What the mechanical forces behind protein folding can tell us about metastatic cancer
Ionel Popa, UWM professor of physics, demonstrates the magnetic tweezers he and his lab members built to measure the mechanical forces that act on proteins as they fold and refold. Proteins are large molecules that carry out the body’s functions required for good health. Credit: Elora Hennessey, UWM

The malfunctioning of Talin allows cancer cells to spread. DCL1 suppresses tumors Scientists don't fully understand how eitherProtein works, or what happens when they don't work the way they should

Scientists know that when DCL1 is present in a cell, it can affect talin's ability to group cells. Scientists may be able to find a treatment option for cancer if they know the steps in the process.

A team of researchers from the University of Wisconsin-Milwaukee built a tool that they used to apply the exact mechanical forces that act on talin in the body.

When DCL1 is present and not present in the cell, the scientists used the single molecule magnetic tweezers to measure the mechanical forces in the cell.

The anti-tumor effect of DLC1 can be explained by the unique behavior of talin, which is caused by mechanical force.

Ionel Popa, a UWM physics professor who led the team, said they didn't know what went wrong with talin. When the DCL1 is missing, talin plays a role in the spread of cells. When DCL1binds to talin, it blocks talin from spreading.

The work is in a journal.

Talin forms a three-dimensional shape that defines its function. It is one of the most complex processes in nature and when it goes awry it can lead to diseases. Popa's lab is investigating forces that can lead to the discovery of new treatments for diseases that start with misfolds.

For talin, mechanical forces inside and outside the cell are needed to get the shape that unlocks it's function. The cells have mechanical forces that prompt talin to unfold.

Popa said that the process is similar to a mechanical computer because it calculates how much force is needed. The forces are telling the cell what's happening around it.

The cell converts mechanical forces to chemical signals when they bind to aProtein The researchers were interested in talin because of the mechanical fine- tuning done by these ligands.

The highest number of ligands available for DCL1 to bind with talin is located in the domain. Both inside and outside the cell, messages are sent. The researchers have been able to correlate and measure the force mechanism of the folding.

There's a way the tweezers can see.

Scientists knew that DCL1 only binding to one domain of the talinProtein. In response to an applied force, talin unfolds and refolds, forming a structure.

Popa said that they gathered the data from the talin molecule as it unfolded and re-folded. It's thought that a weak interaction is not the driver of DCL1's abilities. We found the opposite when we tested it.

The researchers were able to measure a small molecule with the help of the magnetic tweezers. The researchers measure the position of the paramagnetic bead at a freely moving end of the molecule after tethering it between a glass surface and a paramagnetic bead. They apply a magnetic force, replicating the mechanical changes that occur on aProtein in the body, and measure its unfolding and refolding to understand how it changes.

The magnetic tweezers can be used to investigate the effects of those forces over a longer period of time.

There is a role for hormones.

hormones control the activation of talin during cell spreading and tissue building. Stretching and binding takes place in this stage of the process. The process is aided by mechanical forces.

To be activated, talin must be brought to the cell by the messenger that signals from the cell to the matrix.

This process was tracked by Popa's team.

He said that if DLC1 also binding to talin, it won't allow for recruitment to the membranes. Cancer cells can hijack any of the steps controlling cell spreading. DLC1 is suppressed in some instances.

Popa said that missing or malfunctioning DCL1 may not be the sole cause of cancer spread. There is a direction for further study for thisProtein interaction as a potential target for cancer drugs, as shown by the work.

More information: Narayan Dahal et al, Mechanical regulation of talin through binding and history-dependent unfolding, Science Advances (2022). DOI: 10.1126/sciadv.abl7719. www.science.org/doi/10.1126/sciadv.abl7719 Journal information: Science Advances