Researchers have found a new way to observe changes in how proteins interact in cells. This advancement could pave the way for new treatments for diseases such as cancer and Alzheimer’s.
Think of cells as a crowded dance club where various proteins are moving about. Some prefer to hang out on their own, while others mingle and engage in conversations. The nature of their interactions varies; some are brief exchanges, while others are deeper connections with close friends. Similarly, proteins in cells exhibit a wide range of interactions.
Cells contain numerous types of proteins that interact and often collaborate in groups known as complexes. These complexes, acting like molecular machines, rely on the precise engagement of their components to function properly.
Disruption by an Interloper
The interactions between proteins are influenced by the body’s condition. In a healthy environment, two proteins, referred to as blue and red, come together. However, if the body experiences stress, protein blue may swap partners and interact with protein yellow, which can disrupt the normal dynamic.
“Changes in protein interactions can contribute to diseases like Alzheimer’s, Parkinson’s, or cancer,” states Cathy Marulli, a PhD student working with Paola Picotti at the Institute for Molecular Systems Biology at ETH Zurich. “It’s essential to understand how these interactions differ in healthy versus diseased states and to identify the binding sites of these proteins. Detailed knowledge of these interactions could lead to the development of drugs that block harmful interactions and restore cellular balance,” she adds.
Mapping the Protein Interaction Network
To investigate this, the ETH biochemists enhanced an existing method to analyze the entire network of protein interactions, known as the interactome.
The findings of this research were published recently in Nature Biotechnology.
Years earlier, Picotti and her team introduced a technique called LiP mass spectrometry. This revolutionary method allows scientists to analyze structural changes in thousands of proteins from any biological sample without the need for prior purification. They previously used this approach to explore protein functions (see ETH News).
Now, they have expanded LiP mass spectrometry to investigate protein interactions. They started by identifying around 6,000 interaction interfaces between proteins and other areas that shift during their interactions. These sites served as markers to evaluate whether a protein alters its interactions under specific conditions.
Utilizing enzymes that cut proteins at accessible sites allowed them to gather detailed data on protein fragments, aiding in the analysis of protein interactions. This method enabled the examination of around 1,000 proteins at once in a complex cellular environment.
Significant Changes in Stressed Cells
In their study using yeast cells, the researchers compared protein interactions in normal conditions with those under stress induced by a chemical substance.
They found that approximately 60 protein complexes had altered interactions due to stress. Notably, they highlighted a complex called SAGA, which plays a crucial role in the yeast cell’s interaction network. When SAGA was removed, about two-thirds of protein complexes behaved differently under stress. “SAGA acts like the DJ at a party. When it’s silent, many groups stop dancing, affecting others and causing them to withdraw as well. This illustrates that a single component can significantly impact the entire network,” explains Marulli.
Potential for Broader Applications
This newly developed method can also be utilized in other organisms. “For each species of interest, we simply need to create a new set of binding markers to study protein interactions in mouse or human cells,” Marulli explains. The next step is to identify interaction markers for the human interactome to analyze faulty protein interactions more efficiently.
Understanding protein interactions is crucial for disease research. “Our goal is to continue enhancing this technology for diagnostics and exploring disease mechanisms,” Picotti adds. This ambition is backed by encouraging results, as earlier innovations from their lab have already been adopted by the ETH spin-off Biognosys.
Pharmaceutical Targeting of Interactions
Pharmaceutical researchers are also keenly interested in these interaction markers. By identifying interaction sites, scientists can efficiently search for chemical compounds that can disrupt undesired interactions or create new ones.
Drug candidates that alter protein-protein interactions are an exciting new avenue in pharmaceutical research. These compounds could potentially target proteins currently inaccessible to existing medications or lead to the development of new drugs with fewer side effects.
