Kiwi scientist unlocks secrets of troublesome protein

Otago University researcher Dr Peter Mace. Photo / Supplied

Fresh insights into a key protein involved in the development of blood and other cancers could help pave the way to new drug treatments.

Otago University researcher Dr Peter Mace, along with Australian colleagues Dr James Murphy and Dr Isabelle Lucet, have just published new research about Trib1, which plays a vital role in controlling how and when other proteins are degraded.

This is essential for balancing protein levels in the cell.

Trib1 is part of the protein family Tribbles, which play diverse roles in cell signalling and development and are named after the small, furry creatures from Star Trek that reproduce uncontrollably.

Tribbles are unusual types of proteins called pseudokinases, which have been described as "dead" enzymes because their structures evolved to leave them incapable of catalysing chemical reactions.

Dr Mace said the discovery in the early 2000s of a range of pseudokinases persisting in cells was initially puzzling, until it became clear that they were now performing other important non-enzymatic functions.

The researchers used powerful X-ray beams at the Australian Synchrotron to obtain the detailed three-dimensional images of Trib1, revealing that its structure had been hugely contorted compared to related proteins that do function as catalysts.

Instead of driving chemical reactions Trib1 acts as a scaffold to bring many proteins together, and the team discovered how Trib1 "recruits" specific proteins to be degraded.

"As well as explaining how Trib1 functions, our research into its structure could help us design novel therapeutic agents to block its overproduction in acute myeloid leukaemia (AML)," Dr Mace said.

AML is a particularly aggressive cancer typified by an increased number of abnormal white blood cells, called myeloid cells, and kills around half of children diagnosed with it.

In adolescent patients, this rate is even higher.

Beyond AML, the researchers were interested in looking at Trib1 function in other cancers where it is overexpressed.

"There is already some evidence that Trib1 plays a role in prostate cancer but this is fairly new ground so we have a lot to learn."

In collaboration with Department of Biochemistry colleague Dr Anita Dunbier, the team is investigating the role of Trib1 in breast cancer.

The newly-published research, featured today in the international journal Structure, was supported by the Health Research Council of New Zealand, the New Zealand government, the Australian Cancer Research Foundation, the Australian National Health and Medical Research Council and the Victorian Government Operational Infrastructure Support Program.