New insights on a key factor involved in diseases such as Parkinson's, gastric cancer, and melanoma have been demonstrated by a study from the University of Otago, New Zealand, in collaboration with Australian scientists. In findings (“Structural Basis of Autoregulatory Scaffolding by Apoptosis Signal-Regulating Kinase 1”) published in the Proceedings of the National Academy of Science, the team of investigators, led by Otago Department of Biochemistry's Peter Mace, Ph.D., studied a protein called apoptosis signal-regulating kinase 1 (ASK1).

Along with other kinases, ASK1 acts as a signaling protein that controls many aspects of cellular behavior. Kinases put tags onto other proteins that can turn them on or off, which in turn can make a cell divide, die, move, or any number of other responses. Dr. Mace says ASK1 plays an important role in controlling how a cell responds to cell damage and can push the cell toward a process of apoptosis for the good of the body if damage to a cell is too great.

The research team determined ASK1's molecular structure through crystallography studies and also performed biochemical experiments to better understand the protein. They found that ASK1 has unexpected parts to its structure that help control how the protein is turned on, and that an entire family of ASK kinases shares these features.

“We now know a lot more about how ASK1 gets turned on and off,” notes Dr. Mace. “This is important because in diseases such as Parkinson's, stomach cancer, and melanoma, there can be either too much or too little ASK1 activity.” He points out that the new findings add to our understanding of how cells can trigger specific responses to different threats or damage encountered. Such threats can include oxidants, which damage the body's tissues by causing inflammation.

According to Dr. Mace, kinases are excellent targets for developing new drugs because they have a “pocket” in their structure to which such compounds can bind. But to develop better drugs, we need to understand far more about how they are controlled. This is the goal of several projects in his lab, he says.

The study was a collaboration between Otago researchers and scientists at the Walter and Eliza Hall Institute in Melbourne and at the Australian Synchrotron.

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