Crucial role for the VWF A1 domain in binding to type IV collagen
Crucial role for the VWF A1 domain in binding to type IV collagen
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DOI：
10.1182/blood-2014-11-610824
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发表时间：
2015-04-02
期刊：
影响因子：
20.3
通讯作者：
Montgomery, Robert R.
中科院分区：
文献类型：
--
作者：
Flood, Veronica H.;Schlauderaff, Abraham C.;Montgomery, Robert R.
血管性血友病因子（VWF）含有血小板和血管胶原的结合位点，以促进损伤部位的凝块形成。虽然以前的工作已经表明，VWF可以结合IV型胶原（胶原4），这种相互作用的表征已经进行了很少。我们研究了体外VWF与胶原蛋白4的结合，并将此特征扩展到缺陷VWF-胶原蛋白4相互作用的小鼠模型。使用来自健康对照和患有不同类型的血管性血友病（VWD）的受试者的大型研究的血浆样品进一步研究VWF和胶原蛋白4的相互作用。我们的研究结果表明，胶原蛋白4似乎结合VWF只通过VWF A1结构域，并通过VWF患者的样品，并通过在VWF A1结构域中的定点诱变确定的特定序列变异可以减少或消除这种相互作用。此外，在流动条件下VWF依赖性血小板与胶原4的结合需要完整的VWF A1结构域。我们观察到，1型和2型M VWD中与胶原4的结合减少与选择VWF A1结构域序列变异相关。这表明VWF变异体可能改变止血的另一种机制。
Von Willebrand factor (VWF) contains binding sites for platelets and for vascular collagens to facilitate clot formation at sites of injury. Although previous work has shown that VWF can bind type IV collagen (collagen 4), little characterization of this interaction has been performed. We examined the binding of VWF to collagen 4 in vitro and extended this characterization to a murine model of defective VWF-collagen 4 interactions. The interactions of VWF and collagen 4 were further studied using plasma samples from a large study of both healthy controls and subjects with different types of von Willebrand disease (VWD). Our results show that collagen 4 appears to bind VWF exclusively via the VWF A1 domain, and that specific sequence variations identified through VWF patient samples and through site-directed mutagenesis in the VWF A1 domain can decrease or abrogate this interaction. In addition, VWF-dependent platelet binding to collagen 4 under flow conditions requires an intact VWF A1 domain. We observed that decreased binding to collagen 4 was associated with select VWF A1 domain sequence variations in type 1 and type 2M VWD. This suggests an additional mechanism through which VWF variants may alter hemostasis.