Protein trafficking mechanisms in the human malarial parasite P. falciparum

人类疟疾寄生虫恶性疟原虫的蛋白质运输机制

• 批准号: 29282676
• 负责人: Professor Dr. Jude Marek Przyborski
• 金额: --
• 依托单位: Professur für Biochemie und Molekularbiologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2006
• 资助国家: 德国
• 起止时间: 2005-12-31 至 2008-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/29282676?language=en
• 关键词: Protein; trafficking; mechanisms; human; malarial

Having invaded mature human erythrocytes, Plasmodium falciparum the aetiological agent of malaria tropica, exports proteins beyond the boundaries of its own plasma membrane, into the host erythrocyte. Many of these parasite-encoded proteins have been implicated in structural and physiological changes in the infected host cell. Some of these proteins are important factors in the pathology of malaria. The host erythrocyte does not, itself, have the necessary molecular machinery to traffic proteins to their eventual destinations in the host cell. Thus, it appears that the parasite itself exports a functional secretory system into the metabolically ¿dead¿ host cell, an interesting paradigm in cell biology. The unusual nature of the parasites secretory system is further underlined by unusual protein targeting motifs. Thus, it can be shown that many parasite proteins exported into the host erythrocyte do not possess a canonical N¿terminal ER targeting sequence, a pre-requisite for entry into the secretory system. However, many of these proteins do contain a recessed hydrophobic domain towards their N-terminal end. This signal has been suggested to fulfil the function of a secretory signal sequence, however mechanistic data on how this signal mediates ER translocation remain sparse. In this funding period, we shall address the question as to how these hydrophobic domains mediate ER translocation. We have designed experimental strategies to perform an ER translocation assay in order to mechanistically dissect the initial steps in the parasites early secretory pathway. This study may uncover novel ER translocation mechanisms playing a role in ER translocation processes in other cell types. Furthermore, we aim to address how the folding state of proteins affects their trafficking to the cytosol of the host erythrocyte.

恶性疟原虫是热带疟疾的病原体，侵入成熟的人红细胞后，将蛋白质输出到其自身质膜的边界之外，进入宿主红细胞。这些寄生虫编码的蛋白质中有许多与受感染宿主细胞的结构和生理变化有关。这些蛋白质中的一些是疟疾病理学中的重要因素。宿主红细胞本身并不具备将蛋白质运输到宿主细胞中的最终目的地所必需的分子机制。因此，寄生虫本身似乎将功能性分泌系统输出到代谢死亡的宿主细胞中，这是细胞生物学中一个有趣的范例。寄生虫分泌系统的不寻常的性质进一步强调了不寻常的蛋白质靶向基序。因此，可以表明，许多输出到宿主红细胞中的寄生虫蛋白不具有典型的N端ER靶向序列，这是进入分泌系统的先决条件。然而，这些蛋白质中的许多确实含有朝向其N-末端的凹陷的疏水结构域。该信号已被建议履行功能的分泌信号序列，然而，关于该信号如何介导ER易位的机制数据仍然稀少。在此资助期间，我们将解决的问题，这些疏水结构域如何介导ER易位。我们已经设计了实验策略，进行ER易位测定，以机械解剖的寄生虫早期分泌途径的初始步骤。这项研究可能会发现新的ER易位机制，在其他细胞类型的ER易位过程中发挥作用。此外，我们的目标是解决如何折叠状态的蛋白质影响其贩运到宿主红细胞的胞质溶胶。