Disulfide bonds play critical roles in a range of cellular processes - from the stabilization of secreted proteins to the regulation of cellular adhesion and viral fusion. Our multidisciplinary research program addresses how disulfides are generated and isomerized during oxidative protein folding in higher eukaryotes. We exploit a range of techniques including: peptide and protein purification, molecular biology, enzyme kinetics, rapid reaction studies, absorbance and fluorescence spectroscopy, NMR, mass spectrometry, and protein crystallography.

We investigate multidomain disulfide bond-forming catalysts of the secretory pathway and extracellular space: the Quiescin-sulfhydryl oxidase (QSOX) family. These enzymes are particularly abundant in cells with a heavy secretory load and are up-regulated in a number of cancers (including those of prostate and pancreas). Our work shows that QSOXs can cooperate with protein disulfide isomerase (PDI) to efficiently secure the correctly folded structure in proteins with complex disulfide connectivity.

We are also studying the pathways for disulfide generation in the mitochondrial intermembrane space driven by the flavoprotein augmenter of liver regeneration (ALR). The figure shows the crystal structure of human ALR determined in collaboration with Dr. Brian Bahnson.

We are continuing to search for inhibitors of oxidative folding, both as probes of enzyme mechanism, and as lead compounds for possible pharmacological intervention.