Better understanding of hydrogen peroxide regulation can lead to new insights into disease development

The team of prof. Joris Messens at the VIB-VUB Center for Structural Biology has provided new insights into the regulation of an important intracellular messenger molecule, hydrogen peroxide (H₂O₂), whose dysregulation has been linked to the development of several diseases, including cancer.

To fine-tune levels of H₂O₂, cells can sense changes in the concentration of H₂O₂ and respond by activating specific DNA regulation mechanisms. In bacteria, a protein called OxyR functions as such a H₂O₂-sensor. The exact mechanism of how OxyR senses H₂O₂ and changes its DNA binding properties, however, has hitherto remained unexplored.

By combining protein X-ray crystal structures with supporting molecular biological and biochemical experiments, Dr. David Young and Dr. Brandán Pedre together with international collaborators and co-workers of the Messens lab have provided new insight into this question. They have uncovered the precise H₂O₂ binding site and the conformational changes that OxyR uses to bind to DNA and stimulate the regulation of the cellular H₂O₂ concentration.

"Previously, the H₂O₂-induced structural change of OxyR has led to the development of fluorescence-based genetically encoded H₂O₂ sensors, offering a way to visualize compartment-specific endogenous H₂O₂ in real time in living cells in various pathological conditions," explains Dr. David Young (VIB-VUB). Brandán Pedre (VIB-VUB) adds: "This new insight in the structural details of the OxyR protein not only clarifies how the cell arms itself against H₂O₂ changes but will also enable us to create more sensitive and specific OxyR-based fluorescent biosensors. Such sensors will help us to better understand how aberrant H₂O₂ signaling leads to disease and, in the long run, identify new drug targets."