Molecular architecture of a complex between an adhesion protein from the malaria parasite and intracellular adhesion molecule 1.
Molecular architecture of a complex between an adhesion protein from the malaria parasite and intracellular adhesion molecule 1.
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DOI：
10.1074/jbc.m112.416347
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发表时间：
2013-02-22
期刊：
影响因子：
--
通讯作者：
Higgins MK
中科院分区：
文献类型：
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作者：
Brown A;Turner L;Christoffersen S;Andrews KA;Szestak T;Zhao Y;Larsen S;Craig AG;Higgins MK
背景：在疟疾期间，PfEMP 1蛋白导致恶性疟原虫感染的红细胞结合人体组织。结果：IT 4VAR 13胞外域是刚性的、细长的和单体的，呈现出与其配体ICAM-1的结合位点。结论：IT 4VAR 13胞外域不同于VAR 2CSA，其是一种PfEMP 1，其采用具有多个结构域的紧凑结构，有助于配体结合。意义：PfEMP 1蛋白已经进化出不同的结构，以促进配体识别。恶性疟原虫感染的红细胞粘附到人体组织或内皮细胞是疟疾期间由寄生虫引起的病理学的核心。它有助于避免脾脏对寄生虫的清除，并有助于脑型和胎盘型疟疾的特殊病理。粘附蛋白的PfEMP 1家族通过介导与不同的人配体的相互作用来负责这种螯合。此外，作为获得性保护性免疫的主要靶标，PfEMP 1是潜在的疫苗候选者。PfEMP 1含有由CIDR（富含半胱氨酸的结构域间区域）和DBL（Duffy结合样）结构域组成的大细胞外胞外结构域，并在序列、大小和结构域组织方面表现出广泛的变化。在这里，我们使用生物物理学方法来表征IT 4VAR 13，一种与宿主受体，细胞间粘附分子-1（ICAM-1）相互作用的蛋白质的整个300-kDa胞外域。我们通过小角X射线散射表明，IT 4VAR 13是刚性的，细长的，单体。我们还发现，它通过DBLβ结构域单独与ICAM-1相互作用，形成1：1的复合物。这些研究提供了PfEMP 1胞外域与其配体复合的第一个低分辨率结构视图。他们表明，它结合了由单个配体结合结构域组成的模块化结构域排列，以及暴露ICAM-1结合表面以允许粘附的定义的高阶结构。
Background: PfEMP1 proteins cause Plasmodium falciparum-infected erythrocytes to bind human tissues during malaria. Results: The IT4VAR13 ectodomain is rigid, elongated, and monomeric, presenting a binding site for its ligand, ICAM-1. Conclusion: The IT4VAR13 ectodomain is unlike that of VAR2CSA, a PfEMP1 that adopts a compact structure with multiple domains contributing to ligand binding. Significance: PfEMP1 proteins have evolved diverse architectures to facilitate ligand recognition. The adhesion of Plasmodium falciparum-infected erythrocytes to human tissues or endothelium is central to the pathology caused by the parasite during malaria. It contributes to the avoidance of parasite clearance by the spleen and to the specific pathologies of cerebral and placental malaria. The PfEMP1 family of adhesive proteins is responsible for this sequestration by mediating interactions with diverse human ligands. In addition, as the primary targets of acquired, protective immunity, the PfEMP1s are potential vaccine candidates. PfEMP1s contain large extracellular ectodomains made from CIDR (cysteine-rich interdomain regions) and DBL (Duffy-binding-like) domains and show extensive variation in sequence, size, and domain organization. Here we use biophysical methods to characterize the entire ∼300-kDa ectodomain from IT4VAR13, a protein that interacts with the host receptor, intercellular adhesion molecule-1 (ICAM-1). We show through small angle x-ray scattering that IT4VAR13 is rigid, elongated, and monomeric. We also show that it interacts with ICAM-1 through the DBLβ domain alone, forming a 1:1 complex. These studies provide a first low resolution structural view of a PfEMP1 ectodomain in complex with its ligand. They show that it combines a modular domain arrangement consisting of individual ligand binding domains, with a defined higher order architecture that exposes the ICAM-1 binding surface to allow adhesion.