A team of Australian and New Zealand scientists has uncovered vital information about the structure of a particular protein that could be used to fight disease such as Parkinson’s, melanoma and stomach cancer.

The protein, called apoptosis signal-regulating kinase 1 (ASK1), is similar to other kinases (enzymes that transfer chemicals between molecules in cells) in that it controls one aspect of cellular behaviour.

ASK1 has the specific function of controlling how cells respond to cell damage and plays a vital role in programmed cell death, otherwise known as apoptosis. Apoptosis is the controlled death of a cell if it is no longer needed or to balance the process of cell division and maintain the size of tissue in our body. In a human adult, approximately 50 to 70 billion cells die of apoptosis each day (which equates to about 0.5% of our total number of cells).

The team of scientists, led by Dr Peter Mace from the Department of Biochemistry at the University of Otago, examined the structure of ASK1 and discovered unexpected “pockets” which control how the protein is turned on.

Researchers found that the structure of these “pockets” appear to be shared by all ASK kinases and that they act as a mechanism to control ASK activity in response to cellular stress.

“We now know a lot more about how ASK1 gets turned on and off – 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,” Mace said.

Kinases are excellent targets for the development of new drugs, thanks to this “pocket” in their structure that compounds can bind to. However, before we can manufacture drugs for use in this way, more research must be done on how these proteins are controlled.

The research team determined the molecular structure of ASK1 through crystallography studies using the Synchrotron in Melbourne. Dr Tom Caradoc-Davies, principal scientist at the Synchrotron, helped to collect data for the research.

Other scientists on the team include Johannes Weijman, Abhishek Kumar, Sam Jamieson, Chontelle King and Elizabeth Ledgerwood from the Department of Biochemistry at the University of Otago. Also assisting was James Murphy from the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia.

The research paper was published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS).

Image: Gennifer Tsoi