A model of the complex between the PfEMP1 malaria protein and the human ICAM-1 receptor
A model of the complex between the PfEMP1 malaria protein and the human ICAM-1 receptor
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DOI：
10.1002/prot.21691
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发表时间：
2007-11-01
影响因子：
2.9
通讯作者：
Tramontano, Anna
中科院分区：
文献类型：
--
作者：
Bertonati, Claudia;Tramontano, Anna
疟疾是由疟原虫属的原生动物寄生虫引起的。四种疟原虫可以感染人类：恶性疟原虫、三日疟原虫、间日疟原虫和卵形疟原虫。恶性疟原虫是唯一能够粘附于毛细血管后内皮细胞表面的疟原虫。PfEMP 1恶性疟原虫蛋白和人细胞内粘附分子（ICAM-1）之间的相互作用在细胞粘附中起着关键作用，尽管对这种复合物的分子细节知之甚少。在这里，我们提出了一个模型，这种相互作用的基础上的PfEMP 1和ICAM-1的三维结构的功能域的同源模型。我们的模型与许多实验观察的结果是一致的，提供了一个合理的解释不同菌株的恶性疟原虫的不同的结合能力，并解释了降低的结合亲和力的A4株恶性疟原虫的ICAM-1（Kilifi）多态性。在我们的模型的基础上，我们也可以解释为什么鼠ICAM-1，虽然共享70%的序列相似性与其人类同源物，不结合PfEMP 1，以及为什么纤维蛋白原和PfEMP 1的ICAM-1的结合是相互排斥的。这里提出的复合物模型可以作为一个有用的工具，设计和解释的生化和免疫学实验结果。
Malaria is caused by protozoan parasites of the genus Plasmodium. Four species of Plasmodium can infect humans: R falciparum, P. malariae, P. vivax, and P. ovale. P. falciparum is the only able to cytoadhere to the surface of postcapillary endothelial cells. A key role in cytoadherence is played by the interaction between the PfEMP1 P. falciparum protein and the human intracellular adhesion molecule (ICAM-1) although very little is known about the molecular details of this complex. Here we propose a model for this interaction on the basis of a homology model of the functional domain of PfEMP1 and of the ICAM-1 three dimensional structures. Our model is consistent with the results of many experimental observations, provides a rational explanation for the different binding abilities of different strains of R falciparum and explains the reduced binding affinity of the A4 strain of P. falciparum for the ICAM-1(Kilifi) polymorphism. On the basis of our model, we can also explain why the murine ICAM-1, although sharing 70% sequence similarity with its human homologue, does not bind PfEMP1, and why the binding of fibrinogen and PfFMP1 to ICAM-1 is mutually exclusive. The model of the complex proposed here can serve as a useful tool for the design and interpretation of biochemical and immunological experimental results.