How molecular specificity emerges

More than “on” and “off”: German Research Foundation funds new Emmy Noether Group at Philipps-Universität.

How do numerous signals pass through a few channels? A new Emmy Noether junior research group at the University of Marburg is investigating how a limited number of G proteins can trigger a multitude of cellular reactions. Pharmacologist Dr. Hannes Schihada has received 1.9 million euros from the German Research Foundation (DFG) for two three-year funding periods to set up his research group.

Cells have receptors on their surface that sense stimuli from the environment. These receptors transmit the stimuli from the outside to intracellular partners, which in turn cascade the signal to trigger an appropriate response in the cell. This is known as signal transmission or transduction.

Among the best known molecules in such signaling pathways are G proteins. A large number of receptors transmit their signal via G proteins, which is why they are called G protein-coupled receptors, or GPCRs. “More than 30 percent of approved drugs target such receptors,” explains Schihada.

There are more than 800 known GPCRs that sense and translate a wide variety of stimuli. There are far fewer G proteins that transmit signals. How can these few G proteins translate the multitude of stimuli into an equally large number of specific responses within the cell?

Until now, we knew that G proteins change their spatial shape when they switch from an inactive to an active state and vice versa, “like a pair of scissors that you first open in order to cut,” Schihada explains. Experts refer to this as a conformational change, which allows a protein to bind an interaction partner, for example. “According to the current concept, G proteins have two states,” says the scientist: “on and off.

The pharmacologist and his junior research group will be working on a different hypothesis. Schihada explains: “There are different ‘on’ states that enable a variety of signals; this is how their specificity comes about. It is analogous to a lamp that can not only be switched on or off, but can also shine in different colors.”

In order to investigate the presumed diversity of states, Schihada is focusing on the development of sensor systems in living cells. The pharmacologist uses dyes that he couples to G proteins. To stay with the scissors analogy: The dye is attached to the hinge part of the protein. Depending on the state of the protein, it glows more or less brightly. The goal is to characterize the different protein states by detecting them with different sensors: a “fingerprint” of the G proteins.

“I have a lot of experience in developing sensors in my previous research,” says Schihada, “and we have developed a handful of such sensors, but not focused on G proteins, but on their upstream receptors.

Dr. Hannes Schihada is currently a postdoctoral fellow in the group of Professor Dr. Peter Kolb at the Institute of Pharmaceutical Chemistry at the Philipps-Universität. A native of Bavaria, he studied pharmacy in Regensburg, Germany, where he passed the state examination and received his pharmacist license. In 2019, he received his doctorate in natural sciences from the University of Würzburg, followed by two and a half years of research at the Karolinska Institute in Stockholm.

The Emmy Noether Program gives young scientists like Schihada the opportunity to qualify for a university professorship by independently leading a junior research group over a period of six years. One postdoctoral position and three doctoral positions are planned for the new team in Marburg

Wissenschaftliche Ansprechpartner:

Dr. Hannes Schihada
Institut für Pharmazeutische Chemie
Tel.: +49 (0) 6421 28-21351
E-Mail: hannes.schihada@uni-marburg.de

https://www.uni-marburg.de/en