ig) domains of PECAM-1 were constructed using homology modeling and threading methods. Potential heparin/heparan sulfate-binding sites were predicted on the basis of their amino acid consensus sequences and a comparison with known structures of sulfate-binding proteins. Heparin and other GAG fragments have been docked to investigate the structural determinants of their protein-binding specificity and selectivity. The modeling has predicted two regions in PECAM-1 that appear to bind heparin oligosaccharides. A high-affinity binding site was located in Ig domains 2 and 3, and evidence for a low-affinity site in Ig domains 5 and 6 was obtained. These GAG-binding regions were distinct from regions involved in PECAM-1 homophilic interactions.