How do proteins interact with each other?

In order to maintain our health, the proteins in our body cells are required to cooperate with each other. However, until today it was not clear how tens of thousands of different proteins find exactly the right partners for them while they are broken down and rebuilt again and again in the body. Researchers from the University of Copenhagen provide new insights into this fascinating mechanism

[Translation by Dr. Nachmani Moshe]

In order to maintain our health, the proteins in our body cells are required to cooperate with each other. However, until today it was not clear how tens of thousands of different proteins find exactly the right partners for them while they are broken down and rebuilt again and again in the body. Researchers from the University of Copenhagen provide new insights into this fascinating mechanism.

Professor Jens Jørgen from the Department of Chemistry at the University of Copenhagen and his colleagues have just published their research findings regarding a method that helps to reveal the mechanism by which the proteins communicate with each other in a publication entitled: "Specific and nonspecific interactions in ultra-weak protein-protein associations revealed by solvent paramagnetic relaxation enhancement" , in the scientific journal Journal of the American Chemical Society.

Until now, there has been no possible way to document how the proteins actually find each other in living things. This situation caused a big problem since many important biological processes start when two proteins meet and initiate a reaction between them. And when their cooperation goes wrong, it can lead to fatal results: from diabetes, cystic fibrosis to Parkinson's and Alzheimer's - many of these diseases are related to the misfolding of proteins, or the accumulation of proteins together - a process known as protein aggregation. Explains the lead researcher: "Any researcher involved in pharmaceutical development or disease treatment will be able to use our method."

When a certain protein, for example - the growth hormone - must find its partner for activity (what is known as a 'receptor'), there are tens of thousands of proteins from which it can choose. Therefore, the proteins must be equipped with a mechanism that allows them to quickly scan a huge number of possible partners for joint activity. The mechanism, known as 'extremely weak interactions', is a situation where the proteins influence each other through electrostatic forces. It can be compared to a dancer walking along a wall looking for a dance partner. He starts with a bow, and only if the partner nods in agreement, he leads her to the dance floor.

Extremely weak correlations are so weak that they could not be calculated until now using mathematical tools, let alone tested using physical measurements. However, the researchers developed an innovative method that allows observing these interactions with NMR spectroscopy (NMR). A spectrometer makes it possible to examine molecular structures by exposing molecules to a magnetic field. The researchers took advantage of the fact that it is possible to observe the activity of a protein molecule in a magnetic field by adding a paramagnetic substance called gadodiamide (Wikipedia). This substance is ideal for the task since it does not initiate chemical reactions with the proteins, and therefore has no effect on the structure of the protein. Beyond that, removing it at the end of the measurement is simple and easy to perform.

However, the changes in the spectra of the protein GDP are tiny and weak, so finding the appropriate trick was not so simple. "At the first stage, we did not understand what we were looking at. This seems to us to be an uncertainty in the data, and it required us a long time to discover the mechanism."

The new method makes it possible to see exactly how the proteins get to know each other and cooperate with each other. This new knowledge can be utilized in the production of proteins in industrial systems, in the study of disease-related pathways and in the field of protein-based drug development. "It was already known that proteins find each other with the help of extremely weak interactions, but no one knew how to measure them. Now we are able to do that," says the lead researcher. The researchers hope that other scientists will use their discovery, integrate it into their work and develop the knowledge required to use this method also in biological systems within the body itself.

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