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Insights into the molecular mechanism of the mitochondrial intermembrane space sulphydryl oxidase Erv1Ceh Pavia, Efrain January 2014 (has links)
Mitochondria are involved in numerous cellular processes such as respiration, ATP production, calcium signalling and apoptosis. About 99% of mitochondrial proteins are nuclear-encoded and need to be imported into mitochondria for their function. The MIA pathway is used by many cysteine-containing proteins for their import into the mitochondrial intermembrane space (IMS). The pathway comprises two essential proteins: the disulphide carrier and import receptor Mia40, and the FAD-dependent sulphydryl oxidase Erv1. Together these proteins form a disulphide relay system inside the IMS. Initially, substrate proteins are imported in their cysteine-reduced form, which is oxidised by Mia40 in the IMS. Then, the now reduced Mia40 is in turn re- oxidised by Erv1. Finally, reduced Erv1 can transfer the electrons to oxygen directly, or via cyt c, to the respiratory chain. The overall aim of this study is to understand the structural and functional mechanisms of Erv1, from the effect of single mutations (R182H) to its quaternary structure and thermodynamic properties. The results are described in three chapters. First, biophysical techniques were used to evaluate the oligomerisation state of Erv1. Contrary to general belief, the results show that Erv1 adopts a tetramer conformation in solution. Tetramerisation provides Erv1 with a higher thermal stability, though it does not affect its oxidase activity. The second result chapter focuses on understanding the effects of a medically relevant mutant, Erv1 R182H, on the structure and function of the protein. The results show that at the physiological temperature of 37°C the mutant is less stable and becomes completely inactive after a few enzymatic cycles. The activity defect is linked to a weaker binding of the FAD cofactor in the mutant. Lastly, the third result chapter looks at the electron transfer within Erv1 from a thermodynamic perspective. Standard reduction potentials were determined for two of the three redox centres in Erv1. The results differ from those previously published, but are consistent with the current model of electron transfer in Erv1. Taken together, the results presented here offer an insightful perspective into the molecular mechanisms regulating Erv1.
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