Crystallographic analysis of calcium-dependent heparin binding to annexin A2
Crystallographic analysis of calcium-dependent heparin binding to annexin A2
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DOI：
10.1074/jbc.m604502200
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发表时间：
2006-10-20
影响因子：
4.8
通讯作者：
Seaton, Barbara A.
中科院分区：
文献类型：
--
作者：
Shao, Chenghua;Zhang, Fuming;Seaton, Barbara A.
膜联蛋白A2和肝素以高亲和力和钙依赖性方式相互结合，这种相互作用可能在介导纤维蛋白溶解中发挥作用。在这项研究中，三个肝素衍生的寡糖的不同长度的共结晶膜联蛋白A2阐明的相互作用的结构基础。晶体结构获得高分辨率的未复合膜联蛋白A2和肝素寡糖结合膜联蛋白A2的三个复合物。共同的肝素结合位点位于膜联蛋白A2的结构域IV的凸面。在该位点，膜联蛋白A2结合寡糖非还原端的5个糖残基。与大多数肝素结合的共识模式不同，在该位点的肝素结合不依赖于碱性残基阵列;相反，主链和侧链氮原子和两个钙离子在结合中起重要作用。尤其重要的是在肝素结合时形成的新的钙结合位点。肝素衍生物的两个糖残基为该钙离子提供氧配体。所有四种结构的比较表明，肝素结合不引起膜联蛋白A2的显着构象变化。最后，表面等离子体共振测量膜联蛋白A2和肝素多糖在溶液中在pH 7.4或5.0的结合之间的相互作用。综合数据为肝素与膜联蛋白A2结合的钙依赖性提供了明确的依据。
Annexin A2 and heparin bind to one another with high affinity and in a calcium-dependent manner, an interaction that may play a role in mediating fibrinolysis. In this study, three heparin-derived oligosaccharides of different lengths were co-crystallized with annexin A2 to elucidate the structural basis of the interaction. Crystal structures were obtained at high resolution for uncomplexed annexin A2 and three complexes of heparin oligosaccharides bound to annexin A2. The common heparin-binding site is situated at the convex face of domain IV of annexin A2. At this site, annexin A2 binds up to five sugar residues from the nonreducing end of the oligosaccharide. Unlike most heparin-binding consensus patterns, heparin binding at this site does not rely on arrays of basic residues; instead, main-chain and side-chain nitrogen atoms and two calcium ions play important roles in the binding. Especially significant is a novel calcium-binding site that forms upon heparin binding. Two sugar residues of the heparin derivatives provide oxygen ligands for this calcium ion. Comparison of all four structures shows that heparin binding does not elicit a significant conformational change in annexin A2. Finally, surface plasmon resonance measurements were made for binding interactions between annexin A2 and heparin polysaccharide in solution at pH 7.4 or 5.0. The combined data provide a clear basis for the calcium dependence of heparin binding to annexin A2.