“Security check” inside the cell: Self-cleavage as built-in quality control

Cells constantly monitor their surroundings and detect chemical and mechanical signals that control vital functions such as movement, growth and communication. Adhesion G protein-coupled receptors (aGPCRs) – a special family of surface molecules – act as mechanical force sensors and play a key role in processes ranging from muscle growth to the formation of neural networks in the brain. Malfunctioning aGPCRs can cause serious health conditions such as allergies, schizophrenia, and cancer.

The research teams led by Professor Tobias Langenhan of Leipzig University’s Faculty of Medicine and Professor Andrea Sinz from the Institute of Pharmacy at Martin Luther University Halle-Wittenberg discovered that another part of the receptor – the so-called seven-transmembrane (7TM) region – plays a crucial supporting role in the cleavage process. It not only stabilises the GAIN domain but also helps position it correctly within the cell’s protein-producing machinery. In addition, the teams identified helper molecules in the cell that interact with the receptor during this process. These include enzymes that add sugar groups to the newly formed protein.

“Together, these factors ensure that the receptor’s self-cleavage proceeds efficiently. Remarkably, receptors that are unable to cleave themselves can be retained within the cell and fail to reach the surface, where they are needed to receive signals from the external environment,” says Professor Tobias Langenhan. These findings suggest that self-cleavage functions as a built-in quality control mechanism within the cell. This insight opens up new avenues of research into how this checkpoint is implemented and what role it plays in the development of certain medical conditions.

This research stems from a joint project within Collaborative Research Centre (CRC) 1423, Structural Dynamics of GPCR Activation and Signaling. CRC 1423 is a four-year research centre funded by the German Research Foundation (DFG), with five participating institutions: Leipzig University, Martin Luther University Halle-Wittenberg, Charité – Universitätsmedizin Berlin, Heinrich Heine University Düsseldorf, and the University Medical Center Mainz. Researchers from these institutions with backgrounds in biochemistry, biomedicine and computational science are collaborating on an interdisciplinary basis to gain a comprehensive understanding of how structural dynamics affect GPCR function.