Oxidative protein folding in the mitochondrial intermembrane space of parasitic protists

氧化蛋白质折叠是酵母和人类线粒体膜间隙蛋白质的主要输入机制。该过程需要通过衔接酶Mia 40识别和氧化胞质输入底物的半胱氨酸残基。二硫键的形成导致蛋白质底物在膜间空间中折叠和捕获。还原的Mia 40随后将底物的还原当量转移到Erv 1/ALR，Erv 1/ALR起中继作用，将电子输送到细胞色素c和呼吸链。线粒体膜间隙的氧化蛋白折叠和编码Mia 40和Erv 1/ALR的基因是必需的。因此，令人惊讶的是，在许多原生生物的基因组中没有发现Mia 40同源物，包括几种医学和经济上最重要的寄生虫。此外，寄生原生生物的Erv同源物的结构和机制（以及显然的进口）与酵母和人Erv 1/ALR显著不同。因此，寄生原生生物中的氧化蛋白质折叠与人类中的氧化蛋白质折叠根本不同。然而，到目前为止，完全不知道哪种蛋白质在功能上取代了Mia 40，以及氧化蛋白质折叠在寄生原生生物中是如何发生的。该项目的目的是比较鉴定模式寄生虫利什曼原虫tarentolae和最重要的人类疟疾寄生虫恶性疟原虫中假定的Mia 40替代。一方面，这将为重要病原体的氧化蛋白质折叠提供基本的见解。另一方面，所确定的差异和相似之处不仅应该揭示真核生物中这一基本过程的多样性，而且还应该揭示其机械原理的保守性。

Oxidative protein folding is the predominant import mechanism for proteins of the mitochondrial intermembrane space in yeast and human. This process requires the recognition and oxidation of cysteine residues of cytosolic import substrates by the adapter enzyme Mia40. The formation of disulfide bonds results in folding and trapping of the protein substrates in the intermembrane space. Reduced Mia40 subsequently transfers the substrates' reducing equivalents to Erv1/ALR, which functions as a relay and feeds the electrons to cytochrome c and the respiratory chain. Oxidative protein folding in the mitochondrial intermembrane space and the genes encoding Mia40 & Erv1/ALR are essential. Hence, it is rather surprising that no Mia40-homologue can be identified in the genomes of many protists, including several of the medically and economically most important parasites. Moreover, the architecture and mechanism (and apparently the import) of Erv-homologues from parasitic protists deviate significantly from yeast and human Erv1/ALR. Oxidative protein folding in parasitic protists is therefore fundamentally different from oxidative protein folding in human. However, so far it is completely unknown which protein functionally replaces Mia40 and how oxidative protein folding exactly occurs in parasitic protists. The objective of this project is the comparative identification of the postulated Mia40-replacement in the model parasite Leishmania tarentolae and the most important human malaria parasite Plasmodium falciparum. On the one hand, this should provide fundamental insights into oxidative protein folding of important of pathogens. On the other hand, the identified differences and similarities should reveal not only the diversity but also the conservation of mechanistic principles of this essential process in eukaryotes.