Savignygrin, a platelet aggregation inhibitor from the soft tick Ornithodoros savignyi, presents the RGD integrin recognition motif on the Kunitz-BPTI fold
Savignygrin, a platelet aggregation inhibitor from the soft tick Ornithodoros savignyi, presents the RGD integrin recognition motif on the Kunitz-BPTI fold
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DOI：
10.1074/jbc.m112060200
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发表时间：
2002-06-14
影响因子：
4.8
通讯作者：
Neitz, AWH
中科院分区：
文献类型：
--
作者：
Mans, BJ;Louw, AI;Neitz, AWH
Savignygrin是一种血小板聚集抑制剂，具有RGD整合素识别基序，已从软蜱Ornithodoros savignyi中纯化。两种具有相似生物活性的异构体由于其氨基酸序列中的R52 G和N60 G而不同，表明最近的基因重复事件。ADP（IC 50，130 nM），胶原蛋白，凝血酶受体激活肽和肾上腺素诱导的血小板聚集被抑制，尽管血小板被激活并发生形状变化。α-CD 41（P2）与血小板的结合、纯化的α（IIb）β（3）与纤维蛋白原的结合以及血小板与纤维蛋白原的粘附均受到抑制，表明靶向纤维蛋白原受体。相反，表达整合素α（v）β（3）的骨肉瘤细胞对玻连蛋白或纤维蛋白原的粘附不受抑制，表明savignyrin对α（IIb）β（3）的特异性。Savignygrin显示出与disagregin的序列同一性，disagregin是一种来自缺乏RGD基序的蜱Ornithodoros moubata的血小板聚集抑制剂。savignyrin的半胱氨酸排列类似于丝氨酸蛋白酶抑制剂的牛胰腺胰蛋白酶抑制剂家族。基于蜱抗凝肽结构的同源性模型表明，经典BPTI抑制剂的底物结合环上存在RGD基序。然而，savignygrin不抑制丝氨酸蛋白酶fXa、纤溶酶、凝血酶或胰蛋白酶。这是第一次报告的血小板聚集抑制剂，提出的RGD基序使用Kunitz-BPTI蛋白折叠。
Savignygrin, a platelet aggregation inhibitor that possesses the RGD integrin recognition motif, has been purified from the soft tick Ornithodoros savignyi. Two isoforms with similar biological activities differ because of R52G and N60G in their amino acid sequences, indicating a recent gene duplication event. Platelet aggregation induced by ADP (IC50,130 nM), collagen, the thrombin receptor-activating peptide, and epinephrine was inhibited, although platelets were activated and underwent a shape change. The binding of alpha-CD41 (P2) to platelets, the binding of purified alpha(IIb)beta(3) to fibrinogen, and the adhesion of platelets to fibrinogen was inhibited, indicating a targeting of the fibrinogen receptor. In contrast, the adhesion of osteosarcoma cells that express the integrin alpha(v)beta(3) to vitronectin or fibrinogen was not inhibited, indicating the specificity of savignygrin toward alpha(IIb)beta(3). Savignygrin shows sequence identity to disagregin, a platelet aggregation inhibitor from the tick Ornithodoros moubata that lacks an RGD motif. The cysteine arrangement of savignygrin is similar to that of the bovine pancreatic trypsin inhibitor family of serine protease inhibitors. A homology model based on the structure of the tick anticoagulant peptide indicates that the RGD motif is presented on the substrate-binding loop of the canonical BPTI inhibitors. However, savignygrin did not inhibit the serine proteases fXa, plasmin, thrombin, or trypsin. This is the first report of a platelet aggregation inhibitor that presents the RGD motif using the Kunitz-BPTI protein fold.