Implications for collagen I chain registry from the structure of the collagen von Willebrand factor A3 domain complex
Implications for collagen I chain registry from the structure of the collagen von Willebrand factor A3 domain complex
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DOI：
10.1073/pnas.1112388109
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发表时间：
2012-04-03
影响因子：
11.1
通讯作者：
Huizinga, Eric G.
中科院分区：
文献类型：
--
作者：
Brondijk, T. Harma C.;Bihan, Dominique;Huizinga, Eric G.
纤维胶原是脊椎动物体内最丰富的蛋白质，参与了大量的生物相互作用。血浆蛋白血管性血友病因子（VWF）介导血小板与I型、II型和III型纤维胶原的粘附，这对正常止血是必需的。高亲和力VWF结合序列已被确定在同源三聚体胶原蛋白II型和III型，然而，目前还不清楚VWF如何识别异源三聚体胶原蛋白I型，其超结构是未知的。在这里，我们提出的晶体结构的VWF域A3绑定到III型胶原蛋白衍生的同源三聚体肽。我们的结构表明，VWF-A3与所有三种胶原蛋白链相互作用，并通过构象选择结合到一个序列，该序列比以前从血小板和VWF结合研究中认识到的长一个三联体。VWF结合位点与骨粘连蛋白（也称为骨粘连蛋白）和discodin结构域受体2的结合位点重叠，但更延伸并向胶原氨基末端移动。所观察到的VWF-A3的胶原结合模式提供了对胶原I链注册的直接结构约束。VWF结合位点可以由存在于两条α 1（I）链中的序列RGQAGVMF和存在于唯一α 2（I）链中的序列RGEOGNIGF产生，条件是α 2（I）在中间或尾部位置。将这些数据与先前关于整合素与胶原蛋白结合的结构数据相结合，产生了对α 2（I）链的拖尾位置的强有力的支持，从而阐明了胶原蛋白I链注册的基本和长期问题。
Fibrillar collagens, the most abundant proteins in the vertebrate body, are involved in a plethora of biological interactions. Plasma protein von Willebrand factor (VWF) mediates adhesion of blood platelets to fibrillar collagen types I, II, and III, which is essential for normal haemostasis. High affinity VWF-binding sequences have been identified in the homotrimeric collagen types II and III, however, it is unclear how VWF recognizes the heterotrimeric collagen type I, the superstructure of which is unknown. Here we present the crystal structure of VWF domain A3 bound to a collagen type III-derived homotrimeric peptide. Our structure reveals that VWF-A3 interacts with all three collagen chains and binds through conformational selection to a sequence that is one triplet longer than was previously appreciated from platelet and VWF binding studies. The VWF-binding site overlaps those of SPARC (also known as osteonectin) and discodin domain receptor 2, but is more extended and shifted toward the collagen amino terminus. The observed collagen-binding mode of VWF-A3 provides direct structural constraints on collagen I chain registry. A VWF-binding site can be generated from the sequences RGQAGVMF, present in the two alpha 1 (I) chains, and RGEOGNIGF, in the unique alpha 2(I) chain, provided that alpha 2(I) is in the middle or trailing position. Combining these data with previous structural data on integrin binding to collagen yields strong support for the trailing position of the alpha 2(I) chain, shedding light on the fundamental and long-standing question of the collagen I chain registry.