Murphy et al. describe a novel pseudokinase architecture from human TRIB1 and characterize its substrate-recognition motif within the C/EBPα transcription factor. Combined with biophysical studies, this shows how Tribbles proteins eschew catalytic activity in favor of function as signaling scaffolds.
Protein Trib1 plays a vital role in controlling how and when other proteins are degraded, which is essential for managing protein levels in the cell. The finding could be used to develop new drugs to treat cancers such as leukaemia, caused by malfunctioning of the Trib1 protein.
Trib1 is part of the protein family Tribbles, which play diverse roles in cell signalling and development. Tribbles are named after the small, furry creatures from Star Trek that reproduce uncontrollably. Excess Tribbles drive the abnormal production of immune cells, causing a type of blood cancer called acute myeloid leukemia (AML).
“The amount of protein in a cell depends on the balance between production and degradation,” Dr Murphy said. “Defects in protein degradation, or in the controllers of protein degradation, disrupt this balance and can lead to diseases such as cancer.”
Using the Australian Synchrotron, Dr Mace, Dr Murphy and colleagues were able to obtain detailed 3D images of Trib1. “The structure of Trib1 is really exciting,” Dr Murphy said. “We can now see how Trib1 is able to trigger protein destruction, which will provide critical clues for developing drugs that target Trib1 to treat cancers.”
Trib1 acted 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,” Dr Mace 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.”
Dr Murphy said Trib1 was an unusual type of protein called a pseudokinase. “Pseudokinases were once thought to be evolutionary dead ends, but we now know that they play critical roles in cells,” he said.
“The powerful X-ray beams created by the synchrotron enabled us to see that Trib1 has undergone huge contortions compared to its ancestors. These structural changes prevent Trib1 from driving chemical reactions, and instead allow it to act as a scaffold to bring proteins together.” http://www.wehi.edu.au/news/3d-image-cancer-protein-aids-quest-new-treatments
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