Alarmones as drivers in cellular stress

Konstanz chemist Professor Andreas Marx awarded ERC Advanced Grant for the second time

Konstanz chemist Professor Andreas Marx has once again been awarded the prestigious Advanced Grant of the European Research Council (ERC). This is the second time he has received the award and the third time overall that it has gone to the Department of Chemistry at the University of Konstanz. The project examines what are known as alarmones and their function in the modification of proteins in response to cellular stress. The work will help to better understand the role of this process in diseases such as cancer or degenerative disorders of the nervous system.

The genome contains all the inheritable information of a living organism and, for that reason, is often described in a simplified way as the “blueprint for life”. However, with its approximately 20,000 genes, which contain the instructions for protein production, the human genome has far fewer genes than that of a cauliflower, for example. Yet how can it be that the human body is nonetheless so much more complex in its development, structure and function than this vegetable? The solution to this riddle lies partly in the subsequent chemical modification of proteins, which greatly increases the number of protein variants compared to the pure number of genes.

Subsequent protein modification during cellular stress
Konstanz chemist Professor Andreas Marx and his research group are studying a certain form of this subsequent modification – a “chemical disguise”, as it were – of proteins, called AMPylation, within the research project with the short title “AMP-Alarm” funded through the ERC Advanced Grant. In AMPylation, an adenosine monophosphate – in short AMP – attaches to the proteins through a process known as covalent bonding, causing the proteins’ properties to change.

The project will especially shed light on the role that “alarmones” play in this process. Alarmones can serve as AMP donors and owe their name to the fact that they are produced in larger numbers during cellular stress. “We’ve known for decades that alarmones are found in greatly increased concentrations in the cell during stress. There is therefore reason to believe that they serve as signalling agents and regulate the cell’s stress response,” explains Marx. “To date, however, no one knows exactly how this happens. Our project will thus make a fundamental contribution to explaining these processes.”

In search of the protagonists involved
Preliminary work conducted by Marx and his team has already shown that alarmones play a role in the subsequent modification of proteins through AMPylation. One of the current project objectives is to develop suitable chemical tools for identifying further protagonists involved in the process. “It’s highly probable that several proteins are involved in AMPylation. For example, you need ‘writer proteins’ that add the modification, ‘reader proteins’ that interpret the modification and, if necessary, ‘eraser proteins’ that can reverse it,” says Marx, visualizing the process.

The researchers led by Professor Marx have already reached some important initial results: By means of chemically modified alarmones, they discovered an AMPylated human protein and revealed its function for the first time. Since preliminary results indicate a connection between the protein and diseases such as cancer or degenerative disorders of the nervous system, Marx and his research group are now working at full steam to investigate the protein. In the long term, the project will thus also provide new insights for the fight against such diseases.

About the ERC Advanced Grant
The ERC Advanced Grant is one of the most prestigious and lucrative European research prizes. It acknowledges and supports ambitious research projects by established academics who have produced significant research achievements over a period of at least ten years. ERC Advanced Grants are awarded for the duration of five years, with a maximum sum per research project of € 2.5 million.

“Being awarded the ERC Advanced Grant means a great deal to me. It’s a fantastic accolade for our research question, the project and, of course, the team as a whole,” says Marx, expressing his thanks. With regard to his research team, he continues: “It makes me extremely proud to be able to lead this team, and I find it a great privilege to collaborate with these young people.”

Key facts:

  • Advanced Grant of the European Research Council (ERC) for Professor Andreas Marx from the Department of Chemistry at the University of Konstanz
  • Funded project: “Diadenosine Polyphosphate Alarmones as Drivers for Protein AMPylation” (short title: “AMP-Alarm”)
  • Andreas Marx receives prestigious research award for the second time. This is already the third ERC Advanced Grant for the Department of Chemistry
  • The ERC Advanced Grant funds research projects for the duration of five years, each with a maximum sum of € 2.5 million
  • Research concept: Development of chemical tools to elucidate the function of “alarmones” in the modification (here AMPylation) of proteins in response to cellular stress