Oxidative protein folding in the mitochondrial intermembrane space of parasitic protists

• Applicant: Professor Dr. Marcel Deponte
• Subject Area: Biochemistry
• Term: from 2014 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 259182840

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.

• DFG Programme: Research Grants