Researchers discover new insights into a key protein in cell division and cancer
A study, led by University of Leeds and University of Oxford, has revealed new knowledge about an enzyme involved in cancer treatment.
The enzyme, called Aurora-A, is currently used as drug target for some lung cancers because it plays an important role in controlling cell division.
These current cancer treatments work by blocking Aurora-A completely to stop cancer cells from duplicating and spreading, however, in doing so, they also stop Aurora-A from working in healthy cells too. This can lead to side effects for patients such as nausea and a reduced number of white blood cells, which are important in fighting infections.
By understanding the mechanisms of Aurora-A, more precise and kinder treatments that eliminate cancer cells whilst sparing healthy cells could be developed.
What is Aurora-A?
Aurora-A is a type of enzyme called a kinase that modifies other proteins to control their activity.
A master controller of cell division, it organises the mitotic spindle, a structure that pulls apart chromosomes during the cell division process.
Without Aurora-A, the process would be chaotic, leading to errors that could cause diseases like cancer.
“Imagine cell division as a factory making biscuits,” explains Professor Bayliss. “Aurora-A is a quality control robot ensuring the conveyor belt (mitotic spindle) is perfectly aligned. If the conveyor belt is misaligned, some of the biscuits (cells) fall off and can't be sold.
“The current approach is to block Aurora-A completely, equivalent to pressing a red emergency stop button. The problem is that a stop button switches the conveyor belt off completely so whilst it prevents the production of broken biscuits, it also halts the production of perfectly good biscuits.
“Our long-term goal is to find a smarter way to target Aurora-A, so the conveyor belt stops only for defective biscuits while still producing good ones. We can only do this by better understanding how Aurora-A interacts with its environment.”
A hierarchy of interactions
The study reveals the process of how Aurora-A binds to other proteins, CEP192 and TPX2, to perform its role.
Using biophysical techniques including X-ray crystallography and NMR spectroscopy, the team of Leeds scientists including Dr Jennifer Miles and Dr Matthew Batchelor were able to produce a three-dimensional picture of the protein to witness binding interactions taking place.
In doing so, they discovered that CEP192 initially wraps around Aurora-A to compete with other binding proteins.
From these results, scientists were also able to deduct that Aurora-A must first bind to CEP192 before it is passed to another binding partner TPX2.
CEP192 competes against other Aurora-A binding partners by wrapping itself around Aurora-A and obscuring other binding sites. This perhaps explains why it is the first step in controlling Aurora-A and has a greater role than expected.
A team of scientists at Oxford University including Dr James Holder then used this information to remove the Aurora-A binding site on CEP192 using gene-editing technology, CRISPR-Cas9. They found that without CEP192, Aurora-A loses most of its activity and there are much higher error rates in cell division.
This discovery not only offers greater insights into cancer treatment but also takes our understanding of cell division to the next level, shedding light on the complex web of protein interactions and enzyme activity that drive this process.
Other contributions to the study were made by scientists at the University of Birmingham and the University of Georgia in the USA.
This research is part of a five-year programme called ‘Structures and Probes of Intrinsically Disordered Regions (SPIDR)’, funded by the Biotechnology and Biological Sciences Research Council.
For further information, visit the SPIDR project website or contact Prof. Richard Bayliss or Prof. Fanni Gergely.
You can read the full paper, “CEP192 localises mitotic Aurora-A activity by priming its interaction with TPX2” in the EMBO journal.
