Probing Structural Selectivity of Synthetic Heparin Binding to Stabilin Protein Receptors
Probing Structural Selectivity of Synthetic Heparin Binding to Stabilin Protein Receptors
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DOI：
10.1074/jbc.m111.320069
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发表时间：
2012-06-15
影响因子：
4.8
通讯作者：
Harris, Edward N.
中科院分区：
文献类型：
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作者：
Pempe, Elizabeth H.;Xu, Yongmei;Harris, Edward N.
肝素是世界范围内使用最广泛的药物之一，是手术、透析、血栓形成治疗、癌症和一般循环管理所需的基本抗凝剂。稳定蛋白-2是一种清道夫清除受体，在肝窦内皮中有高表达。据信稳定蛋白-2是肝脏中未分级和低分子量肝素清除的主要受体。在这里，我们确定了肝素聚合物的修饰和长度，这些修饰和长度是由两种人稳定蛋白受体结合和内吞作用所需的：稳定蛋白-2及其同系物稳定蛋白-1（也存在于肝内皮中）。使用酶促合成的S-35标记的硫酸乙酰肝素低聚物，我们确定N-硫酸化葡糖胺（GlcNS）的3-OH位置的硫酸化是通过两种稳定蛋白受体进行结合和内吞的最有益修饰。此外，我们的数据表明，十糖是结合稳定蛋白受体的最小尺寸。这些发现定义了从血液循环中有效清除所需的肝素结构的物理参数。这些结果也将有助于设计具有所需清除率的合成肝素。
As one of the most widely used drugs worldwide, heparin is an essential anticoagulant required for surgery, dialysis, treatment of thrombosis, cancer, and general circulatory management. Stabilin-2 is a scavenger clearance receptor with high expression in the sinusoidal endothelium of liver. It is believed that Stabilin-2 is the primary receptor for the clearance of unfractionated and low molecular weight heparins in the liver. Here, we identify the modifications and length of the heparin polymer that are required for binding and endocytosis by both human Stabilin receptors: Stabilin-2 and its homolog Stabilin-1 (also found in liver endothelium). Using enzymatically synthesized S-35-labeled heparan sulfate oligomers, we identified that sulfation of the 3-OH position of N-sulfated glucosamine (GlcNS) is the most beneficial modification for binding and endocytosis via both Stabilin receptors. In addition, our data suggest that a decasaccharide is the minimal size for binding to the Stabilin receptors. These findings define the physical parameters of the heparin structure required for efficient clearance from blood circulation. These results will also aid in the design of synthetic heparins with desired clearance rates.