King's College London

A new technique to studying protein folding – how complex molecules that play critical roles in the body form and break apart, has been developed by physicists at King’s College London. The research, published in Nature Physics, could play a key role in furthering our understanding of the causes of a number of diseases, including Alzheimer's, Parkinson's and Huntington's disease.

Proteins are essential to life, carrying out key tasks in cells. Yet, how they come together and break apart – fold and unfold - in the body, remains a central question in biology. A better understanding of this process, including when proteins become misfolded –losing their functional three-dimensional shape– could be key to unlocking our understanding of certain diseases.

Previously, studying protein folding has been limited to short time periods of only a few hours, but thanks to the development of a new technique involving a set of magnetic tweezers, the investigation team, led by Dr Rafael Tapia-Rojo, Dr Marc Mora and Professor Sergi Garcia-Manyes from the Department of Physics, extended this time period to several hours and even days, collecting cutting edge data on this process.

Dr Rafael Tapia-Rojo said:

“With previous experimental assays, we could observe a single molecule under force for a few seconds or minutes, which gave us a limited understanding of its dynamic behaviour. By using a new technique involving magnetic tweezers which we specially developed for the experiment, we can now watch a single protein folding for much longer allowing us to capture previously inaccessible events.

“This new approach opens avenues to understanding how proteins behave over longer timescales, for instance, enabling us to observe proteins ageing in real-time and describe how their malfunctioning is linked to age-related diseases.”

Dr Tapia-Rojo, Dr Mora and Professor Garcia-Manyes are experts in mechanobiology - an emerging multidisciplinary field that investigates how physical forces and changes in the mechanical properties of cells and tissues, contribute to biological processes, including how cells develop, differentiate, degenerate and cause diseases.

The study, ‘Enhanced statistical sampling reveals microscopic complexity in the talin mechanosensor folding energy landscape’ published in Nature Physics, specifically looked at protein folding in talin, a protein that’s fundamental to converting mechanical stimulus into biochemical activity in the body.

Through their novel method of experimentation, Dr Tapia-Rojo and Dr Mora were able to observe how talin loses its biological function over time in terms of being able to bind with another key protein partner, vinculin, due to the appearance of misfolded states. The unique data collected by the team, reveals that the process of protein folding is much more complicated than previously thought.

Going forward, it is hoped the new technique will enable scientists to look into chemical modifications that occur in proteins and correlate them with the loss of function in a protein, which is often due to ageing. This could provide key insights into the many diseases underpinned by protein ageing.