Tribulations of Tribbles

Australian and New Zealand leukaemia researchers have used the Australian Synchrotron in Melbourne to solve the 3D structure of a key protein involved in the development of leukaemias and certain other cancers.

The protein, Trib1, belongs to an enigmatic class of proteins known as pseudokinases.

One of the study’s authors, Dr James Murphy of the Walter and Eliza Hall Institute for Medical Research (WEHI) in Melbourne, said the detailed 3D structure is an important step towards designing a novel, small-molecule drug for some leukaemias.

Overexpression of Trib1 is a disease marker in patients with acute myeloid leukaemia. AML is one of the most aggressive and therapeutically intractable forms of leukaemia; it is characterised by uncontrollable proliferation of immature white blood cells.

Dr Peter Mace, of the University of Otago in New Zealand, was the lead investigator on the Trib1 research project. Dr Murphy and WEHI colleague Dr Isabelle Lucat were co-authors on the paper, which was published in the journal Structure.

Drosophila geneticists named Tribbles-1 after small, furry aliens in the popular TV science-fiction drama Star Trek who proliferate uncontrollably, consuming resources at an exponentially increasing rate.

According to Dr Murphy, pseudokinases were half a decade ago the subject of a “raging debate” over whether they were true kinases. Structurally, they resemble degenerate kinases — specialised enzymes that catalyse the activation of other proteins with a high-energy ‘kiss’ that transfers a phosphate molecule to the target protein.

“Some pseudokinases have been shown to have unconventional catalytic mechanisms — for a long time, it was contentious as to whether they were truly catalytic,” Dr Murphy said.

Geneticists subsequently identified human and mouse homologs of Tribbles-1 in Drosophila — but it was unclear whether the contorted structure of the Drosophila mutant in the human and mouse homologs was conserved in such distantly related species as mice and man.

Dr Murphy said the synchrotron’s detailed, 3D solution confirmed that it is — the human Tribbles-1 protein has the same, contorted structure of the Drosophila protein.

Tribbles-1 is classed as a pseudokinase because the normal form of the protein lacks the classic leucine residue that normally resides within the catalytic site of leucine kinases, but Dr Murphy said an atypical leucine that resides nearby may get the job done.

According to Dr Mace, Trib1 acts as a scaffold to bring many proteins together, forming a large complex that caused specific proteins to be degraded.

“As well as explaining how Trib1 functions, our research could help us design novel therapeutic agents for the treatment of AML,” he said. “For example, some AML patients have too much Trib1, which causes a loss of proteins that would normally inhibit cancer. Understanding the structure of Trib1 provides critical clues about how we could block Tribbles for the treatment of AML.”

Image caption: A Star Trek fan holding a Tribble. Image courtesy of Nathan Rupert under CC BY-NC-ND 2.0