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首页> 外文期刊>Journal of thrombosis and haemostasis: JTH >The interaction of von Willebrand factor-A1 domain with collagen: mutation G1324S (type 2M von Willebrand disease) impairs the conformational change in A1 domain induced by collagen.
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The interaction of von Willebrand factor-A1 domain with collagen: mutation G1324S (type 2M von Willebrand disease) impairs the conformational change in A1 domain induced by collagen.

机译：von Willebrand因子-A1结构域与胶原蛋白的相互作用：突变G1324S（2M型von Willebrand疾病）损害了胶原蛋白诱导的A1结构域的构象变化。

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摘要

BACKGROUND: It is established that the A3 domain in von Willebrand factor (VWF) contains the major collagen-binding site. However, there are conflicting reports describing the capacity of the A1 domain to interact with collagen types I and III. METHODS: In this study, we have used recombinant VWF-A1 polypeptides, as well as conformation-specific monoclonal antibodies (mAb), to analyze the A1-collagen interaction. RESULTS: The A1 domain bound to collagen with K(d) approximately 8.0 nm and this binding was blocked by the mAb 6G1, which blocks the interaction between ristocetin and VWF. In addition, collagen-bound A1 protein was able to support flow-dependent adhesion of platelets, demonstrating that the binding sites for collagen and glycoprotein (GP)Ib are different. Analysis with two conformation-specific mAb demonstrated that the structure of the A1 domain changed as a result of the binding to collagen. In contrast, the antibodies failed to detect conformational change in the G1324S mutant (type 2M von Willebrand disease). Thus, direct binding to collagen induces a change in the structural conformation within the VWF-A1 domain, and the G1324S substitution prevents this conformational change. CONCLUSION: This study has shown that the isolated A1 domain can simultaneously bind to collagen and platelet GPIb, supporting platelet adhesion under high-flow conditions. In addition, this study has used mAb to demonstrate that the binding of the isolated A1 domain or full-length VWF to collagen is accompanied by a conformational change in A1 domain.
机译：背景：已确定血管性血友病因子（VWF）中的A3结构域包含主要的胶原结合位点。但是，有相互矛盾的报道描述了A1域与I型和III型胶原蛋白相互作用的能力。方法：在这项研究中，我们使用重组VWF-A1多肽以及构象特异性单克隆抗体（mAb）来分析A1胶原蛋白的相互作用。结果：A1结构域以约8.0 nm的K（d）与胶原结合，该结合被mAb 6G1阻断，mAb 6G1阻断了瑞斯托素与VWF之间的相互作用。此外，胶原蛋白结合的A1蛋白能够支持血小板的血流依赖性粘附，表明胶原蛋白和糖蛋白（GP）Ib的结合位点不同。用两种构象特异性mAb分析表明，由于与胶原蛋白结合，A1结构域的结构发生了变化。相反，这些抗体未能检测到G1324S突变体（2M型von Willebrand病）的构象变化。因此，与胶原蛋白的直接结合诱导了VWF-A1域内结构构象的变化，而G1324S取代阻止了这种构象变化。结论：这项研究表明分离的A1结构域可以同时结合胶原蛋白和血小板GPIb，在高流量条件下支持血小板粘附。此外，这项研究已使用mAb证明分离的A1结构域或全长VWF与胶原蛋白的结合伴随着A1结构域的构象变化。

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