Studies of a trypanosomal sulfhydryl oxidase

Kurek, Jennifer Marie
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University of Delaware
Trypanosomal augmenter of liver regeneration (ALR) is a fascinating protein operating in the intermembrane space of mitochondria. It is a key participant in the disulfide relay system of the mitochondrial intermembrane space assembly (MIA) pathway where it helps to correctly fold proteins imported into the intermembrane space. The MIA pathway in most eukaryotes is initiated by Mia40, the first protein in the disulfide relay system. The role ALR plays in the MIA pathway in trypanosomes is unknown, as they lack Mia40 altogether. Does ALR perform the function of Mia40 and act alone, or is there a partnership with a Mia40 homolog not yet identified? Trypanosomal ALR proved to be an extremely problematic protein to purify and characterize due to its tendency to aggregate. Following an introduction to oxidative protein folding, sulfhydryl oxidases, and the parasite, Trypanosoma brucei, this thesis addresses the problem of aggregation and the paths taken to circumvent it. Following a serendipitous discovery involving arsenic from the 1900s, possible therapeutics against the African Sleeping Sickness targeting the protein were also explored, along with kinetic and structural aspects of the protein.