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One of the key structures involved in the division of eukaryotic cells – those with a nucleus – is the actomyosin ring, a complex circle of proteins that contracts like a drawstring to divide cells into two.
The actomyosin ring behaves in a similar manner to muscles – myosin motor proteins tug at filaments made of actin – but the layout is far more complicated. This cellular machine is made up of over 120 different types of proteins present in varying amounts. What’s more, some of the components constantly recycle themselves every 40 seconds or so, making it devilishly hard for scientists to study under a microscope.
“It’s like a family photo shoot, just before you take the photo a few members change positions, and this happens again and again,” says Mohan Balasubramanian, professor of Biomedical Sciences at the University of Warwick.
Starting from scratch
“If you want to understand something, you have to build it,” adds Balasubramanian. The EU-funded ACTOMYOSIN RING project, supported by the European Research Council, aimed to rebuild the ring from its individual components. Using yeast cells as a model, the team employed a series of state-of-the-art biochemical and imaging techniques to purify all of the ring proteins and reconstruct the ring apparatus.
In doing so, the researchers made key observations of the physical principles behind the ring structure. “The biophysics of actin filaments play a really important role in the assembly of the ring,” says Balasubramanian. “When the ring is assembled, it tries to take the path of least curvature, unless constrained by other proteins.” The work identified several key proteins crucial for stabilising the actin filaments in their curved formation.
One of the main achievements of the project was developing a method to purify actin. Rather than gathering it from animal skeletal muscles, it’s now possible to use actin genes from any organism and create the required proteins in the lab using engineered yeast.
New avenues into healthcare research
The work holds great potential for medical research, Balasubramanian says. “Actin mutations result in many health conditions – there are four or five hundred different actin mutations that cause human disease,” he explains. Some 70 mutations in the heart actin gene are known to give rise to cardiomyopathy, a disease of the heart muscle.
The system can now be used to purify defective actomyosin ring proteins and search for novel compounds that can reverse the issue. “We were delighted that our work has led us into commercialisation and drug discovery, something never on the horizon when we started the work,” Balasubramanian remarks. The team will soon apply for more EU funding from the European Research Council to deepen their research in this area.