Interaction of heparin and heparin-derived oligosaccharides with synthetic peptide analogues of the heparin-binding domain of heparin/heparan sulfate-interacting protein.
Interaction of heparin and heparin-derived oligosaccharides with synthetic peptide analogues of the heparin-binding domain of heparin/heparan sulfate-interacting protein.
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DOI：
10.1016/j.bbagen.2009.09.002
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发表时间：
2009-12
期刊：
影响因子：
--
通讯作者：
Jing Wang;D. Rabenstein
中科院分区：
文献类型：
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作者：
Jing Wang;D. Rabenstein
背景：虽然鱼精蛋白作为肝素的解毒剂是有效的，但由于其副作用，需要替代鱼精蛋白。据报道，HIP肽可以中和肝素的抗凝血活性。本文研究了肝素类似肽与肝素及肝素衍生低聚糖的相互作用。方法合成肝素/硫酸肝素相互作用蛋白（HIP）中肝素结合域的7个类似物，并利用肝素亲和层析、等温滴定量热法和核磁共振对它们与肝素的相互作用进行表征。结果snmr结果表明，含组氨酸的Hip类似肽His侧链的咪唑基团在pH 5.5时与肝素发生位点特异性相互作用。肝素对手性相反的HIP类似肽具有相同的亲和力。反离子缩合理论分析表明肽ac - srpkakakakakdqtk - nh2与肝素平均产生~ 3个离子相互作用，导致~ 2个Na+离子位移。和离子相互作用占∼46%的结合自由能的Na +浓度0.15 M.CONCLUSIONSThe亲和肽肝素的强烈依赖于阳离子侧链的性质和博士的热力学参数测量髋关节肽的相互作用与肝素类似物强烈依赖于肽序列和pH.GENERAL SIGNIFICANCEThe这一研究获得的信息将被使用在设计中和的新代理肝素的抗凝血活性。质子化组氨酸侧链与肝素的位点特异性结合为肝素和硫酸肝素蛋白聚糖对β-淀粉样肽的ph依赖性结合提供了分子水平上的解释，并可能与淀粉样蛋白的形成有关。
BACKGROUNDAlthough protamine is effective as an antidote of heparin, there is a need to replace protamine due to its side effects. HIP peptide has been reported to neutralize the anticoagulant activity of heparin. The interaction of HIP analog peptides with heparin and heparin-derived oligosaccharides is investigated in this paper.METHODSSeven analogues of the heparin-binding domain of heparin/heparan sulfate-interacting protein (HIP) were synthesized, and their interaction with heparin was characterized by heparin affinity chromatography, isothermal titration calorimetry, and NMR.RESULTSNMR results indicate the imidazolium groups of the His side chains of histidine-containing Hip analog peptide interact site-specifically with heparin at pH 5.5. Heparin has identical affinities for HIP analog peptides of opposite chirality. Analysis by counterion condensation theory indicates the peptide AC-SRPKAKAKAKAKDQTK-NH2makes on average ∼3 ionic interactions with heparin that result in displacement of ∼2 Na+ions, and ionic interactions account for ∼46% of the binding free energy at a Na+concentration of 0.15 M.CONCLUSIONSThe affinity of heparin for the peptides is strongly dependent on the nature of the cationic side chains and pH. The thermodynamic parameters measured for the interaction of HIP peptide analogs with heparin are strongly dependent on the peptide sequence and pH.GENERAL SIGNIFICANCEThe information obtained in this research will be of use in the design of new agents for neutralization of the anticoagulant activity of heparin. The site-specific binding of protonated histidine side chains to heparin provides a molecular-level explanation for the pH-dependent binding of β-amyloid peptides by heparin and heparan sulfate proteoglycan and may have implications for amyloid formation.