Semaphorin-7A is an erythrocyte receptor for P. falciparum merozoite-specific TRAP homolog, MTRAP.
Semaphorin-7A is an erythrocyte receptor for P. falciparum merozoite-specific TRAP homolog, MTRAP.
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Semaphorin-7a是一种用于恶性疟原虫的红细胞受体。
DOI：
10.1371/journal.ppat.1003031
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Wright GJ
中科院分区：
文献类型：
--
作者：
Bartholdson SJ;Bustamante LY;Crosnier C;Johnson S;Lea S;Rayner JC;Wright GJ
疟原虫的运动和侵袭被认为需要细胞质肌动蛋白-肌球蛋白运动，该运动与属于TRAP（血栓反应相关匿名蛋白）家族的细胞表面配体相关。目前的入侵模型通常调用宿主细胞表面trap家族配体的特异性受体的存在；然而，这些受体的身份在很大程度上仍然未知。在这里，我们通过一种旨在检测细胞外蛋白相互作用的系统筛选方法，确定gpi连接蛋白Semaphorin-7A （CD108）是恶性疟原虫merozote特异性TRAP同源物（MTRAP）的红细胞受体。通过表明结合是饱和的，并通过使用表面等离子体共振量化平衡和动力学生物物理结合参数，证明了相互作用的特异性。我们发现两个MTRAP单体通过它们的串联TSR结构域与Semaphorin-7A同型二聚体的Sema结构域相互作用。已知的Semaphorin-7A自然发生的多态性不会定量地影响MTRAP结合，也不会影响受体上聚糖的存在。在体外红细胞侵袭试验中，用重组蛋白和抗体阻断这种相互作用的尝试没有显示出明显的抑制作用，这表明这种复合物对蛋白阻断剂是不可接近的。这些发现现在提供了重要的实验证据来支持寄生虫trap家族配体在细胞入侵过程中与特定宿主受体相互作用的模型。顶复合体寄生虫是感染人类的最重要病原体之一，其中包括导致疟疾的疟原虫——恶性疟原虫。这些寄生虫严重依赖于它们的人类宿主，必须侵入我们的细胞才能繁殖；因此，了解这一入侵过程，并最终以治疗预防为目标，一直是科学研究的重点。入侵机制的一个关键组成部分是一个蛋白质家族（“TRAP”家族），它穿过寄生虫周围的膜：留在寄生虫体内的部分连接到一个分子马达，为入侵提供动力，而表面暴露的区域被认为与目标宿主细胞表面的蛋白质相互作用。一个尚未解决的主要问题是trap的宿主受体的身份。在我们的论文中，我们使用了一种专门设计用于检测宿主和病原体蛋白质之间细胞外空间发生的相互作用的方法，以揭示疟疾寄生虫血液阶段使用的trap家族成员-一种称为MTRAP的蛋白质-称为Semaphorin-7A的宿主受体。因此，这种宿主-寄生虫相互作用的特征可能导致基于防止寄生虫入侵的新疗法。
The motility and invasion of Plasmodium parasites is believed to require a cytoplasmic actin-myosin motor associated with a cell surface ligand belonging to the TRAP (thrombospondin-related anonymous protein) family. Current models of invasion usually invoke the existence of specific receptors for the TRAP-family ligands on the surface of the host cell; however, the identities of these receptors remain largely unknown. Here, we identify the GPI-linked protein Semaphorin-7A (CD108) as an erythrocyte receptor for the P. falciparum merozoite-specific TRAP homolog (MTRAP) by using a systematic screening approach designed to detect extracellular protein interactions. The specificity of the interaction was demonstrated by showing that binding was saturable and by quantifying the equilibrium and kinetic biophysical binding parameters using surface plasmon resonance. We found that two MTRAP monomers interact via their tandem TSR domains with the Sema domains of a Semaphorin-7A homodimer. Known naturally-occurring polymorphisms in Semaphorin-7A did not quantitatively affect MTRAP binding nor did the presence of glycans on the receptor. Attempts to block the interaction during in vitro erythrocyte invasion assays using recombinant proteins and antibodies showed no significant inhibitory effect, suggesting the inaccessibility of the complex to proteinaceous blocking agents. These findings now provide important experimental evidence to support the model that parasite TRAP-family ligands interact with specific host receptors during cellular invasion. Apicomplexan parasites are one of the most significant groups of pathogens infecting humans and include Plasmodium falciparum, the parasite responsible for malaria. These parasites critically depend on their human host and must invade our cells to multiply; therefore, understanding this invasion process - with the eventual aim of therapeutically preventing it - has been a focus for scientific investigation. A key component of the invasion machinery is a family of proteins (the “TRAP” family) which traverse the membrane surrounding the parasite: the part remaining within the parasite connects to a molecular motor that powers invasion, whilst the surface-exposed region is thought to interact with proteins on the surface of the target host cell. One major question that remains unanswered is the identity of the host receptors for the TRAPs. In our paper, we use a method specifically designed to detect interactions that occur in the extracellular space between host and pathogen proteins to reveal a host receptor called Semaphorin-7A for the TRAP-family member used by the blood stage of the malarial parasite – a protein called MTRAP. The characterization of this host-parasite interaction may therefore lead to novel therapies based upon preventing parasite invasion.
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