Structural analysis of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) intracellular domain reveals a conserved interaction epitope.
Structural analysis of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) intracellular domain reveals a conserved interaction epitope.
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DOI：
10.1074/jbc.m111.330779
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发表时间：
2012-03-02
期刊：
影响因子：
--
通讯作者：
Vakonakis I
中科院分区：
文献类型：
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作者：
Mayer C;Slater L;Erat MC;Konrat R;Vakonakis I
背景：PfEMP 1的定位和连接到红细胞的细胞骨架是必要的细胞粘附。结果如下：PfEMP 1胞内结构域（ATS）在结构上是保守的，并通过柔性表位与新的寄生虫蛋白直接相互作用。结论：ATS表位介导的相互作用可能是至关重要的细胞粘附。意义：这是ATS与PHIST域相互作用的第一次演示。恶性疟原虫感染的红细胞粘附于内皮细胞，从而阻塞微血管。红细胞粘附与严重疟疾和疾病致死率增加直接相关，并且由PfEMP 1家族介导。PfEMP 1聚集在红细胞膜上的旋钮样突起中对于细胞粘附至关重要，然而该系统背后的分子机制仍然难以捉摸。在这里，我们表明，PfEMP 1家族（ATS）的细胞内结构域共享一个独特的分子结构，其中包括一个最小的折叠核心和广泛的灵活的元素。ATS中心处的保守柔性段最小限度地受到折叠芯的约束。酵母双杂交数据和一种新的序列分析方法表明，该中心段包含一个保守的蛋白质相互作用表位。有趣的是，溶液中的ATS未能结合寄生虫旋钮相关的富含组氨酸的蛋白质（KAHRP），一个必不可少的细胞粘附成分。相反，我们证明，ATS与PFI1780w，疟原虫螺旋散布亚端粒（PHIST）家族的成员。PHIST结构域广泛存在于输出的寄生虫蛋白中，然而这是分配给该家族的任何变体的第一个特定分子功能。我们建议PHIST结构域促进蛋白质相互作用，保守的ATS表位可能被靶向破坏寄生虫细胞粘附系统。
Background: PfEMP1 localization and connection to the red blood cell cytoskeleton is necessary for cytoadherence. Results: The PfEMP1 intracellular domain (ATS) is structurally conserved and interacts directly with a novel parasite protein through a flexible epitope. Conclusion: The ATS epitope mediate interactions that may be critical for cytoadherence. Significance: This is the first demonstration of ATS interacting with PHIST domains. Plasmodium falciparum-infected red blood cells adhere to endothelial cells, thereby obstructing the microvasculature. Erythrocyte adherence is directly associated with severe malaria and increased disease lethality, and it is mediated by the PfEMP1 family. PfEMP1 clustering in knob-like protrusions on the erythrocyte membrane is critical for cytoadherence, however the molecular mechanisms behind this system remain elusive. Here, we show that the intracellular domains of the PfEMP1 family (ATS) share a unique molecular architecture, which comprises a minimal folded core and extensive flexible elements. A conserved flexible segment at the ATS center is minimally restrained by the folded core. Yeast-two-hybrid data and a novel sequence analysis method suggest that this central segment contains a conserved protein interaction epitope. Interestingly, ATS in solution fails to bind the parasite knob-associated histidine-rich protein (KAHRP), an essential cytoadherence component. Instead, we demonstrate that ATS associates with PFI1780w, a member of the Plasmodium helical interspersed sub-telomeric (PHIST) family. PHIST domains are widespread in exported parasite proteins, however this is the first specific molecular function assigned to any variant of this family. We propose that PHIST domains facilitate protein interactions, and that the conserved ATS epitope may be targeted to disrupt the parasite cytoadherence system.