Mechanismus der Thioloxidase Mia40

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Recently, disulfide-bonded proteins were found in the inter-membrane space of mitochondria, and a disulfide relay system was discovered that mediates the oxidative folding of these proteins. The key components of this system, Mia40 and Erv1 are essential for viability of yeast. The basic principles of their function in vivo and in vitro are known, and crystal and NMR structures of Mia40 and several substrate proteins are available. It is our aim to elucidate the kinetic mechanism of Mia40/Erv1- mediated oxidative folding at the molecular level. We will examine how Mia40 catalyzes the individual steps of thiol-disulfide exchange reactions in the substrate proteins, how conformational folding and Mia40-mediated disulfide bond formation are coupled, how the kinetics of Mia40 are affected by its co-factors Erv1 and Hot13, and, in particular, how Mia40 differs in its enzymatic mechanism from the thioldisulfide exchange enzymes that catalyze oxidative folding in the endoplasmic reticulum and in the bacterial periplasm. We expect that these studies will be helpful not only to understand the molecular mechanism of this newly discovered folding system in the mitochondria, but that it also provides a good access to understanding the basic molecular mechanisms of catalyzed oxidative folding.